Estevez M, Gardner KL
the genetics of migraine.
Hum Genet. 2004 Feb;114(3):225-35.
field of migraine genetics has seen an explosion of information over the last
year. In a recent breakthrough, missense mutations in a chromosome 1q23 gene,
ATP1A2, encoding a Na+, K+-ATPase, have been identified in four distinct pedigrees
with a rare form of familial hemiplegic migraine (FHM). ATP1A2 is expressed in
the brain, like the voltage gated calcium channel gene, CACNA1A, previously identified
as the first hemiplegic migraine gene (FHM1). The shared hemiplegic migraine phenotype
of mutations in ATP1A2 and CACNA1A raises the possibility that they coordinately
regulate ion homeostasis that determines susceptibility to the initiation of both
migraine aura and the pain phase of migraine. For the more common and genetically
complex forms of migraine, genome-wide screens have identified several new loci
on 4q24, 6p12.2-21.1, 11q24, and 14q21.2-q22.3, suggesting additional migraine
genes in these regions. In addition, a recent large case-control association study
has linked single nucleotide polymorphisms in the insulin receptor/INSR gene with
migraine. However, these polymorphisms do not result in detectable changes in
receptor function. The continuing genetic identification of key proteins involved
in migraine will refine our understanding of this common and sometimes debilitating
disorder, which can strike during the most productive years of a person's life.
Given the co-morbidity of migraine with depression and bipolar disorder, our knowledge
of the causes of migraine may also contribute to our understanding of these disorders.
EE, Vanmolkot KR, Haan J, Frants RR, van den Maagdenberg AM, Ferrari MD
findings in headache genetics.
Curr Opin Neurol.
PURPOSE OF REVIEW: The progress in headache genetics,
especially migraine genetics, recently jumped ahead with some major discoveries.
RECENT FINDINGS: Family and epidemiological studies further strengthen the genetic
contribution to migraine and two recent observations gave new molecular insights
in the disease. Studies on the genetics of familial hemiplegic migraine revealed,
in addition to the previously identified familial hemiplegic migraine type 1 gene
CACNA1A on chromosome 19, the familial hemiplegic migraine type 2 gene ATP1A2,
encoding the alpha2-subunit of sodium/potassium pumps. Recent genome screens in
families with migraine identified susceptibility loci on chromosomes 4, 6, 11
and 14. SUMMARY: The findings in familial hemiplegic migraine confirm that dysfunction
in ion transport is a key factor in migraine pathophysiology and might help us
in the elucidation of migraine molecular pathways. The identification of several
migraine susceptibility loci underline its genetically complex nature. [Abstract]
I, Grimaldi LM, Salani G, Valfrč W, Rivoiro C, Savi L, Pinessi L
between the tumor necrosis factor-alpha -308 G/A gene polymorphism and migraine.
2004 Jan 13;62(1):141-3.
In a group of 299 migraine patients and 306 control
subjects, the association of the -308 G/A polymorphism in the tumor necrosis factor-alpha
gene (TNFalpha) with the occurrence and clinical characteristics of migraine was
tested. Homozygosity for the G allele was associated with an increased risk of
migraine (odds ratio [OR] = 2.85, p < 0.001). When the patients were divided
into subgroups, the association was confirmed in patients affected by migraine
without aura (OR = 3.30, p < 0.001) but not in migraine with aura. These data
suggest that the TNFalpha gene or a linked locus significantly modulates the risk
for migraine. [Abstract]
S, Brioli G, Lulli P, Morellini M, Giacovazzo M, Cicciarelli G, Martelletti P
necrosis factor gene polymorphism in migraine.
OBJECTIVE: To better define the involvement of human
leukocyte antigen region (HLA) genes in migraine via an association study of the
tumor necrosis factor (TNF) genes, located in the HLA class III region, with migraine
with and without aura. BACKGROUND: Migraine without aura and migraine with aura
are disorders involving multiple factors-environmental and genetic. In a previous
study, we hypothesized a protective role for the HLA-DR2 antigen, providing additional
basis for the proposed genetic heterogeneity between migraine without aura and
migraine with aura. The cytokines produced by TNF genes are polypeptide effectors
of inflammatory reaction and endothelial function.METHODS: Tumor necrosis factor
(TNF)-308 (TNF-308A and TNF-308G alleles) and lymphotoxin alpha (TNFB*1 and TNFB*2
alleles) polymorphisms were analyzed by the NcoI-cleaved polymerase chain reaction-amplified
fragments in 47 patients with migraine without aura, 32 patients with migraine
with aura, and 101 migraine-free controls.RESULTS: The frequency of TNFB*2 allele
was significantly increased in our patients with migraine without aura as compared
with the control group (78.72% versus 61.4%, Pc =.004), but no significant differences
were found between patients with migraine with aura and controls. Additionally,
there was a significant decrease of TNFB*1 homozygotes in patients with migraine
without aura compared with the control group (2.13% versus 16.8%, Pc =.0201).
Carriage of the TNFB*2 allele confers a high risk for the development of migraine
without aura. No significant association was found at TNF-308 polymorphism. CONCLUSION:
These data support the hypothesis that lymphotoxin alpha could be a susceptibility
gene in migraine without aura and confirm previous data indicating that migraine
with and without aura are distinct entities with different genetic backgrounds.
RA, Ovcaric M, Sundholm J, MacMillan J, Griffiths LR
methylenetetrahydrofolate reductase gene variant C677T influences susceptibility
to migraine with aura.
BMC Med. 2004 Feb 12;2(1):3.
The C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene is associated
with increased levels of circulating homocysteine and is a mild risk factor for
vascular disease. Migraine, with and without aura (MA and MO), is a prevalent
and complex neurovascular disorder that may also be affected by genetically influenced
hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene
is associated with migraine susceptibility we utilised unrelated and family-based
case-control study designs. METHODS: A total of 652 Caucasian migraine cases were
investigated in this study. The MTHFR C677T variant was genotyped in 270 unrelated
migraine cases and 270 controls as well as 382 affected subjects from 92 multiplex
pedigrees. RESULTS: In the unrelated case-control sample we observed an over-representation
of the 677T allele in migraine patients compared to controls, specifically for
the MA subtype (40% vs. 33%) (chi2 = 5.70, P = 0.017). The Armitage test for trend
indicated a significant dosage effect of the risk allele (T) for MA (chi2 = 5.72,
P = 0.017). This linear trend was also present in the independent family-based
sample (chi2 = 4.25, Padjusted = 0.039). Overall, our results indicate that the
T/T genotype confers a modest, yet significant, increase in risk for the MA subtype
(odds ratio: 2.0 - 2.5). No increased risk for the MO subtype was observed (P
> 0.05). CONCLUSIONS: In Caucasians, the C677T variant in the MTHFR gene
influences susceptibility to MA, but not MO. Investigation into the enzyme activity
of MTHFR and the role of homocysteine in the pathophysiology of migraine is warranted.
Site Link: Migraine with Aura and Homocysteine
Oterino A, Valle N, Bravo Y, Muńoz P, Sánchez-Velasco
P, Ruiz-Alegría C, Castillo J, Leyva-Cobián F, Vadillo A, Pascual J
T677 homozygosis influences the presence of aura in migraineurs.
It has been suggested that folate metabolism could be
involved in migraine pathogenesis. We analysed the 5',10'-methylenetetrahydrofolate
reductase (MTHFR) genotypic distribution in a large migraine sample. We genotyped
230 migraine patients (152 migraine without aura (MO) and 78 migraine with aura
(MA)) and 204 nonheadache controls. The incidence of TT homozygosis for migraine
in general (12%), MO (9%) and MA (18%) did not significantly differ from that
found in healthy controls (13%). Differences were significant when the frequency
of TT homozygosis between MA and MO (P = 0.03, OR = 2.34, 95% CI = 1.04-5.26)
was compared. There was a tendency for a higher frequency of the MTHFR T allele
in the MA group (42%) as compared to MO (29%) and controls (36%). These differences
were significant only in the case of MA vs. MO (P = 0.006, OR = 1.75, 95% CI =
1.15-2.65). These results could indicate that the MTHFR C677T polymorphism, causing
mild hyperhomocystinaemia, might be a genetic risk factor for experiencing aura
among migraineurs. Overall, however, there was no association between migraine
and the C677T MTHFR polymorphism. [Abstract]
I, Sazci A, Ergul E, Kaya G, Kilic G
the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase
gene in patients with migraine risk.
Brain Res Mol
Brain Res. 2003 Mar 17;111(1-2):84-90.
Although controversial, diminished activity
of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine
metabolism, may predispose to migraine in Turkish people. In a case-control study,
we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C,
in 102 migraine patients (23 migraine with aura, 70 migraine without aura and
nine with tension-type headache) and compared it to that of 136 healthy controls.
The frequencies of the T allele of MTHFR677 and the C allele of MTHFR1298 were
significantly higher in the total migraine population (33.82%, 33.82%) than in
controls (25.38% and 24.26%), respectively.The genotypes T677T and C1298C were
the only genotypes significantly associated with migraine (OR=5.702; 95% CI=1.184-27.457;
P=0.015) and (OR=8.933; 95% CI=1.953-40.869; P=0.001), respectively). Individuals
with migraine with aura with C1298C and C677C/C1298C genotypes were even more
profoundly associated with migraine risk than others (OR=14.105; 95% CI=2.417-82.320;
P=0.0001) and (OR=10.050; 95% CI=1.580-63.907; P=0.003), respectively. However
individuals with migraine without aura with T677T and C1298C genotypes showed
the same susceptibility (OR=7.444; 95% CI=1.503-36.863); P=0.005). Patients with
C1298C and C677C/C1298C genotypes may also predispose to tension-type headache
(OR=8.375; 95% CI=0.685-102.458); P=0.049). [Abstract]
H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K
homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a
genetic risk factor for migraine.
Am J Med Genet.
2000 Dec 4;96(6):762-4.
Increased homocysteine levels are associated with various
pathological conditions in humans, including stroke and cardiovascular disorders.
Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold
of migraine headache. Frosst et al.  reported an association between the
homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR)
gene and serum homocysteine levels. This study was designed to determine the prevalence
of the MTHFR mutation in Japanese patients with migraine and tension-type headache
(TH). Seventy-four patients with migraine headaches (22 with aura and 52 without
aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR
C677T polymorphism was performed by polymerase chain reaction-restriction fragment
length polymorphism. We detected that the incidence of the homozygous transition
(T/T) in migraine sufferers (20.3%) was significantly higher than that in controls
(9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine
headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent
in the migraine group than in the control group. Our results support the conclusion
that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor
for migraine. [Abstract]
NJ, Lea RA, Quinlan S, MacMillan J, Griffiths LR
estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility
in two independent case/control groups.
Migraine is a painful and debilitating disorder with
a significant genetic component. Steroid hormones, in particular estrogen, have
long been considered to play a role in migraine, as variations in hormone levels
are associated with migraine onset in many sufferers of the disorder. Steroid
hormones mediate their activity via hormone receptors, which have a wide tissue
distribution. Estrogen receptors have been localized to the brain in regions considered
to be involved in migraine pathogenesis. Hence it is possible that genetic variation
in the estrogen receptor gene may play a role in migraine susceptibility. This
study thus examined the estrogen receptor 1 (ESRalpha) gene for a potential role
in migraine pathogenesis and susceptibility. A population-based cohort of 224
migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism
located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant
difference between migraineurs and non-migraineurs in both the allele frequencies
(P=0.003) and genotype distributions (P=0.008) in this sample. An independent
follow-up study was then undertaken using this marker in an additional population-based
cohort of 260 migraine sufferers and 260 matched controls. This resulted in a
significant association between the two groups with regard to allele frequencies
(P=8 x 10(-6)) and genotype distributions (P=4 x 10(-5)). Our findings support
the hypothesis that genetic variation in hormone receptors, in particular the
ESR1 gene, may play a role in migraine. [Abstract]
C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alpérovitch A
between migraine and endothelin type A receptor (ETA -231 A/G) gene polymorphism.
2001 May 22;56(10):1273-7.
BACKGROUND: Previous studies have described an association
between migraine and endothelin, a potent vasoconstrictor. OBJECTIVE: To test
the association between migraine and gene polymorphisms of the endothelin system.
METHODS: A population-based study of elderly individuals (n = 1,188) in Nantes
(western France) was conducted. Lifetime migraine was defined according to the
International Headache Society criteria, after an interview with a headache specialist.
Five polymorphisms in genes encoding endothelin 1, endothelin type A (ET(A)),
and type B receptors were determined in more than 90% of the sample. RESULTS Migraine
was diagnosed in 140 participants (11.9%). The ETA (-231 A/G) polymorphism was
the only polymorphism significantly associated with migraine. There was a trend
of decreasing prevalence of migraine with number of copies of the G allele (AA
genotype: 15.7% of participants with migraine, AG: 9.7%, GG: 2.9%; p < 0.001).
Carrying the G allele was associated with a sex- and age-adjusted odds ratio of
0.50 (95% CI, 0.34 to 0.74). The association was observed in both sexes and was
stronger in participants with a family history of severe headaches than in those
without. CONCLUSIONS: A variant of the ET(A) receptor gene modulates the risk
for migraine. These results offer new insights into the pathophysiology of the
vascular component of migraine. [Abstract]
S, Di Pasquale P, D'Angelo A, Seidita G, Tuttolomondo A, Cardinale A, Maniscalchi
T, Follone G, Giubilato A, Tarantello M, Licata G
enzyme gene deletion polymorphism determines an increase in frequency of migraine
attacks in patients suffering from migraine without aura.
Many authors have reported an association between
the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and
other cardiovascular diseases. The mechanism underlying the positive associations
between the ACE-D alleles and diseases are not yet clear. Previous reports showed
an association between migraine without aura and ACE-D allele polymorphism. The
study is aimed to evaluate if the DD genotype could also be associated with the
frequency and duration of migraine without aura. In 302 patients suffering from
migraine without aura (at least for 1 year), with no history of cardiovascular
diseases and major risk factors for ischemic events, the genotypes of the ACE
gene, plasma ACE activity, and the frequency (weekly) and duration of migraine
attacks were evaluated. No drugs were given before (4 weeks) and during the study.
The same evaluations were performed in 201 subjects without migraine. The molecular
biologist and the physician evaluating the patient data were blinded to the clinical
history and ACE-DD gene determination. Genotypes were determined by polymerase
chain reaction amplification. Plasma ACE activity was performed by the HPLC method.
The groups were similar for sex, age and smoking habit (migraines: 302 patients
(200 F/102 M), mean age 37.8 +/- 8.2 years; control: 201 subjects (127 F/74 M),
mean age 37.5 +/- 9.3 years). Patients with migraine without aura showed higher
incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p <
0.05. The frequency of migraine (average attacks per week) was higher in patients
with DD (2.11 +/- 1.9) than in patients with ID (1.54 +/- 1. 44), p < 0.05.
No difference in duration of migraine attacks (hours per week) was observed. Plasma
ACE activity was increased in patients with the ACE-DD gene. Our data suggest
that ACE-DD gene polymorphism could have an important role in determining migraine
attacks and the frequency of these attacks. Further data are needed through further
studies, especially on the biomolecular level. [Abstract]
I, Pinessi L, Salani G, Valfrč W, Rivoiro C, Savi L, Gentile S, Giudice RL, Grimaldi
A polymorphism in the interleukin-1alpha gene influences
the clinical features of migraine.
OBJECTIVE: To evaluate whether a particular genotype of the
interleukin-1alpha (IL1A) gene affects the clinical features of migraine.BACKGROUND:
Proinflammatory mediators have been reported to play a role in the pathophysiology
of migraine. Recent studies suggest that polymorphisms in the interleukin-1 genes
influence the age at onset and subsequent course of several chronic inflammatory
diseases.METHODS: In a group of 269 patients with migraine, we tested the association
of the -889 C/T biallelic polymorphism of the IL1A gene with several clinical
features of the disease. RESULTS:Patients with migraine carrying the T/T genotype
show an age at onset of the disease that is significantly (P <.01) lower than
IL1A C/C or C/T carriers. In addition, the same genotype was significantly (P
<.05) more frequent in patients with migraine with aura than in patients with
migraine without aura.CONCLUSIONS: The results of our study suggest a role for
the IL1A gene in modifying the clinical features of migraine. [Abstract]
M, Ishizaki K, Kowa H, Adachi Y, Takeshima T, Sakai F, Nakashima K
S-transferase polymorphisms: susceptibility to migraine without aura.
Migraine is considered to be a polygenic multifactorial
disease with various environmental and genetic etiologies. We investigated glutathione
S-transferase (GST) P1 Ile(105)Val, T1 and M1 polymorphisms in 174 Japanese headache
sufferers and 372 Japanese controls. The headache group consisted of 38 cases
of migraine with aura, 95 migraine without aura (MWOA) and 41 tension-type headache
sufferers. The M1 homozygous deletion genotype was significantly higher in MWOA
(64%) compared with controls (46%; p < 0.01; odds ratio = 2.18, 95% confidence
interval: 1.32-3.61, adjusted for age and gender). In a comparison of the current
smokers, the M1 null frequencies in MWOA were further increased. GSTM1 may be
one of the genetic risk factors for MWOA in the Japanese population. [Abstract]
ME, Herken H, Yilmaz M, Bayazit YA
the T102C polymorphism of 5-HT2A receptor gene with aura in migraine.
Neurol Sci. 2001 Jul 15;188(1-2):99-101.
OBJECTIVE: To find out the significance
of the 5-HT2A receptor gene polymorphism in migraine. Study design: A PCR study
in which 61 migraineurs and 44 healthy controls were included. METHODS: The T102C
polymorphism of the 5-HT2A receptor gene was studied. The results of the migraineurs
and controls were compared. The relationship between the gene polymorphism and
aura was also assessed. RESULTS: The representations of the 5-HT2A genotypes were
similar in migraineurs and controls (p>0.05) as well as in the male and female
migraineurs (p>0.05). The family history of migraine did not associate with
5-HT2A receptor gene polymorphism (p>0.05). There was a significant relationship
between the presence of C/C genotype and migraine with aura (p=0.02) while C/T
and T/T genotypes were over represented in the patients with migraine without
aura (p<0.01). CONCLUSION: The T102C polymorphism of the 5-HT2A receptor gene
is not directly related to the increased risk of migraine. The associations between
the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism
may be involved in determining the subtypes of or accompanying symptoms in the
migraine disease. [Abstract]
Site Link: Migraine with Aura and 5-HT2A Receptors
DR, Curtain RP, Gaffney PT, Brimage P, Goadsby PJ, Griffiths LR
association and linkage analyses of the human 5-hydroxytryptamine (5HT2A) receptor
Cephalalgia. 1996 Nov;16(7):463-7.
(5HT), commonly known as serotonin, which predominantly serves as an inhibitory
neurotransmitter in the brain, has long been implicated in migraine pathophysiology.
This study tested an MspI polymorphism in the human 5HT2A receptor gene (HTR2A)
and a closely linked microsatellite marker (D13S126), for linkage and association
with common migraine. In the association analyses, no significant differences
were found between the migraine and control populations for both the MspI polymorphism
and the D13S126 microsatellite marker. The linkage studies involving three families
comprising 36 affected members were analysed using both parametric (FASTLINK)
and non-parametric (MFLINK and APM) techniques. Significant close linkage was
indicated between the MspI polymorphism and the D13S126 microsatellite marker
at a recombination fraction (theta) of zero (lod score = 7.15). Linkage results
for the MspI polymorphism were not very informative in the three families, producing
maximum and minimum lod scores of only 0.35 and -0.39 at recombination fractions
(theta) of 0.2 and 0.00, respectively. However, linkage analysis between the D13S126
marker and migraine indicated significant non-linkage (lod < -2) up to a recombination
fraction (theta) of 0.028. Results from this study exclude the HTR2A gene, which
has been localized to chromosome 13q14-q21, for involvement with common migraine.
M, Araki H, Ijiri T, Kowa H, Adachi Y, Takeshima T, Sakai F, Nakashima K
2C receptor gene Cys23Ser polymorphism: a candidate genetic risk factor of migraine
with aura in Japanese population.
Acta Neurol Scand.
OBJECTIVES: The goal of this study is to clarify the
association between migraine and Serotonin 2C receptor Cys23Ser polymorphism in
Japanese population. MATERIALS AND METHOD: This study included 37 individuals
with migraine with aura (MWA), 80 with migraine without aura, 43 with tension
type headache (TH) and 360 with controls. The genotypes of Cys23Ser polymorphism
were confirmed by polymerase chain reaction-restriction fragment length polymorphism
techniques. RESULTS: The Ser allele frequency in control subjects is much less
than that in Caucasian population. The Ser allele frequency in patients with MWA
was higher than that in control subjects. CONCLUSION: The present study provides
that 5HTR2c Cys23Ser polymorphism may be associated with MWA in Japanese population.
MP, Lea RA, Curtain RP, MacMillan JC, Griffiths LR
investigation of the 5-HT2C receptor gene as a migraine candidate gene.
J Med Genet. 2003 Feb15;117B(1):86-9.
Migraine is a common complex disorder,
currently classified into two main subtypes, migraine with aura (MA) and migraine
without aura (MO). The strong preponderance of females to males suggests an X-linked
genetic component. Recent studies have identified an X chromosomal susceptibility
region (Xq24-q28) in two typical migraine pedigrees. This region harbours a potential
candidate gene for the disorder, the serotonin receptor 2C (5-HT(2C)) gene. This
study involved a linkage and association approach to investigate two single nucleotide
variants in the 5-HT(2C) gene. In addition, exonic coding regions of the 5-HT(2C)
gene were also sequenced for mutations in X-linked migraine pedigrees. Results
of this study did not detect any linkage or association, and no disease causing
mutations were identified. Hence, results for this study do not support a significant
role of the 5-HT(2C) gene in migraine predisposition. [Abstract]
PW, Harrison PJ, Goodwin GM, Battersby S, Ogilvie AD, Olesen J, Russell MB
variation in the serotonin 5-HT2C receptor gene and migraine.
1997 Aug 18;8(12):2651-3.
The 5-HT2C (serotonin-2C) receptor has been implicated
along with other components of the 5-HT system in the pathophysiology and pharmacotherapy
of migraine. To investigate whether the 5-HT2C receptor gene contributes to the
risk of migraine we performed an association study of allelic variation at codon
23 (Cys or Ser) of the gene in 242 migraineurs, including 73 with aura, and 129
controls. No differences nor trends in allele or genotype frequencies were seen
in the migraineurs compared to the controls. Neither did the frequencies vary
significantly in migraineurs with and without aura, or if men and women were analysed
separately. In conjunction with an earlier negative linkage study, these data
indicate that the 5-HT2C receptor gene does not contribute to the genetic predisposition
to migraine. [Abstract]
A, Welch SK, Peroutka SJ
Exclusion of 5-HT2A and 5-HT2C
receptor genes as candidate genes for migraine.
Several lines of investigation suggest that the serotonergic
system may be involved in the pathogenesis of migraine. In particular, drugs which
block 5-HT2 receptor subtypes appear to be effective migraine prophylactic agents.
Therefore, chromosomal DNA regions overlapping the 5-HT2A (13q14-q22) and 5-HT2C(Xq22-25)
receptor loci were analyzed for possible linkage to the clinical diagnosis of
migraine. No evidence for linkage to either chromosomal region was found, although
a small subset of migrainous families showed positive likelihood of odds (LOD)
scores. However, a homogeneity (HOMOG) analysis provided no statistical evidence
for locus heterogeneity. The coding region of the 5-HT2A and 5-HT2C receptor genes
was also analyzed in migraine patients and unaffected controls using polmerase
chain reaction and direct sequencing. No mutations were found in the deduced amino
acid sequence of either receptor in the sample of migraineurs tested. These results
indicate that DNA-based mutations in the 5-HT2A and 5-HT2C receptors are not generally
involved in the pathogenesis of migraine. [Abstract]
M, Leone M, Porrello E, Rigamonti A, Govoni S, Sironi M, Montomoli C, Bussone
Familial migraine with aura: association study with
5-HT1B/1D, 5-HT2C, and hSERT polymorphisms.
BACKGROUND: The serotonergic system has a significant
role in the pathophysiology and pharmacology of migraine. OBJECTIVE: To study
the association between the occurrence of migraine with aura and 5-HT(1B/1D) and
5-HT(2C) receptor gene and the human serotonin transporter (hSERT) gene polymorphisms
in 18 unrelated families with multiple affected members. METHOD: Two polymorphisms
in the 5-HT(1B/1D) receptor gene and one polymorphism in the 5-HT(2C) receptor
gene were studied by restriction fragment length polymorphism analysis. Allelic
variation of the hSERT, with 9, 10, and 12 copies of a "repetitive element,"
was studied by polymerase chain reaction amplification of the variable number
tandem repeat region. RESULTS: Allelic distribution of 5-HT(1B/1D) and 5-HT(2C)
receptor gene polymorphisms in affected patients did not differ in either of the
control groups (unaffected relatives or unrelated healthy individuals). A trend
toward a significant effect of the 12-repeat hSERT allele as a risk factor for
migraine with aura versus unrelated controls was observed. CONCLUSION: Our data
do not support the involvement of 5-HT(1B/1D) and 5-HT(2C) receptor gene polymorphisms
in migraine with aura, yet do suggest a possible role for a locus at or near the
hSERT gene in the susceptibility to migraine with aura. [Abstract]
G, Zsombok T, Laszik A, Gonda X, Sotonyi P, Faludi G, Bagdy G
analysis of 5-HTTLPR variants, 5-HT2a receptor gene 102T/C polymorphism and migraine.
Neurogenet. 2003 Apr-Sep;17(2-3):231-40.
It is well known that migraine has
a strong genetic component, although the type and number of genes involved is
not yet clear. There is evidence to suggest that serotonin-related genes participate
in the pathogenesis of migraine. Previous studies have shown that gender differences
influence the serotonergic neurotransmission and, in addition, the migraine prevalence
is higher in females than males. Therefore, we investigated the functional polymorphism
in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR)
and the 102T/C polymorphism of the 5-HT2A receptor gene in the Hungarian female
population. These genes were analysed in 126 migraine sufferers (with or without
aura)and 101 unrelated healthy controls using case control design. A borderline
association (chi2 = 3.84, df = 1, p = 0.049; OR = 1.45, 95% CI = 1.00-2.12) between
5-HTTLPR short (S) allele and migraine was found. No significant difference between
migraine sufferers and controls was observed for the 102T/C polymorphism of 5-HT2A
receptor gene. Furthermore, there was no significant interaction between5-HTTLPR
and 102T/C polymorphisms in our study population. In conclusion, our results support
that the genetic susceptibility of migraine may be associated with a locus at
or near the 5-HT transporter gene. [Abstract]
G, Zsombok T, Laszik A, Jakus R, Faludi G, Sotonyi P, Bagdy G
the general correlation of the serotonin transporter gene regulatory region polymorphism
(5-HTTLPR) and platelet serotonin concentration, lower platelet serotonin concentration
in migraine patients is independent of the 5-HTTLPR variants.
Lett. 2003 Oct 16;350(1):56-60.
Platelet serotonin (5-HT) concentrations in
a headache-free period during the mid-follicular phase and the serotonin transporter
gene regulatory region polymorphism (5-HTTLPR) were measured in female migraine
patients without aura (n = 64) and healthy controls (n = 42). High-pressure liquid
chromatography (HPLC) was used to determine the platelet 5-HT concentration and
genetic polymorphism was determined by polymerase chain reaction. Significantly
lower platelet 5-HT concentrations were found in migraine patients compared to
controls. Concerning the 5-HTTLPR polymorphism, the S/S genotype was associated
with a significantly higher platelet 5-HT concentration (P = 0.027) in the whole
study population. This association between the 5-HTTLPR genotypes and platelet
5-HT concentrations was independent of the diagnosis. In addition, the platelet
5-HT concentration was lower in migraineurs in all genotypes (S/S, S/L, L/L).
In conclusion, 5-HTTLPR variants may have an effect on the platelet 5-HT concentrations,
but the lower 5-HT concentrations in migraine patients seem to be determined by
other factors. [Abstract]
K, Shimomura T, Shimomura F, Ikawa S, Nanba E
in the serotonin transporter gene regulatory region and frequency of migraine
Headache. 2002 Oct;42(9):893-5.
The serotonergic system has been thought to play an important part in the pathophysiology
of migraine. OBJECTIVE: To study an association between the polymorphism of serotonin
(5-hydroxytryptamine [5-HT]) transporter gene-linked polymorphic region (5-HTTLPR)
and migraine. Method.-We compared 151 patients with migraine with 190 healthy
unrelated control subjects. The 5-HTTLPR polymorphism was detected using polymerase
chain reaction. Migraine patients were interviewed regarding attack frequency
in the last 6 months. RESULTS: We denoted the products of the 484-base pair (bp)
fragments as the short (s) and those of 528 bp as the long (l) allele according
to the previously reported manner. Migraine patients with s/s genotype were compared
with those with l/s and l/l genotype. We did not find significant differences
in the genotype and allele frequencies of 5-HTTLPR between patients with migraine
and control subjects. Among patients with migraine, those with s/s type had significantly
more frequent attacks than those with the l/s or l/l type. CONCLUSIONS: This polymorphism
does not appear to be involved in a genetic predisposition to the disease but
may affect the frequency of attacks in patients with migraine. These findings
may contribute to our understanding of factors that influence the clinical severity
of migraine. [Abstract]
M, Erdal ME, Herken H, Cataloluk O, Barlas O YA
of serotonin transporter gene polymorphism in migraine.
Neurol Sci. 2001 May 1;186(1-2):27-30.
OBJECTIVE: To elucidate significance
of the serotonin transporter gene (STG) polymorphism in migraine, and to address
the polymorphic patterns of STG, both in the migraineurs and healthy people in
this country. STUDY DESIGN: A PCR study of STG in 52 migraineurs and 80 healthy
controls. METHODS: Using the PCR technique, STG polymorphism was studied in the
DNA obtained from leukocytes of the patients and healthy controls. Polymorphism
of the two regions (VNTR and 5-HTTLPR) of STG was assessed. RESULTS: VNTR STin
2.10 and STin 2.12 alleles were detected in migraineurs and healthy controls.
Both homozygous and heterozygous STin 2.10 allele predominated in the migraine
group (p=0.01), while STin 2.12 allele was more frequent in the healthy controls
(p=0.02). There was no relationship between the migraine type, family history
of migraine and STG polymorphism. CONCLUSION: STin 2.10 and STin 2.12 alleles
of VNTR are frequent in this country. While the presence of STin 2.10 allele increases
the risk of migraine, 5-HTTLPR polymorphism is not associated with this risk.
AD, Russell MB, Dhall P, Battersby S, Ulrich V, Smith CA, Goodwin GM, Harmar AJ,
Altered allelic distributions of the serotonin
transporter gene in migraine without aura and migraine with aura.
Allelic variation of the human serotonin transporter gene
(HSERT), a highly plausible candidate gene for susceptibility to migraine, was
investigated in 266 individuals with migraine, including 173 having migraine without
aura (MO), 94 having migraine with aura (MA), 18 with co-occurrence of MO and
MA, plus 133 unaffected controls. The distribution of a polymorphism with different
forms of a variable tandem number repeat (VNTR) in intron 2 were compared. The
MO group had an over-representation of genotypes with two twelve repeat alleles
(STin2.12) and a reduction of genotypes containing one ten repeat (STin2.10) compared
to controls. The MA group showed a similar pattern, but also a trend towards an
increase in genotypes containing the nine repeat allele of the VNTR (STin2.9).
Genotypes containing this allele were found in 6.4% of the MA group compared to
2.3% of controls. The group with co-occurrence of MO and MA had a significantly
different pattern of overall allele frequency distribution from controls, reflecting
a reduction in genotypes containing the STin2.10 allele and a shift both to STin2.9
carriers and to STin2.12 homozygosity. These results support the view that susceptibility
to MO and MA has a genetic component, that these disorders are distinct, and that
genetic susceptibility may in some cases be associated with a locus at or near
the serotonin transporter gene. [Abstract]
M, Cevoli S, Cortelli P, Pierangeli G, Soriani S, Scapoli C, Montagna P
genetic association study of migraine with dopamine receptor 4, dopamine transporter
and dopamine-beta-hydroxylase genes.
We assessed the role of some dopamine metabolism genes
in the genetic susceptibility to migraine. We performed an association study using
three functional polymorphisms: a 48-base-pair (bp) tandem repeat in the D4 dopamine
receptor gene ( DRD4), a 40-bp tandem repeat in the dopamine transporter gene
( DAT) and a dinucleotide repeat in the dopamine beta-hydroxylase ( DBH) gene.
Allelic and genotypic frequencies for each polymorphism were assayed in two migraine
populations (93 individuals with migraine with aura (MA) and 101 with migraine
without aura (MO)) and were compared with those in a control group (117 individuals).
No significant differences were found between control and migraine groups for
DAT and DBH polymorphisms. Instead, the distribution of alleles for the DRD4 gene
in the MO group was significantly different from those in both MA and control
groups, with the shortest and longest alleles being less frequent in MO. Our data
indicate that MO, but not MA, shows significant genetic association with DRD4.
RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR
for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility
to typical migraine.
Neurogenetics. 2000 Sep;3(1):35-40.
is a debilitating neurological disorder characterized by recurrent attacks of
severe headache. The disorder is highly prevalent, affecting approximately 12%
of Caucasian populations. It is well known that migraine has a strong genetic
component, although the type and number of genes involved is not yet clear. However,
the calcium channel gene, CACNA1A, on chromosome 19 contains mutations responsible
for familial hemiplegic migraine, a rare and severe subtype of migraine. There
is also evidence to suggest that serotonin- and dopamine-related genes may be
involved in the pathogenesis of migraine. This study employed a linkage and association
approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms
within the dopamine beta-hydroxylase (DBH) gene, serotonin transporter gene (SERT),
and dopamine receptor gene (DRD2) were tested in 177 unrelated Caucasian migraineurs
and 182 control individuals. In addition, an independent sample of 82 families
affected with migraine was examined. Unrelated case-control association analysis
of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution
between migraine and control groups (chi2 = 16.53, P=0.019). Furthermore, the
transmission/disequilibrium test, which was implemented on the family data, also
indicated distortion of allele transmission for the same DBH marker (chi2 = 4.44,
P=0.035). Together, these results provide evidence for allelic association of
the DBH gene with typical migraine susceptibility (Fisher's combined P value =0.006)
and indicate that further research into the role of the DBH gene in the etiology
of migraine is warranted. [Abstract]
Erdal M, Herken H, Yilmaz M, Bayazit YA
of the catechol-O-methyltransferase gene polymorphism in migraine.
Res Mol Brain Res. 2001 Oct 19;94(1-2):193-6.
The objective was to assess the
significance of the catechol-o-methyltransferase (COMT) enzyme polymorphism in
migraine. For this reason, 62 migraineurs and 64 healthy volunteers were included
in the study. The analysis of COMT polymorphism was performed using PCR. The H/H
genotype was more frequent in the control group than in the patients group (P=0.032).
The homozygous or heterozygous L allele was over represented in the migraineurs
compared with the controls (P=0.013). The L/L genotype was over represented in
the migraineurs who also had a family history of migraine (P=0.003). There was
no relationship between aura and COMT genotypes. In conclusion, the COMT polymorphism
may be of potential pharmacological importance regarding the individual differences
in the metabolism of catechol drugs in migraineurs. Although altered catecholamine
activity due to polymorphism of COMT gene may be one of the mechanisms involved
in the pathogenesis of migraine, these mechanisms are not related to presence
or absence of aura. [Abstract]
N, Rainero I, Parziale A, Rosina F, Pavanelli E, Rubino E, Mazza C, Ostacoli L,
Lack of interaction between a polymorphism
in the dopamine D2 receptor gene and the clinical features of migraine.
The purpose of this study was to evaluate whether a particular
genotype of the dopamine D2 receptor (DRD2) gene would affect the clinical features
of migraine. In a group of 118 migraineurs (55 migraine with aura and 63 migraine
without aura patients), we tested the association of the biallelic C/T NcoI DRD2
polymorphism with several characteristics of the disease. Genotype and allele
frequencies resulted similarly distributed in migraine with aura and migraine
without aura patients (chi2 = 1.58, P = 0.45 and chi2 = 0.09, P = 0.77, respectively).
The different DRD2 genotypes (C/C, C/T and T/T) had no significant effects on
age at onset of migraine, presence of premonitory phenomena, frequency of headache
attacks, associated symptoms, psychological features and quality of life of our
migraine patients. The results of our study do not support a role for the DRD2
gene in modifying the clinical features of migraine. [Abstract]
S, Curtin J, Breen G, Collier D, Russell G, Shaw D, Clair DS
-141C Ins/Del polymorphism of the dopamine D2 receptor gene is not associated
with either migraine or Parkinson's disease.
Genet. 2001 Mar;11(1):49-52.
Abnormalities in dopamine neurotransmission at
the dopamine D2 receptor (DRD2) have been implicated in both migraine and Parkinson's
disease. Positive associations have also been found between polymorphisms within
the DRD2 gene and both of these conditions. The -141C Ins/Del polymorphism in
the DRD2 receptor gene is a putative functional polymorphism. The purpose of this
study was to determine whether it and any genes in linkage disequilibrium with
this marker are involved in either of these conditions. We have compared the genotype
and allele frequencies of the -141C Ins/Del polymorphism in 200 migraineurs and
260 Parkinson's disease cases with 464 controls. We have found no association
between the receptor gene and either condition (P = 0.89 and P = 0.56 respectively).
Our findings do not support the hypothesis that this polymorphism is involved
in the aetiology of migraine or Parkinson's disease. [Abstract]
M, Förderreuther S, Deiterich M, Pfaffenrath V, Gasser T
D2 receptor NcoI allele: absence of allelic association with migraine with aura.
SJ, Wilhoit T, Jones K
Clinical susceptibility to
migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles.
Migraine has a major genetic component. Although most
recent scientific studies have focused on the role of 5-hydroxytryptamine and
neuropeptides in migraine, dopaminergic systems are also implicated in the pathogenesis.
Therefore, the dopamine D2 receptor (DRD2) was analyzed as a candidate gene since
antagonists of this receptor have been reported to be effective in the acute treatment
of migraine. Individuals with migraine with aura (n = 52) have an increased frequency
(0.84) of the DRD2 NcoI C allele (chi-square = 6.47; p < 0.005) compared with
control individuals (n = 121; C allele frequency = 0.71). Individuals with migraine
without aura (n = 77) showed the same DRD2 T allele frequency (0.70) as the control
group. Migraine with aura was present in 27% of the C/C individuals, 16% of the
C/T individuals, and 5.2% of the T/T individuals. These data suggest that activation
of the DRD2 receptor plays a modifying role in the pathophysiology of migraine
with aura. As a result, these data provide a molecular rationale for the documented
efficacy of DRD2 antagonists in the treatment of migraine with aura. [Abstract]
AG, Lea RA, Hutchins C, Jordan KL, Brimage PJ, Griffiths LR
receptor genes and migraine with and without aura: an association study.
OBJECTIVE: To investigate the role of the dopamine receptor
genes, DRD1, DRD3, and DRD5 in the pathogenesis of migraine. BACKGROUND: Migraine
is a chronic debilitating disorder affecting approximately 12% of the white population.
The disease shows strong familial aggregation and presumably has a genetic basis,
but at present, the type and number of genes involved is unclear. The study of
candidate genes can prove useful in the identification of genes involved in complex
diseases such as migraine, especially if the contribution of the gene to phenotypic
expression is minor. Genes coding for proteins involved in dopamine metabolism
have been implicated in a number of neurologic conditions and may play a contributory
role in migraine. Hence, genes that code for enzymes and receptors modulating
dopaminergic activity are good candidates for investigation of the molecular genetic
basis of migraine. METHODS: We tested 275 migraineurs and 275 age- and sex-matched
individuals free of migraine. Genotypic results were determined by restriction
endonuclease digestion of polymerase chain reaction products to detect DRD1 and
DRD3 alleles and by Genescan analysis after polymerase chain reaction using fluorescently
labelled oligonucleotide primers for the DRD5 marker. RESULTS: Results of chi-square
statistical analyses indicated that the allele distribution for migraine cases
compared to controls was not significantly different for any of the three tested
gene markers (chi2 = 0.1, P =.74 for DRD1; chi2 = 1.8, P =.18 for DRD3; and chi2
= 20.3, P =.08 for DRD5). CONCLUSIONS: These findings offer no evidence for allelic
association between the tested dopamine receptor gene polymorphisms and the more
prevalent forms of migraine and, therefore, do not support a role for these genes
in the pathogenesis of the disorder. [Abstract]
Zompo M, Cherchi A, Palmas MA, Ponti M, Bocchetta A, Gessa GL, Piccardi MP
between dopamine receptor genes and migraine without aura in a Sardinian sample.
BACKGROUND: Migraine seems to be caused by a combination
of environmental and genetic factors. Clinical and pharmacologic evidence supports
the hypothesis that dopaminergic transmission is involved in the pathogenesis
of migraine. OBJECTIVE: The current report concerns a genetic study to test the
involvement of genes for dopamine (DA) receptors D2 (DRD2), D3 (DRD3), and D4
(DRD4) in migraine without aura, particularly in a subgroup with enhanced DA sensitivity.
METHODS: For the first time, a family-based association method--the Transmission
Disequilibrium Test (TDT)--was used to examine an isolated population, such as
Sardinians. We studied 50 nuclear families of patients affected by migraine without
aura. The subgroup of dopaminergic migraineurs was selected based on the presence
of both nausea and yawning immediately before or during the pain phase of migraine.
RESULTS: No association was detected using the TDT between DRD3, DRD4, and migraine
without aura either in the overall sample or in the subgroup. No difference was
observed in DRD2 allelic distribution in the overall sample, although the allelic
distribution at the DRD2 locus differed significantly in the subgroup of dopaminergic
migraineurs (p = 0.004). Allele 1 of the TG dinucleotide intronic noncoding polymorphism
of the DRD2 locus was the individual allele that appeared to be in disequilibrium
with migraine without aura (p = 0.02). CONCLUSIONS: Our data suggest that a genetic
approach could be useful in providing molecular support to the hypothesis that
hypersensitivity of the dopaminergic system may represent the pathophysiologic
basis of migraine, at least in a subgroup of patients. [Abstract]
ME, Asuni C, Congiu D, Del Zompo M, Severino G
study between the phenotype migraine without aura-panic disorder and dopaminergic
Pharmacol Res. 2003 Nov;48(5):531-4.
and epidemiological evidence suggests that migraine often co-occurs with psychopathological
conditions. Several longitudinal and population-based studies have suggested that
migraine and panic disorder might share a common predisposition. An abnormal dopaminergic
function has been hypothesized to be involved as etiological factor in panic disorder
as well as in migraine. Epidemiological and molecular data suggest the role of
genetic factors in the pathogenesis of both migraine and panic attack disorder.
We assessed the presence of panic disorder in 100 probands suffering from migraine
without aura and the present study was designed to analyse the possible association
of the migraine-panic phenotype with dopaminergic genes. In our sample, 17 out
of 100 migraineurs were affected by panic disorder and were thus considered for
the genetic association study. The allele frequencies of DRD1, DRD3, DRD5, DRD2
in probands did not differ from that of parental non-transmitted chromosomes.This
result does not seem to support, in our limited sample, a common pathological
basis, with regard to the dopaminergic system, between migraine and panic. Should
migraine and panic disorder share some common mechanisms, these could be sought
in neuro-chemical systems other than the dopaminergic one. [Abstract]
M, Mössner R, Benninghoff J, Syagailo YV, Lesch KP, Sommer C
analysis of the functional monoamine oxidase A gene promotor polymorphism in migraine.
Neural Transm. 2004 May;111(5):603-9.
Migraine affects about 15% of the adult
population. Serotonergic and dopaminergic systems are believed to be involved
in its pathophysiology. One of the key enzymes in the degradation of serotonin
and to a lesser extent of dopamine is monoamine oxidase A (MAO-A). In this study
we investigated a functionally relevant gene-linked polymorphic repetitive sequence
(LPR) located approximately 1.2 kb upstream of the ATG codon in the MAO-A-promotor
gene. 119 patients with migraine and 229 controls were tested. The allelic distribution
of the controls and the migraine patients did not show significant differences
with respect to the low- and high-activity alleles. Moreover, effectiveness of
the potent serotonergic antimigraine agents, triptans, which are metabolized by
MAO-A, was clinically not affected by the MAO-A-LPR in our patients. These findings
thus indicate that there is no association between the functional MAO-A-LPR and
susceptibility to migraine. [Abstract]
VanDenBrink A, Vergouwe MN, Ophoff RA, Naylor SL, Dauwerse HG, Saxena PR, Ferrari
MD, Frants RR
Chromosomal localization of the 5-HT1F
receptor gene: no evidence for involvement in response to sumatriptan in migraine
Am J Med Genet. 1998 Jun 5;77(5):415-20.
5-HT1F receptor, which is present in both human vascular and neuronal tissue,
may mediate the therapeutic effect and/or side-effects of sumatriptan. We investigated
the chromosomal localization of the 5-HT1F receptor gene and the relation between
eventually existing polymorphisms and the clinical response to sumatriptan in
migraine patients. The 5-HT1F receptor gene was localized using a monochromosomal
mapping panel, followed by a radiation-reduced hybrid mapping and fluorescent
in situ hybridization. The results of these techniques show that the 5-HT1F receptor
gene is localized at 3p12. We investigated the presence of polymorphisms by single
strand conformation polymorphism analysis in 14 migraine patients who consistently
responded well to sumatriptan, 12 patients who consistently experienced recurrence
of the headache after initial relief, 12 patients with no response to sumatriptan,
and in 13 patients who consistently experienced chest symptoms after use of sumatriptan.
No polymorphisms were detected in any of the patients. We therefore conclude that
genetic diversity of the 5-HT1F receptor gene is most probably not responsible
for the variable clinical response to sumatriptan. [Abstract]
A, Vergouwe MN, Ophoff RA, Saxena PR, Ferrari MD, Frants RR
receptor polymorphism and clinical response to sumatriptan.
The 5-HT1 receptor agonist, sumatriptan, is highly effective
in the treatment of migraine. Some patients, however, do not respond or experience
recurrence of the headache. In addition, some patients report chest symptoms after
sumatriptan. We investigated whether these different responses could be attributed
to genetic diversity of the 5-HT1B receptor, which most likely mediates the therapeutic
action and the coronary side effects of sumatriptan. Allele frequencies of two
polymorphisms in the 5-HT1B receptor gene (G861C and T-261G) were investigated
in migraine patients with consistently good response to sumatriptan (n = 14),
with no response (n = 12), with recurrence of the headache (n = 12), with chest
symptoms (n = 13), and in patients without chest symptoms (n = 27). Allele frequencies
(G:0.74; C:0.26 at nt 861 and T:0.39; G:0.61 at nt -261) did not differ between
patient groups, indicating that genetic diversity of the 5-HT1B receptor does
not seem to be involved in the different clinical responses to sumatriptan. [Abstract]
SJ, Price SC, Jones KW
The comorbid association of
migraine with osteoarthritis and hypertension: complement C3F and Berkson's bias.
Migraine is known to have a major genetic component and
has been associated with a wide variety of comorbid disorders including arthritis
and heart disease. Since migraine and some of its comorbid disorders involve inflammation,
complement C3, a protein involved in acute inflammation, was selected for analysis
as a candidate gene in an ongoing study of the genetic basis of migraine. Polymorphism
frequencies for complement C3F (0.19) and C3S (0.81) in a sample of 137 unrelated
migraineurs were found to be consistent with a control group as well as previous
population studies, indicating that this common polymorphism has no association
with migraine susceptibility. However, C3F positive individuals with migraine
were found to have an increased incidence of osteoarthritis (Chi square = 10.06;
p < 0.0008) and hypertension (Chi square = 5.18; p < 0.01). Therefore,
the data in the present study indicate that certain migraine comorbidities that
have been reported in the literature may result from Berkson's bias as opposed
to a shared pathophysiological variation in the C3 gene. [Abstract]
LR, Nyholt DR, Curtain RP, Goadsby PJ, Brimage PJ
association and linkage studies of an endothelial nitric oxide synthase (NOS3)
Neurology. 1997 Aug;49(2):614-7.
shows strong familial aggregation. However, the number of genes involved in the
disorder is unknown and not identified. Nitric oxide is involved in the central
processing of pain stimuli and plays an important role in the regulation of basal
or stimulated vasodilation. Nitric oxide synthase, which controls the synthesis
of nitric oxide, could possibly be a cause, or candidate gene, in migraine etiology.
In this study, we detected a polymorphism for endothelial nitric oxide synthase
by polymerase chain reaction and tested this for association and linkage to migraine.
Results from the study did not show an association of the nitric oxide synthase
microsatellite when tested in 91 affected and 85 unaffected individuals. Using
the FASTLINK program for parametric linkage analysis, the polymorphism did not
show significant linkage to migraine when tested in four migraine pedigrees composed
of 116 individuals, 52 affected. Total LOD scores excluded linkage up to 8.5 cM
between the nitric oxide synthase polymorphism and migraine. Results using the
nonparametric affected pedigree member form of analysis also did not support a
role for this gene in migraine etiology. [Abstract]
JA, Corral J, González-Conejero R, Rivera J, Vicente V
genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular
Headache. 1999 Jul-Aug;39(7):486-9.
role of hemostatic elements in stroke has been clearly defined but several prothrombotic
polymorphisms of hemostatic factors, important for other thromboembolic disorders,
seem not to be very significant in stroke. Recently, the high prevalence of factor
V Leiden in patients with stroke and a history of migraine has suggested an association
between migraine and prothrombotic genetic risk factors. Stroke being a multifactorial
disease, the aim of this study was to test whether prothrombotic tendencies increase
the risk of stroke in patients with migraine. We determined the prevalence of
four prothrombotic genetic risk factors (factor V R/Q 506, factor II 20210 G/A,
decanucleotide insertion/deletion in the factor VII promoter, and the platelet
HPA-1 alloantigen system) in 17 patients with coexisting ischemic cerebrovascular
disease and migraine, 107 patients with ischemic cerebrovascular disease, 106
patients with migraine, and 202 control subjects. Genotyping for all polymorphisms
analyzed in our study were performed after specific genomic polymerase chain reaction,
and confirmed by single-strain conformation polymorphism analysis. In the group
of patients with coexisting ischemic cerebrovascular disease and migraine, the
prevalence of prothrombotic genotypes (factor V Leiden, 5.8%; factor II 20210
A, 0%; factor VII A1, 70.6%; and HPA-1b, 35.3%) was similar to that obtained in
all other groups. We can conclude that the studied polymorphisms do not seem to
be associated with the development of ischemic cerebrovascular disease in those
patients with migraine. [Abstract]
J, Iniesta JA, González-Conejero R, Lozano ML, Rivera J, Vicente V
and prothrombotic genetic risk factors.
It has been suggested that during attacks of migraine
both platelet activation and plasma coagulability are increased. We investigated
the prevalence of several prothrombotic genetic risk factors in patients with
migraine: factor V R/Q 506, factor II 20210 G/A, decanucleotide insertion/deletion
in the factor VII promoter, and the platelet HPA-1 and HPA-2 alloantigenic systems,
by genotypic identification in an age- and sex-matched case-control study including
106 patients with migraine (49 with aura, and 57 without aura). The prevalence
of all genotypes was similar among case patients and controls. No association
in relation to the type of migraine was detected in the factor II, factor VII,
HPA-1, or HPA-2 polymorphisms. Our results showed a high prevalence of factor
V Leiden in those patients with migraine with aura (6.1%), though that association
was not statistically significant. The studied prothrombotic genetic factors do
not seem to be associated with the development of migraine and, therefore, are
not likely relevant in the previously reported hypercoagulability and platelet
hyperaggregability in this disease. [Abstract]
McCarthy LC, Hosford DA, Riley JH, Bird MI, White
NJ, Hewett DR, Peroutka SJ, Griffiths LR, Boyd PR, Lea RA, Bhatti SM, Hosking
LK, Hood CM, Jones KW, Handley AR, Rallan R, Lewis KF, Yeo AJ, Williams PM, Priest
RC, Khan P, Donnelly C, Lumsden SM, O'Sullivan J, See CG, Smart DH, Shaw-Hawkins
S, Patel J, Langrish TC, Feniuk W, Knowles RG, Thomas M, Libri V, Montgomery DS,
Manasco PK, Xu CF, Dykes C, Humphrey PP, Roses AD, Purvis IJ
polymorphism alleles in the insulin receptor gene are associated with typical
Genomics. 2001 Dec;78(3):135-49.
have identified a migraine locus on chromosome 19p13.3/2 using linkage and association
analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of
which we genotyped 24 in a Caucasian population comprising 827 unrelated cases
and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor
gene showed significant association with migraine. This association was independently
replicated in a case-control population collected separately. We used experiments
with insulin receptor RNA and protein to investigate functionality for the migraine-associated
single-nucleotide polymorphisms. We suggest possible functions for the insulin
receptor in migraine pathogenesis. [Abstract]
M, Cevoli S, Cortelli P, Pierangeli G, Scapoli C, Soriani S, Montagna P
of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura.
Neurol Sci. 2003 Sep 15;213(1-2):7-10.
We performed a genetic association study
with the LDL receptor gene (LDLR) on chromosome 19p13.2 in 360 migraine patients,
220 with migraine without aura (MO) and 140 with migraine with aura (MA), and
200 controls, by analysing two polymorphic markers, a G142A transition in exon
10 and a triallelic (TA)n repeat in exon 18. The allelic distribution of the (TA)n
polymorphism was significantly different between migraine without aura (MO) and
both controls and migraine with aura (MA). We suggest a possible predisposition
to MO in the studied population through this polymorphism or another polymorphism
in linkage disequilibrium with (TA)n. [Abstract]
KW, Ehm MG, Pericak-Vance MA, Haines JL, Boyd PR, Peroutka SJ
with aura susceptibility locus on chromosome 19p13 is distinct from the familial
hemiplegic migraine locus.
Genomics. 2001 Dec;78(3):150-4.
is a common neurological disease with a major genetic component. Recently, it
has been proposed that a single locus on chromosome 19p13 contributes to the genetic
susceptibility of both rare familial hemiplegic migraine (FHM) and more common
types of migraine, migraine with aura and migraine without aura. We analyzed 16
families for co-segregation of migraine with aura and chromosome 19p13 markers.
Using multipoint model-free linkage analysis, we obtained a lod score of 4.28
near D19S592. Using an affecteds-only model of linkage, we observed a lod score
of 4.79 near D19S592. We were able to provide statistical evidence that this locus
on chromosome 19p13 is most likely not the gene CACNA1A, mutations in which cause
FHM. These data indicate that chromosome 19p13 contains a locus which contributes
to the genetic susceptibility of migraine with aura that is distinct from the
FHM locus. [Abstract]
JC, Kim GW, Dudding KA, Baloh RW
No mutations in CACNA1A
and ATP1A2 in probands with common types of migraine.
Neurol. 2004 Jun;61(6):926-8.
BACKGROUND: Mutations in CACNA1A, encoding a
neuronal calcium channel subunit, and ATP1A2, encoding a catalytic subunit of
a sodium-potassium-ATPase, have been found in some families with dominantly inherited
hemiplegic migraine. OBJECTIVE: To determine the prevalence of mutations in these
genes in individuals with different migraine syndromes. DESIGN: Prospective screening
study. SETTING: University outpatient neurology clinic.Subjects Probands of 19
families with hemiplegic migraine, 7 with basilar migraine, 25 with migraine without
aura, and 18 with migraine with aura, as well as 40 unaffected relatives of probands.
INTERVENTIONS: All known exons and flanking introns of CACNA1A and ATP1A2 were
subjected to denaturing high-performance liquid chromatography analysis of polymerase
chain reaction-amplified genomic DNA. Exons with atypical elution patterns were
sequenced by standard techniques. MAIN OUTCOME MEASURES: Presence of mutations
in CACNA1A and ATP1A2. RESULTS: A single mutation (T666M) was found in CACNA1A
in a patient with hemiplegic migraine and ataxia. No other mutation was identified
in either gene. The frequency of a previously reported intronic insertion in ATP1A2
was not significantly different between patients with migraine and control subjects.
CONCLUSION: These 2 genes are not associated with more common migraine syndromes
and are not the most common hemiplegic migraine genes. [Abstract]
SE, Dyment DA, Cader MZ, Ganapathy R, Brown JD, Rice GP, Ebers GC
with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13.
2002 Oct 8;59(7):1099-101.
Two microsatellite markers, tightly linked to CACNA1A,
were genotyped in migraine with aura (MA) families to determine if this gene,
which underlies the 19p13 linked forms of familial hemiplegic migraine, is also
linked to MA. Two-point parametric lod and nonparametric linkage scores did not
support linkage. Transmission disequilibrium testing provided no evidence for
linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors
did not find evidence to support an MA susceptibility gene in the region of 19p13.
GM, Ophoff RA, van Eijk R, Vergouwe MN, Haan J, Frants RR, Sandkuijl LA, Ferrari
Involvement of the CACNA1A gene containing region
on 19p13 in migraine with and without aura.
2001 Apr 24;56(8):1028-32.
OBJECTIVE: To assess the involvement of the 19p13
familial hemiplegic migraine (FHM) locus in migraine with and without aura. BACKGROUND:
Migraine with and without aura are likely to be polygenetic multifactorial disorders.
FHM is a rare dominantly inherited type of migraine with aura. In about 50% of
families, FHM is caused by mutations in the P/Q-type calcium channel alpha(1A)-subunit
(CACNA1A) gene on chromosome 19p13. The CACNA1A gene is thus a good candidate
gene for "nonhemiplegic" migraine with or without aura. METHODS: The
authors performed an affected sibpair analysis using flanking and CACNA1A intragenic
markers. The authors assessed the occurrence of shared parental marker alleles
among 189 affected siblings from 36 extended families with typical migraine with
or without aura. RESULTS: Sibling pairs with any form of migraine had inherited
the same 19p13 CACNA1A-containing region significantly more frequently than expected
by chance (maximum multipoint lod score = 1.22). This result was almost exclusively
dependent on the increased sharing found in sibling pairs with migraine with aura
(maximum multipoint lod score = 1.41). The locus-specific relative risk for a
sibling (lambda(s)) to suffer from migraine with aura, defined as the increase
in risk of the trait attributable to the 19p13 locus, was lambda(s) = 1.56. When
combining migraine with and without aura, lambda(s) was 1.22. CONCLUSIONS: The
increased allele sharing in the CACNA1A gene region on 19p13 is consistent with
an important involvement of this region in migraine, especially migraine with
DR, Lea RA, Goadsby PJ, Brimage PJ, Griffiths LR
typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity.
Migraine is a frequent familial disorder that, in common
with most multifactorial disorders, has an unknown etiology. The authors identified
several families with multiple individuals affected by typical migraine using
a single set of diagnostic criteria and studied these families for cosegregation
between the disorder and markers on chromosome 19, the location of a mutation
that causes a rare form of familial hemiplegic migraine (FHM). One large tested
family showed both cosegregation and significant allele sharing for markers situated
within or adjacent to the FHM locus. Multipoint GENEHUNTER results indicated significant
excess allele sharing across a 12.6-cM region containing the FHM Ca2+ channel
gene, CACNL1A4 (maximum nonparametric linkage Z score = 6.64, p = 0.0026), with
a maximum parametric lod score of 1.92 obtained for a (CAG)n triplet repeat polymorphism
situated in exon 47 of this gene. The CAG expansion did not, however, appear to
be the cause of migraine in this pedigree. Other tested families showed neither
cosegregation nor excess allele sharing to chromosome 19 markers. HOMOG analysis
indicated heterogeneity, generating a maximum HLOD score of 3.6. It was concluded
that Chr19 mutations either in the CACNL1A4 gene or a closely linked gene are
implicated in some pedigrees with familial typical migraine, and that the disorder
is genetically heterogeneous. [Abstract]
T, Mueller C, Evers S, Zierz S, Deufel T
known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients
with common migraine: implications for genetic testing.
Chem Lab Med. 2003 Mar;41(3):272-5.
Mutations in the gene CACNA1A have been
known to cause familial hemiplegic migraine (FHM); it has been suggested, based
on indirect genetic studies, that this gene may also be involved in common forms
of migraine. To obtain data from direct gene analysis to test this hypothesis,
we investigated 143 patients with common migraine, irrespective of their family
history, for the presence of mutations known to result in the FHM phenotype; the
mutations V714A, R192Q, R583Q, T666M, V1457L, and 11811L were absent in our patient
sample. Furthermore, exons 4, 16, 17, and 36 were completely screened by single-strand
conformation polymorphism (SSCP), and no other, hitherto unknown, mutations were
detected. Bearing in mind that, in particular, the T666M mutation contributes
to a large proportion of FHM linked to chromosome 19, we conclude that common
migraine is distinct from FHM in its molecular basis and, therefore, most likely
also in its pathophysiology. The possibility, however, of the existence of allelic
disorders, with mutations located in other regions of the CACNA1A gene, cannot
be ruled out. Molecular testing, therefore, is at present not a feasible option
for the diagnosis and classification of migraine. [Abstract]
J, van Vliet JA, Kors EE, Terwindt GM, Vermeulen FL, van den Maagdenberg AM, Frants
RR, Ferrari MD
No involvement of the calcium channel
gene (CACNA1A) in a family with cluster headache.
It is very likely that genetic factors play a role
in the pathophysiology of cluster headache (CH). As CH shares its paroxysmal character
with migraine, and migraine has been described in coexistence with CH in some
families, we hypothesized that both diseases might share a genetic aetiology.
In this study, we tested whether the migraine CACNA1A gene on chromosome 19 is
involved in CH in an extended pedigree. Haplotype analysis did not reveal an obvious
disease haplotype, and SSCP analysis of all 47 exons of the CACNA1A gene did not
reveal a causative mutation. CH in this family is not caused by mutations in the
CACNA1A gene. [Abstract]
C, Giedratis V, Ekbom K, Waldenlind E, Hillert J
gene polymorphisms in cluster headache.
Cluster headache (CH) is a primary headache disorder
where the aetiological and pathophysiological mechanisms still are largely unknown.
An increased risk of CH in first- and second-degree relatives suggests the importance
of genetic factors. Mutations of the P/Q type calcium channel alpha 1 subunit
(CACNA1A) gene on chromosome 19p13 have been shown to cause several neurological
disorders with a wide clinical spectrum, mainly episodic diseases. Missense mutations
of the gene cause familial hemiplegic migraine (FHM) and it is also likely to
be involved in the more common forms of migraine. The CACNA1A gene is thus a promising
candidate gene for CH. In this study we performed an association analysis of an
intragenic polymorphic (CA)n-repeat with marker D19S1150 and a (CAG)n-repeat in
the 3'UTR region, in 75 patients with CH according to IHS criteria and 108 matched
controls. Genotypes and allele frequencies were similarly distributed in patients
and controls. Linkage disequilibrium between the two markers was similar in patients
and controls. We conclude that an importance of the CACNA1A gene in sporadic CH
is unlikely. [Abstract]
M, Kallela M, Kaunisto MA, Marttila P, Sobel E, Hartiala J, Oswell G, Leal SM,
Papp JC, Hämäläinen E, Broas P, Joslyn G, Hovatta I, Hiekkalinna T, Kaprio J,
Ott J, Cantor RM, Zwart JA, Ilmavirta M, Havanka H, Färkkilä M, Peltonen L, Palotie
A susceptibility locus for migraine with aura, on
Am J Hum Genet. 2002 Mar;70(3):652-62.
is a complex neurovascular disorder with substantial evidence supporting a genetic
contribution. Prior attempts to localize susceptibility loci for common forms
of migraine have not produced conclusive evidence of linkage or association. To
date, no genomewide screen for migraine has been published. We report results
from a genomewide screen of 50 multigenerational, clinically well-defined Finnish
families showing intergenerational transmission of migraine with aura (MA). The
families were screened using 350 polymorphic microsatellite markers, with an average
intermarker distance of 11 cM. Significant evidence of linkage was found between
the MA phenotype and marker D4S1647 on 4q24. Using parametric two-point linkage
analysis and assuming a dominant mode of inheritance, we found for this marker
a maximum LOD score of 4.20 under locus homogeneity (P=.000006) or locus heterogeneity
(P=.000011). Multipoint parametric (HLOD = 4.45; P=.0000058) and nonparametric
(NPL(all) = 3.43; P=.0007) analyses support linkage in this region. Statistically
significant linkage was not observed in any other chromosomal region. [Abstract]
U, Chiarugi A, Bolay H, Moskowitz MA.OMIM
- Online Mendelian Inheritance in Man: Nuclear
factor-kappaB subunit 1
Nuclear factor-kappaB as a
molecular target for migraine therapy.
Ann Neurol. 2002
Nitric oxide (NO) generated from inducible NO synthase (iNOS)
participates in immune and inflammatory responses in many tissues. The NO donor
glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into
migraineurs and also causes iNOS expression and delayed inflammation within rodent
dura mater. Sodium nitroprusside, an NO donor as well, also increases iNOS expression.
Because inflammation and iNOS are potential therapeutic targets, we examined transcriptional
regulation of iNOS following GTN infusion and the consequences of its inhibition
within dura mater. We show that intravenous GTN increases NO production within
macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor, attenuates
the NO signal, emphasizing the importance of enzymatic activity to delayed NO
production. iNOS expression is preceded by significant nuclear factor kappa B
(NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-kappa-Balpha
(IkappaBalpha) and activation of NF-kappaB after GTN infusion. IkappaBalpha degradation,
NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg),
the active constituent of feverfew, an anti-inflammatory drug used for migraine
treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation
with a time course consistent with migraine attacks in susceptible individuals.
We conclude, based on results with this animal model, that blockade of NF-kappaB
activity provides a novel transcriptional target for the development of anti-migraine
[The NFKB1 gene has been located at 4q23-q24]
Björnsson A, Gudmundsson G, Gudfinnsson E, Hrafnsdóttir
M, Benedikz J, Skúladóttir S, Kristjánsson K, Frigge ML, Kong A, Stefánsson K,
Localization of a gene for migraine without
aura to chromosome 4q21.
Am J Hum Genet. 2003 Nov;73(5):986-93.
is a common form of headache and has a significant genetic component. Here, we
report linkage results from a study in Iceland of migraine without aura (MO).
The study group comprised patients with migraine recruited by neurologists and
from the registry of the Icelandic Migraine Society, as well as through the use
of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses
were made and confirmed using diagnostic criteria established by the International
Headache Society. A genome-wide scan with multipoint allele-sharing methods was
performed on 289 patients suffering from MO. Linkage was observed to a locus on
chromosome 4q21 (LOD=2.05; P=.001). The locus reported here overlaps a locus (MGR1)
reported elsewhere for patients with migraine with aura (MA) in the Finnish population.
This replication of the MGR1 locus in families with MO indicates that the gene
we have mapped may contribute to both MA and MO. Further analysis indicates that
the linkage evidence improves for affected females and, especially, with a slightly
relaxed definition of MO (LOD=4.08; P=7.2 x 10(-6)). [Abstract]
ZM, Noble-Topham S, Dyment DA, Cherny SS, Brown JD, Rice GP, Ebers GC
linkage to migraine with aura on chromosome 11q24.
Mol Genet. 2003 Oct 1;12(19):2511-7.
Migraine with aura (MA) is a prevalent
neurological condition with strong evidence for a genetic basis. Familial hemiplegic
migraine, a rare Mendelian form of MA, can be caused by mutations in the calcium
channel gene, CACNA1A or in the ATP1A2 gene, a Na+/K+ pump. Susceptibility genes
for the more prevalent forms of migraine have yet to be identified despite several
reports of linkage including loci on 4q24, 1q31, 19p13 and Xq24-28. We have undertaken
a genome-wide screen of 43 Canadian families, segregating MA with families chosen
for an apparent autosomal dominant pattern of transmission. Diagnosis was based
upon International Headache Society Criteria. Parametric linkage analysis revealed
a novel locus on 11q24 with a two-point LOD score of 4.2 and a multi-point parametric
LOD score of 5.6. We did not find any support for linkage at previously reported
loci. The lack of consensus amongst linkage studies, including this study, is
probably an indication of the heterogeneity that is inherent for MA. Nevertheless,
the finding of a highly significant locus with a LOD score of 5.6 is powerful
evidence that a gene increasing susceptibility to MA resides on 11q24. Several
candidate genes map to this region of the genome including a number of ion channel
genes such as GRIK4, SCNB2, KCNJ5 and KCNJ1. [Abstract]
BS, Leung K, Meltzer PS, Lewis KA, Wagner-McPherson C, Evans GA, Nabel GJ.
of the gene encoding R kappa B (NFRKB), a tissue-specific DNA binding protein,
to chromosome 11q24-q25.
Genomics. 1992 Oct;14(2):270-4.
NF (nuclear factor)-kappa B binds in vitro to several of the kappa B regulatory
elements found in cellular and viral genes, another DNA binding protein, R kappa
B, also binds to a related variant of the kappa B site that regulates interleukin-2
receptor alpha-chain gene expression, a critical event in T cell activation. Southern
blot analysis of a human-mouse somatic cell hybrid panel and in situ hybridization
using a fluorescent genomic R kappa B probe have allowed assignment of the R kappa
B gene (NFRKB) to 11q24-q25. The NFRKB locus is in close proximity to the chromosomal
breakpoint implicated in Ewing sarcoma, but it does not appear to span this region.
Nonetheless, NFRKB may be particularly useful as the most telomeric marker thus
far assigned to 11q.[Abstract]
T cells expressing IL-2 receptor in migraine.
Neurol (Napoli). 1991 Oct;13(5):448-56.
We studied a group of migraine patients
for circulating immune complexes, lymphocyte subpopulations, IgG4 and anti-IgG
antibodies, before, after 4 hours and after 72 hours a specific challenge test.
We found an increased incidence of circulating immune complexes. Total T cells
showed a marked increase after challenge test. The most important finding was
the presence of T-activated cells. Also K and NK cells showed an early increase
after the challenge. In commenting the outcomes of this investigation, it must
be stressed that the evidence of an early lymphocyte activation after the challenge
test indicates an involvement of interleukin-2 related receptor in food-induced
migraine. The results have reinforced the idea of immune mechanism involvement
in food-induced migraine, but it seems to be localized at different step from
that until now hypothesized, with the involvement of the complex cytokines network.[Abstract]
D, Vettori A, Carraro G, Marchioni E, Vazza G, Bellini S, Tupler R, Savoldi F,
A locus for migraine without aura
maps on chromosome 14q21.2-q22.3.
Am J Hum Genet.
Migraine is a common and disabling neurological disease
of unknown origin characterized by a remarkable clinical variability. It shows
strong familial aggregation, suggesting that genetic factors are involved in its
pathogenesis. Different approaches have been used to elucidate this hereditary
component, but a unique transmission model and causative gene(s) have not yet
been identified. We report clinical and molecular data from a large Italian pedigree
in which migraine without aura (MO) segregates as an autosomal dominant trait.
After exclusion of any association between MO and the known familial hemiplegic
migraine and migraine with aura loci, we performed a genomewide linkage analysis
using 482 polymorphic microsatellite markers. We obtained significant evidence
of linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum
two-point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint
parametric analysis (maximum LOD score of 5.25 between markers D14S976 and D14S978)
and haplotype construction showed strong evidence of linkage in a region of 10
cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3. These
results indicate the first evidence of a genetic locus associated with MO on chromosome
DW, Feniuk W, Humphrey PP.
Characterization of the prostanoid receptor
types involved in mediating calcitonin gene-related peptide release from cultured
rat trigeminal neurones.
Br J Pharmacol. 2001 Nov;134(6):1296-302.
Prostaglandins and the vasodilator neuropeptide, calcitonin-gene related peptide
(CGRP), have both been implicated in the pathogenesis of migraine headache. We
have used primary cultures of adult rat trigeminal neurones to examine the effects
of prostanoids on CGRP release in vitro. 2. CGRP release was stimulated by prostaglandin
E2 (PGE2) and the IP receptor agonist, carbaprostacyclin (cPGI2). These responses
were extracellular calcium-dependent, and the PGE2-induced CGRP release was unaltered
by inhibition of nitric oxide synthase (NOS), ATP receptor blockade, or the addition
of adenosine deaminase. 3. Increases in CGRP levels were also observed in response
to prostaglandin D2 (PGD2), and the EP2 receptor selective agonist, butaprost.
No increases in CGRP release were observed in response to prostaglandin F2alpha
(PGF2alpha) or the TP receptor selective agonist, U46619, or the EP3 receptor
selective agonist, GR63799X. 4. The selective DP receptor antagonist, BWA868C,
antagonized the PGD2-, but not PGE2- or cPGI2-induced release. Furthermore, the
EP1 selective antagonist, ZM325802, failed to antagonize the PGE2-induced CGRP
release from these cells. 5. These data indicate that activation of DP, EP and
IP receptors can each cause CGRP release from trigeminal neurones, and suggest
that the predominant EP receptor subtype involved may be the EP2 receptor. Together
with evidence that the cyclo-oxygenase inhibitor, aspirin, particularly when administered
intravenously is effective in treating acute migraine, these findings further
suggest a role for prostaglandins in migraine pathophysiology." [Abstract]
Mechanisms in adverse reactions to food. The brain.
"Specific chemical mediator release such as histamine
and the prostaglandins (PG2a or PGD2) associated with headaches has been found
in a few patients who were repeatedly challenged with specific foods, using DBPCFC
Site Link: Prostaglandins in Migraine
- Online Mendelian Inheritance in Man: Prostaglandin
E Receptor 2 (EP2)
[The PTGER2 gene has been located at 14q22]
- Online Mendelian Inheritance in Man: Prostaglandin
[The PGDS gene has been located at 14q21-q22]
A, Forsgren L, Nylander PO, Hellman U, Forsman-Semb K, Holmgren G, Holmberg D,
Identification of a susceptibility locus
for migraine with and without aura on 6p12.2-p21.1.
2002 Dec 10;59(11):1804-7.
Migraine is the most common type of chronic episodic
headache. To find novel susceptibility genes for familial migraine with and without
aura, a genomewide screen was performed in a large family from northern Sweden.
Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point
lod score of 5.41 for marker D6S452. The patients with migraine shared a common
haplotype of 10 Mb between markers D6S1650 and D6S1960. [Abstract]
R, Cui L, Yong C, Bowyer S, Klein RM, Welch KM, Berman NE.
spreading depression and gene regulation: relevance to migraine.
Neurol. 2002 Apr;51(4):499-506.
Cortical spreading depression (CSD) may be
the underlying mechanism of migraine aura. The role of CSD in initiating a migraine
headache remains to be determined, but it might involve specific changes in gene
expression in the brain. To examine these changes, four episodes of CSD at 5-minute
intervals were induced in the mouse brain by application of 300mM KCl, and gene
expression was examined 2 hours later using cDNA array and reverse transcriptase-polymerase
chain reaction. Controls consisted of groups that received anesthesia only, attachment
of recording electrodes only, and application of 0.9% NaCl. Of the over 1,180
genes examined in our experiments, those consistently regulated by CSD included
vasoactive peptides; the vasodilator atrial natriuretic peptide was induced by
CSD, while the vasoconstrictor neuropeptide Y was downregulated. Other genes specifically
regulated by CSD were involved in oxidative stress responses (major prion protein,
glutathione-S-transferase-5, and apolipoprotein E). L-type calcium channel mRNA
was upregulated. In summary, CSD regulates genes that are intrinsic to its propagation,
that identify accompanying vascular responses as a potential source of pain, and
that protect against its potential pathological consequences. We believe these
observations have strong relevance to the mechanisms of migraine and its outcomes.
OMIM - Online Mendelian Inheritance in Man: Glutathione
[The Glutathione S-transferase alpha-5 gene has been
located at 6p12.2]
Martelletti P, Lulli P, Morellini M,
Mariani B, Pennesi G, Cappellacci S, Brioli G, Giacovazzo M, Trabace S
6p-encoded HLA-DR2 determination discriminates migraine without aura from migraine
Hum Immunol. 1999 Jan;60(1):69-74.
analysis indicates that migraine without aura (MWoA) and migraine with aura (MWA)
have multifactorial inheritance, but involved genetic and environmental factors
are largely unknown. A controlled study was performed to assess the HLA-driven
liability to migraine and to verify if the heterogeneity between MWoA and MWA
is HLA-linked. Forty-five migraine patients (31 MWoA, 14 MWA) and 53 healthy blood
donors as controls, coming from the same geographic area, were studied. Tissue
typing was performed using the standard complement-dependent microlymphocytotoxicity
technique for HLA Class I and by PCR-SSP (Sequences Specific Primers) typing for
HLA Class II. Data emerging from the present study showed no altered distribution
for HLA Class I A, B, C antigen frequency in migraine (MWoA, MWA) if compared
to the control group. HLA Class II DR2 antigen showed a decreased frequency in
MWA group if compared with both MWoA (p = 0.01) and control group (p = 0.039,
RR = 0.21). These results seem to support the hypothesis of a protective role
of DR2 antigen in MWA and provide additional basis for the proposed difference
within MWoA and MWA. [Abstract]
RA, Shepherd AG, Curtain RP, Nyholt DR, Quinlan S, Brimage PJ, Griffiths LR
typical migraine susceptibility region localizes to chromosome 1q31.
Migraine (with and without aura) is a prevalent neurovascular
disease that shows strong familial aggregation, although the number of genes involved
and the mode of inheritance is not clear. Some insight into the disease has been
gained from genetic studies into a rare and very severe migraine subtype known
as familial hemiplegic migraine (FHM). In this study, we took a family-based linkage
and association approach to investigate the FHM susceptibility region on chromosome
1q31 for involvement in typical migraine susceptibility in affected Australian
pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage
of Chrlq31 markers to typical migraine in a large multigenerational pedigree.
The 1-LOD* unit support interval for suggestive linkage spanned approximately
18 cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782
(P=0.00004). Subsequent analysis of an independent sample of 82 affected pedigrees
added support to the initial findings with a maximum LOD* of 1.24 (P=0.008). Utilising
the independent sample of 82 pedigrees, we also performed a family-based association
test. Results of this analysis indicated distortion of allele transmission at
marker D1S249 [global chi2 (5) of 15.00, P=0.010] in these pedigrees. These positive
linkage and association results will need further confirmation by independent
researchers. However, overall they provide good evidence for the existence of
a typical migraine locus near these markers on Chrlq3l, and reinforce the idea
that an FHM gene in this genomic region may also contribute to susceptibility
to the more common forms of migraine. [Abstract]
K, Barmada MM, Ptacek LJ, Hoffman EP.
A new locus for hemiplegic
migraine maps to chromosome 1q31.
Neurology. 1997 Nov;49(5):1231-8.
single familial hemiplegic migraine locus has been previously mapped to 19p13.1
and associated with mutations in a calcium channel gene (CACNL1A4). We describe
a new 39-member four-generation family from Wyoming of German-Native American
descent with autosomal dominant familial hemiplegic migraine that is not linked
to the chromosome 19p locus. Affected individuals showed a stereotypic pattern
of migrainous headache associated with hemisensory and hemiparetic attacks, without
other headache types. Eighty-three percent reported minor head trauma as a trigger
for individual attacks. Seventy-two percent reported other typical migraine triggers
for the attacks. Attack frequency decreased with age and the overall course was
benign. Genetic linkage studies of this family found strong evidence for the disease
gene in this family being located at chromosome 1q31. Multipoint analysis showed
lod scores > 3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance
and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking
markers, suggested incomplete penetrance and variable expressivity of the disease.
A single affected patient who reports atypical symptoms including daily headaches
likely represents a phenocopy. This new locus for hemiplegic migraine suggests
that mutations of additional calcium channels in the region may cause the disease."
DR, Curtain RP, Griffiths LR
Familial typical migraine:
significant linkage and localization of a gene to Xq24-28.
Genet. 2000 Jul;107(1):18-23.
In a previous study we found evidence for an
X-linked genetic component for familial typical migraine in two large Australian
white pedigrees, designated MF7 and MF14. Significant excess allele sharing was
indicated by nonparametric linkage (NPL) analysis using GENEHUNTER (P=0.031 and
P=0.012, respectively), with a combined analysis of the two pedigrees showing
further increased evidence for linkage, producing a maximum NPL score of 2.87
(P=0.011 ) at DXS 1123 on Xq27. The present study was aimed at refining the localization
of the migraine X-chromosomal component by typing additional markers, performing
haplotype analysis and applying a more powerful technique in the analysis of linkage
data from these two pedigrees. Results from the haplotype analyses, coupled with
linkage analyses that produced a peak GENEHUNTER-PLUS LOD* score of 2.388 (P=0.0005),
provide compelling evidence for the presence of a migraine susceptibility locus
on chromosome Xq24-28. [Abstract]
DR, Dawkins JL, Brimage PJ, Goadsby PJ, Nicholson GA, Griffiths LR
for an X-linked genetic component in familial typical migraine.
Mol Genet. 1998 Mar;7(3):459-63.
Migraine is a common complex disorder that
shows strong familial aggregation. There is a general increased prevalence of
migraine in females compared with males, with recent studies indicating that migraine
affects 18% of females compared with 6% of males. This preponderance of females
among migraine sufferers coupled with evidence of an increased risk of migraine
in first degree relatives of male probands but not in relatives of female probands
suggests the possibility of an X-linked dominant gene. We report here the localization
of a typical migraine susceptibility locus to the X chromosome. Of three large
multigenerational migraine pedigrees two families showed significant excess allele
sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from
all three pedigrees gave significant evidence in support of linkage and heterogeneity
(HLOD = 3.1). These findings provide conclusive evidence that familial typical
migraine is a heterogeneous disorder. We suggest that the localization of a migraine
susceptibility locus to the X chromosome could in part explain the increased risk
of migraine in relatives of male probands and may be involved in the increased
female prevalence of this disorder. [Abstract]
EJ, Van Baal C, Gaist D, Kallela M, Kaprio J, Svensson DA, Nyholt DR, Martin NG,
MacGregor AJ, Cherkas LF, Boomsma DI, Palotie A
and environmental influences on migraine: a twin study across six countries.
Res. 2003 Oct;6(5):422-31.
Migraine is a common neurovascular brain disorder
that is manifested in recurrent episodes of disabling headache. The aim of the
present study was to compare the prevalence and heritability of migraine across
six of the countries that participate in GenomEUtwin project including a total
number of 29,717 twin pairs. Migraine was assessed by questionnaires that differed
between most countries. It was most prevalent in Danish and Dutch females (32%
and 34%, respectively), whereas the lowest prevalence was found in the younger
and older Finnish cohorts (13% and 10%, respectively). The estimated genetic variance
(heritability) was significant and the same between sexes in all countries. Heritability
ranged from 34% to 57%, with lowest estimates in Australia, and highest estimates
in the older cohort of Finland, the Netherlands, and Denmark. There was some indication
that part of the genetic variance was non-additive, but this was significant in
Sweden only. In addition to genetic factors, environmental effects that are non-shared
between members of a twin pair contributed to the liability of migraine. After
migraine definitions are homogenized among the participating countries, the GenomEUtwin
project will provide a powerful resource to identify the genes involved in migraine.
V, Gervil M, Kyvik KO, Olesen J, Russell MB
of migraine with aura estimated by means of structural equation modelling.
Med Genet. 1999 Mar;36(3):225-7.
Studies of migraine with aura (MA) have shown
familial aggregation of the disorder, which cannot be explained by simple mendelian
inheritance. The interest in a genetic basis for the disorder has increased after
identification of three genetic loci for familial hemiplegic migraine (FHM), which
is a rare subtype of MA with autosomal dominant inheritance. Both genetic and
environmental factors seem to be important in the expression of MA. To elucidate
the molecular pathogenesis of MA, knowledge of the relative role of genetic and
environmental factors is essential. Twin studies are a classic way to analyse
this. We applied structural equation modelling on MA with twin data obtained from
a population based twin register in order to evaluate the effects of genes and
environment. The correlation in liability of MA was 0.68 in monozygotic (MZ) and
0.22 in dizygotic (DZ) twin pairs, indicating a high degree of genetic determination
in the total variance of liability. The best fitting model combined additive genetic
effects and environmental effects that were not shared by the twins. The estimate
of heritability was 0.65 and similar in males and females. [Abstract]
M, Ulrich V, Kyvik KO, Olesen J, Russell MB
without aura: a population-based twin study.
Neurol. 1999 Oct;46(4):606-11.
To investigate the importance of genetic and
environmental factors to the etiology of migraine without aura and to compare
the symptomatology of migraine without aura in monozygotic and dizygotic twins,
2,680 twin pairs were recruited from the population-based Danish Twin Registry.
Monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs, where at least one twin
had self-reported migraine or self-reported severe headache with accompanying
symptoms, were telephone interviewed by a physician. The participation rate in
the telephone interview was 90%. The pairwise concordance rate was significantly
higher in MZ than in DZ twin pairs (28% vs 18%). The probandwise concordance rate
was 40% (95% CI, 33-48%) in MZ and 28% (95% CI, 23-33%) in DZ twin pairs. The
pairwise concordance rates for the different pain characteristics and accompanying
symptoms were not significantly different in MZ and DZ twin pairs. However, comparing
all of the pairwise concordance rates of pain characteristics and accompanying
symptoms together, MZ twin pairs were significantly more concordant than DZ twin
pairs. Our data demonstrate a significant genetic factor in migraine without aura.
The size of this factor is modest and the demonstration of susceptibility genes
is predicted to be laborious and difficult. [Abstract]
V, Russell MB, Ostergaard S, Olesen J
31 families with an apparently autosomal-dominant transmission of migraine with
aura in the nuclear family.
Am J Med Genet. 1997
We analyzed 31 families selected for an apparently autosomal-dominant
mode of inheritance of migraine with aura (MA) in the nuclear family. The nuclear
families were expanded with first- and second-degree relatives. All interviews
were made by physicians experienced in headache diagnoses. The criteria of the
International Headache Society were used. The population relative risk among children
in nuclear families was similar to the estimated population relative risk of MA
assuming an autosomal-dominant mode of inheritance. The population relative risk
tended to decrease among first-degree relatives outside nuclear families and further
among second-degree relatives. Both first- and second-degree relatives outside
the nuclear families had a statistically significant lower risk of MA than expected.
Thus, autosomal-dominant inheritance with or without reduced penetrance was unlikely.
Autosomal-recessive inheritance was unlikely because of the unequal sex distribution.
Other modes of inheritance were considered as well. Mitochondrial and X-linked
inheritance were excluded because of paternal transmission. The female preponderance
was too low to explain sex-influenced inheritance. We conclude that MA most likely
has a multifactorial inheritance even in high-risk families with MA. [Abstract]
MB, Iselius L, Olesen J
Migraine without aura and
migraine with aura are inherited disorders.
The familial occurrence and mode of inheritance were
analysed in families with migraine without aura (MO) and migraine with aura (MA).
The probands were found among 4000 persons from the general population. All persons
with MA were included as probands, and an equivalent number of probands with MO
was selected as a random sample among those with MO. Spouses and first-degree
relatives were blindly interviewed. All interviews were performed by one neurological
research fellow. The distinct familial patterns indicate that MO and MA have a
different aetiology. Compared with the general population, the first-degree relatives
of probands with MO had a 1.9-fold increased risk of MO while spouses had a 1.5-fold
increased risk of MO, indicating that both genetic and environmental factors are
important in MO. The first-degree relatives of probands with MA had a four-fold
increased risk of MA while spouses had no increased risk of MA, indicating that
MA is determined largely by genetic factors. The complex segregation analysis
indicated that both MO and MA have multifactorial inheritance without generational
RA, Hilton DA, MacMillian JC, Griffiths LR
of clinical characteristics in genetically linked migraine-affected pedigrees.
Migraine is a common complex disorder characterized
by severe recurrent headache and usually accompanied by nausea and vomiting. Previous
studies in our laboratory have utilized three large multigenerational Australian
pedigrees affected with migraine to indicate that the disease is genetically heterogeneous,
with linkage results implicating genomic susceptibility regions on both chromosomes
19p and Xq. The present study explores the possibility of a correlation between
genetic and clinical heterogeneity in these affected pedigrees. Specifically,
the clinical characteristics of migraine including subtype, age of onset, frequency,
duration, and disease symptoms were compared between the migraine pedigrees, and
gender differences were also assessed. Our exploratory analyses revealed no significant
differences in any of the clinical characteristics tested between the chromosome
19-linked family and the two X-linked families. Also, we did not detect any differences
in male vs. female clinical features for these pedigrees. In conclusion, migraine
is considered to be a clinically and genetically heterogeneous disorder; however,
our study provided no conclusive evidence that variation in genomic susceptibility
region is related to heterogeneity at the clinical level in these migraine-affected
MB, Ulrich V, Gervil M, Olesen J
aura and migraine with aura are distinct disorders. A population-based twin survey.
OBJECTIVE: To investigate the co-occurrence of migraine
without aura (MWOA) and migraine with aura (MWA) in a population-based twin survey.
BACKGROUND: Migraine without aura and MWA are multifactorial disorders. If MWOA
and MWA share common genes, co-occurrence should be observed more frequently than
expected, ie, the product of the prevalence in the general population. MATERIAL
AND METHODS: The study population included all living Danish monozygotic (MZ)
and same-gender dizygotic (DZ) twin pairs born between 1953 and 1960: 5360 twins
(2026 MZ, 3334 DZ). The sample included 2840 men and 2520 women. All received
a posted questionnaire, and those with possible migraine were interviewed via
telephone by trained physicians (V.U. or M.G.). Twins who did not respond to the
questionnaire and who had a co-twin with possible migraine were contacted by telephone.
The questionnaire response rate was 87% (4660 of 5360), and the telephone interview
was participated in by 90% (2035 of 2272). The physician interviewers were unaware
of questionnaire answers, zygosity, and the clinical diagnosis of the co-twin.
The criteria of the International Headache Society were used to establish a diagnosis
of migraine. RESULTS: Lifetime prevalence in the twin sample: 7% of men and 19%
of women had MWOA, while 7% of men and 8% of women had MWA. Lifetime prevalence
of MWA in twin pairs with MWOA: MZ men, 2% (1 of 47); MZ women, 6% (5 of 90);
DZ men, 9% (7 of 75); and DZ women, 10% (19 of 182). Lifetime prevalence of MWOA
in twin pairs with MWA: MZ men, 3% (1 of 33); MZ women, 5% (3 of 58); DZ men,
9% (4 of 44); and DZ women, 13% (10 of 76). The observed and the expected numbers
of twins with co-occurrence of MWOA and MWA based on the prevalence in the general
population were not significantly different in either men or women (men, P=.1
and women, P=.5). CONCLUSION: The results strongly suggest that MWOA and MWA are
distinct disorders, and identification of common genes for MWOA and MWA, thus,
should not be expected to result from future genetic research. [Abstract]
M, Wessman M, Havanka H, Palotie A, Färkkilä M
migraine with and without aura: clinical characteristics and co-occurrence.
J Neurol. 2001 Sep;8(5):441-9.
Migraine with aura (MwA) and migraine without
aura (MwoA) are the two common forms of migraine. Many migraine patients suffer
from both kinds of attacks. In a questionnaire-based study using the current International
Headache Society (IHS) criteria we determined the clinical characteristics and
occurrence of MwA + MwoA in 1000 migraine patients belonging to 210 Finnish migraine
families. Nine hundred and six patients were able to indicate whether they suffered
from MwA (but not MwoA), migraine aura without headache (migraine equivalent)
(but not MwA) or MwA and MwoA. Of these patients, 3.2% had experienced MwoA, 11.1%
MwA, 40.6% MwA + MwoA, 23.5% MwoA and 20.3% MwA-like symptoms not meeting the
IHS criteria. The high prevalence of MwA attacks in the families studied supports
the belief that aura has a strong hereditary component. The MwA + MwoA patients
had significantly more severe attacks, more typical headache and more prodromal
symptoms than the MwA and MwoA subjects. Therefore, it is possible that there
is a continuum with pure MwA at the neural and pure MwoA at the headache end of
the spectrum, and MwA + MwoA lying in between the two. The MwA + MwoA patients
would thus be liable to both types of migraine, making their attacks more characteristic
and more severe. This would also explain why the co-occurrence of MwA and MwoA
is more common in the clinic compared with population based epidemiological studies.
These findings have consequences for future research on liability genes for migraine.
M, Wessman M, Färkkilä M, Palotie A, Koskenvuo M, Honkasalo ML, Kaprio J
characteristics of migraine in a population-based twin sample: similarities and
differences between migraine with and without aura.
OBJECTIVE: To look into clinical differences between
migraine with and without aura in a population-based sample of migraineurs. BACKGROUND:
Migraine presents in two major forms, migraine with and migraine without aura.
With the exception of the aura phase, the clinical characteristics of these entities
are very similar. Despite this, however, the recent epidemiological data underline
differences between migraine with and without aura. We tried to examine whether
other features besides the aura differ between these two major forms of migraine.
METHODS: We studied 321 twins suffering from migraine with aura and 166 twins
with migraine without aura from the population-based Finnish Twin Cohort. Migraine
was diagnosed according to the criteria of the International Headache Society
(IHS). Analysis was based on the combination of a mailed questionnaire and a telephone
interview by a neurologist. Special attention was paid to differences between
migraine with and without aura. RESULTS: Some qualities of headaches differed
between IHS defined migraine with and without aura. Unilateral headache (Chi-squared
p = 0.039) and photophobia (Chi-squared p = 0.010) were more typical for migraine
with aura, while nausea was more typical for migraine without aura (Chi-squared
p = 0.002). Duration of headache in migraine without aura was also longer than
in migraine with aura (Mann-Whitney U-test 0.007). CONCLUSIONS: There are clinical
differences between IHS defined migraine with and without aura; even the headache
phase between the two entities differs. It is worthwhile distinguishing between
them when looking for the elusive genes for these more common forms of migraine.
DR, Gillespie NG, Heath AC, Merikangas KR, Duffy DL, Martin NG
class and genetic analysis does not support migraine with aura and migraine without
aura as separate entities.
Genet Epidemiol. 2004
Latent class and genetic analyses were used to identify subgroups
of migraine sufferers in a community sample of 6,265 Australian twins (55% female)
aged 25-36 who had completed an interview based on International Headache Society
(IHS) criteria. Consistent with prevalence rates from other population-based studies,
703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine
without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied
the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent
class analysis (LCA) of IHS symptoms identified three major symptomatic classes,
representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately
severe form of migraine, typically without visual aura symptoms (although 40%
of individuals in this class were positive for aura), and 3) a severe form of
migraine typically with visual aura symptoms (although 24% of individuals were
negative for aura). Using the LCA classification, many more individuals were considered
affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore,
genetic model fitting indicated a greater genetic contribution to migraine using
the LCA classification (heritability, h(2)=0.40; 95% CI, 0.29-0.46) compared with
the IHS classification (h(2)=0.36; 95% CI, 0.22-0.42). Exploratory latent class
modeling, fitting up to 10 classes, did not identify classes corresponding to
either the IHS MO or MA classification. Our data indicate the existence of a continuum
of severity, with MA more severe but not etiologically distinct from MO. In searching
for predisposing genes, we should therefore expect to find some genes that may
underlie all major recurrent headache subtypes, with modifying genetic or environmental
factors that may lead to differential expression of the liability for migraine.
V, Gervil M, Olesen J
The relative influence of environment
and genes in episodic tension-type headache.
2004 Jun 8;62(11):2065-9.
OBJECTIVE: To examine the relative importance of
genetic and environmental influence for the development of tension-type headache
by analyses of twins. METHODS: The authors screened by questionnaire a population
of 5,360 twins born during 1953 to 1960 from the general population for migraine
and headache symptoms. The response rate of the questionnaire was 87%. All twin
pairs with at least one twin of the pair reporting migraine or headache symptoms
were interviewed by telephone by a physician. Correlation of liability and structural
equation modeling were applied on tension-type headache. RESULTS: A total of 1,417
subjects had tension-type headache equivalent to a 1-year prevalence of 62%. The
male: female ratio was 1:1.24. Chronic tension-type headache was found in 49 twins
corresponding to a prevalence of 2% with a male:female ratio of 1:1.21. The prevalence,
pain characteristics, frequency, and duration of tension-type headache were similar
to what has been found in the general Danish population. The correlation of liability
of tension-type headache was low and not significantly different in monozygotic
and dizygotic twin pairs: 0.21 (0.03 to 0.39), 0.08 (0 to 0.24). The best fitting
model of phenotypic variation consisted of 81% non-shared environmental effects
and of 19% additive genetic effects. CONCLUSIONS: Environmental influence is of
major importance for episodic tension-type headache and a genetic factor, if it
exits, is minor. In chronic tension-type headache the genetic factor may be more
important. These data clearly separate episodic tension-type headache from migraine
without aura where the phenotypic variation consists of non-shared environmental
effects of 39% and of 61% additive genetic effects. [Abstract]
L, Mochi M, Valentino ML, Arnaldi C, Cortelli P, De Monte A, Pierangeli G, Prologo
G, Scapoli C, Soriani S, Montagna P
migraine genes: exclusion of 290 cM out of the whole human genome.
J Neurol Sci. 1997 Oct;18(5):277-82.
A linkage and association analysis was
made on 14 Italian families with recurrent migraine. We analyzed five chromosomal
regions surrounding the candidate genes 5HT1D (1p36.3-34.3), 5HT1B (6q13), 5HT2A
(13q14-21), 5HT transporter (17q11.2-12), CACNLB1 (17q11.2-22) and FHM (19p13),
using 29 DNA polymorphic markers. All two-point lod scores were negative, and
the chi 2 sib-pair analyses were not significant, thus indicating the probable
exclusion of these regions as sites of migraine genes in our population. [Abstract]
I, Salani G, Valfrč W, Savi L, Rivoiro C, Ferrero M, Pinessi L, Grimaldi LM
of linkage between the interleukin-6 gene (-174 G/C) polymorphism and migraine.
Lett. 2003 Jun 12;343(3):155-8.
To assess the role of interleukin-6 (IL-6)
in migraine, we analyzed the -174 G/C IL-6 gene polymorphism in 268 patients with
migraine and 305 controls. No significant difference in the distribution of IL-6
genotypes (chi(2)=0.601, P=0.74) and allelic frequencies (chi(2)=0.024, P=0.876)
was found. When patients were subdivided into subgroups (migraine with aura, migraine
without aura and mixed headaches), IL-6 alleles were similarly distributed. Comparison
of the clinical features of the disease with the -174 G/C IL-6 genotypes showed
no significant difference. In conclusion, we found no significant association
between the -174 G/C IL-6 polymorphism and the occurrence or the clinical features
of migraine. [Abstract]
T, Fukuhara Y, Adachi Y, Ishizaki K, Kusumi M, Kowa H, Iigaya M, Sakai F, Nakashima
Leukocyte mitochondrial DNA A to G polymorphism
at 11084 is not a risk factor for Japanese migraineurs.
Mitochondrial dysfunction has been reported in patients
with migraine. We investigated leukocyte mitochondrial DNA 11084 A to G polymorphism
in 166 Japanese migraineurs and 483 Japanese controls. The migraine group consisted
of 43 patients suffering from migraine with aura (MWA) and 123 from migraine without
aura (MOA). The frequency of the transition was 7.2% (12/166) in the migraine
group and 7.3% (35/483) in the controls. The frequency of the transition was 4.7%
in MWA and 8.1% in MOA. There was no significant difference among the groups (chi-square
test). The mitochondrial DNA 11084 A to G transition was more common in Japanese
subjects than reported in Caucasians; however, this polymorphism is not a genetic
risk factor for migraine in Japanese patients. [Abstract]
I, Grimaldi LM, Salani G, Valfrč W, Savi L, Rivoiro C, Gentile S, Pinessi L
E gene polymorphisms in patients with migraine.
Lett. 2002 Jan 11;317(2):111-3.
To investigate the role of apolipoprotein E
(APOE) polymorphisms in migraine, we analyzed the APOE genotypes of 241 migraine
patients and 587 controls. The results of a Chi-square analysis indicated that
APOE alleles were similarly distributed (chi(2)=2.89, P=0.24) between cases and
controls. However, we found a significant (P<0.001) increase of the varepsilon2-varepsilon4
genotype in the group of migraine patients. Patients were divided into three subgroups:
migraine with aura; migraine without aura; and mixed headaches (migraine associated
with tension-type headache). Subgroup analysis showed that the varepsilon2-varepsilon4
genotype was significantly increased only in patients with mixed headaches. The
stratification of patients by APOE status did not reveal significant associations
with the clinical features of the disease. In conclusion, we observed no significant
association between APOE polymorphisms and migraine. The association between the
APOE varepsilon2-varepsilon4 genotype and the tension-type headache deserves further
JA, Corral J, González-Conejero R, Díaz Ortuńo A, Martínez Navarro ML, Vicente
Role of factor XIII Val 34 Leu polymorphism in patients
Cephalalgia. 2001 Oct;21(8):837-41.
present, it is contradictory to determine if the combination of certain prothrombotic
polymorphisms and migraine increases the risk to develop ischaemic cerebrovascular
disease. Recently, the common Val34Leu polymorphism of the A-chain factor XIII
gene, associated with variations in factor XIII activity, has been suggested to
play a significant role in the development of arterial and venous thrombotic disorders.
We analysed the prevalence of this polymorphism in 17 patients with coexisting
ischaemic cerebrovascular disease and migraine (5 with aura, and 12 without aura),
89 patients with migraine (43 with aura, and 46 without aura), 116 patients with
ischaemic cerebrovascular disease, and 467 healthy Caucasian controls from the
South of Spain. Genomic PCR amplification, using a mutated oligonucleotide, and
allele-specific restriction assays were used for genotyping. The factor XIII Leu
34 variant was present in 47.1; 40.5; 34.9; and 35.1% of patients with coexisting
ischaemic cerebrovascular disease and migraine, ischaemic cerebrovascular disease,
migraine, and control subjects, respectively. These data suggest that the factor
XIII Leu 34 allele does not play a protective role against these disorders in
our population. [Abstract]
RA, Curtain RP, Shepherd AG, Brimage PJ, Griffiths LR
evidence for involvement of the human inducible nitric oxide synthase (iNOS) gene
in susceptibility to typical migraine.
Am J Med Genet.
2001 Jan 8;105(1):110-3.
Migraine is a debilitating disorder affecting approximately
12% of Caucasian populations. The disease has a large genetic component, although
at present the type and number of genes involved is unclear. Candidate gene studies
may be useful strategies for identifying genes involved in complex diseases such
as migraine, especially if the gene being examined contributes only a minor effect
to the overall phenotype. Nitric oxide (NO) is emerging as a key molecule affecting
the pain associated with migraine. Since NO synthase (NOS) enzymes catalyze the
synthesis of NO, the genes that code for these enzymes are good candidates for
migraine molecular genetic analysis. This study investigated the role of a functionally
relevant bi-allelic tetranucleotide polymorphism located in the promoter region
of the human inducible nitric oxide synthase (iNOS) gene in migraine etiology.
A large group of migraine affected individuals (n = 261) were genotyped and compared
with an age- and sex-matched group of unaffected controls (n = 252). Results of
a chi-squared analysis indicated that allele distributions for both migraine cases
and controls were not significantly different (chi2 = 1.93, P = 0.16). These findings
offer no evidence for an allelic association of the tested iNOS polymorphism with
the common forms of the disease and therefore do not support a role for this gene
in migraine pathogenesis. [Abstract]
Gennaro G, Buzzi MG, Ciccarelli O, Santorelli FM, Pierelli F, Fortini D, D'Onofrio
M, Costa A, Nappi G, Casali C
Assessing the relative
incidence of mitochondrial DNA A3243G in migraine without aura with maternal inheritance.
OBJECTIVE: To determine whether patients with migraine
without aura with maternal "inheritance" are affected by a monosymptomatic
form of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis,
and strokelike episodes) or carry the most common mitochondrial DNA (mtDNA) mutation
associated with MELAS, namely the A3243G transition in the transfer RNA (tRNA)Leu(UUR)
gene. BACKGROUND: The association between migraine and abnormal mitochondrial
function has been suggested on clinical, biochemical, and neuroradiological grounds.
Migraine attacks with vomiting and cerebral infarctions, most often in the posterior
cerebral regions, which are reminiscent of complicated migraine, are typical features
of MELAS. The observation that migrainous patients have affected mothers more
often than affected fathers suggests a possible role for maternally transmitted
genetic factors. METHODS: We studied 25 patients with migraine with aura whose
mothers were also affected. A sensitive polymerase chain reaction restriction
fragment length polymorphism analysis was used to detect mutated genomes. CONCLUSIONS:
We failed to detect the MELAS mutation, but migraine may still be associated with
point mutations of mtDNA other than A3243G or with as-yet-unidentified nuclear
DNA factors related to mitochondrial function. [Abstract]
J, Terwindt GM, Maassen JA, Hart LM, Frants RR, Ferrari MD
for mitochondrial DNA mutations in migraine subgroups.
It has been suggested that mitochondrial mutations cause
migraine(-like) symptoms. The presence of mtDNA mutations (3243, 3271, 11084,
and deletions) was investigated in three migraine subgroups (maternally transmitted
migraine with and without aura, migrainous infarction, and nonfamilial hemiplegic
migraine). No mutations were found. These mutations and deletions probably are
not involved in the migraine subgroups studied, although an investigation of other
material (e.g., muscle tissue) would have shown this with more certainty. [Abstract]
MB, Diamant M, Nřrby S
Genetic heterogeneity of migraine
with and without aura in Danes cannot be explained by mutation in mtDNA nucleotide
Acta Neurol Scand. 1997 Sep;96(3):171-3.
Migraine is a genetic heterogeneous disorder. The 11084 A to G base substitution
is in the gene for the ND4 subunit of the respiratory complex I, and leads to
a Thr to Ala amino acid replacement. This mutation had been found in 25% of Japanese
migraineurs, while tension-type headache sufferers and non-migraineurs did not
have it. MATERIAL AND METHODS: We investigated the importance of this mutation
in Danish migraineurs without aura, migraineurs with aura and non-migraineurs
from the general population. RESULTS: We did not detect this mutation in Danes.
CONCLUSION: Our result excludes a significant role of this mutation in the etiology
of migraine in Denmark, and its absence in non-migraineurs supports that this
mutation is rare in non-Japanese populations. [Abstract]
T, May A, Seibel P, Papagiannuli E, Diener HC, Reichmann H
DNA in migraine with aura.
Neurology. 1996 Jun;46(6):1735-8.
and the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like
episodes) syndrome have some clinical features in common. First, cerebral infarctions,
most often in the posterior cerebral regions, which are a main symptom of MELAS,
may complicate migraine. Second, migrainous headache with vomiting is also a characteristic
feature of the MELAS syndrome. Less frequently, hemicranial headache is present
in another mitochondrial disease, myoclonic epilepsy with ragged-red fibers (MERRF).
Moreover, there is a mild bias toward maternal transmission in migraine. Apart
from clinical resemblance, there is some experimental evidence for mitochondrial
dysfunction in migraine. There may be depression of respiratory chain enzyme activity
in muscle and platelets, and magnetic resonance spectroscopy has revealed a defective
energy metabolism in brain and muscle of migraine patients. There has not been
a systematic study of mitochondrial DNA in migraine, however. We therefore analyzed
the mitochondrial DNA in lymphocytes of 23 migraine patients with aura. Southern
blot and polymerase chain reaction analysis of mitochondrial DNA failed to detect
any large-scale deletions or point mutations at base pair 3243 (MELAS) and base
pair 8344 (MERRF). Our data show that deletions of mitochondrial DNA and the most
frequent point mutations of MELAS and MERRF syndromes are not common in migraine
with aura. In particular, these data do not support the hypothesis that some cases
of migraine may be monosymptomatic forms of a MELAS syndrome. We cannot exclude,
however, that migraine may be associated with different point mutations of mitochondrial
DNA or with mutations of autosomally coded respiratory chain subunit genes. [Abstract]
P, Bjelfman C, Lundberg PO, Rane A
2D6 and glutathione S-transferase M1 genotypes and migraine.
J Clin Invest. 2000 Apr;30(4):367-71.
BACKGROUND: Migraine is thought to be
a disease of the brain and trigeminovascular system. Migraine patients often claim
that stress, food, and beverages trigger their attacks. Chemical substances in
these foodstuffs with the property of triggering migraine attacks have not yet
been characterised. Cytochrome P450 2D6 (CYP2D6) and glutathione S-transferase
M1 (GSTM1) are thought to be present in the brain. They metabolise numerous environmental
compounds. The genes exhibit genetic polymorphism that is associated with altered
enzyme activity. The aim of this study was to determine if the genotypes of these
two enzymes are associated with migraine. MATERIALS AND METHODS: The study included
100 female patients and 245 female controls from the general population. Genomic
DNA was isolated from whole blood. Allele specific PCR methods were used to identify
the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4 alleles. Initially
all samples were genotyped only for GSTM1 plus (+) and GSTM1 null (-) variants.
All samples positive for GSTM1 were further analysed for the presence of allelic
variants GSTM1*A and GSTM1*B. RESULTS: None of the CYP2D6 and GSTM1 genotypes
was associated with migraine. We observed an odds ratio (OR) for the poor metaboliser
genotype of CYP2D6 of 1.4 (95% CI = 0.5-3.6) and for the GSTM1 null genotype of
1.0 (95% CI = 0.6-1.5). CONCLUSION: The results of this study indicate that deficient
metabolism because of mutated CYP2D6 alleles or GSTM1 allele variants is not important
in the aetiology of migraine. [Abstract]