|
Estevez M, Gardner KL Update on
the genetics of migraine. Hum Genet. 2004 Feb;114(3):225-35. The
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.
[Abstract] Kors
EE, Vanmolkot KR, Haan J, Frants RR, van den Maagdenberg AM, Ferrari MD Recent
findings in headache genetics. Curr Opin Neurol.
2004 Jun;17(3):283-8. 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] Rainero
I, Grimaldi LM, Salani G, Valfrè W, Rivoiro C, Savi L, Pinessi L Association
between the tumor necrosis factor-alpha -308 G/A gene polymorphism and migraine. Neurology.
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] Trabace
S, Brioli G, Lulli P, Morellini M, Giacovazzo M, Cicciarelli G, Martelletti P Tumor
necrosis factor gene polymorphism in migraine. Headache.
2002 May;42(5):341-5. 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.
[Abstract] Lea
RA, Ovcaric M, Sundholm J, MacMillan J, Griffiths LR The
methylenetetrahydrofolate reductase gene variant C677T influences susceptibility
to migraine with aura. BMC Med. 2004 Feb 12;2(1):3. BACKGROUND:
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.
[Abstract] On
Site Link: Migraine with Aura and Homocysteine
Derivatives Oterino A, Valle N, Bravo Y, Muñoz P, Sánchez-Velasco
P, Ruiz-Alegría C, Castillo J, Leyva-Cobián F, Vadillo A, Pascual J MTHFR
T677 homozygosis influences the presence of aura in migraineurs. Cephalalgia.
2004 Jun;24(6):491-4. 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] Kara
I, Sazci A, Ergul E, Kaya G, Kilic G Association of
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] Kowa
H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K The
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. [1995] 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] Colson
NJ, Lea RA, Quinlan S, MacMillan J, Griffiths LR The
estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility
in two independent case/control groups. Neurogenetics.
2004 Jun;5(2):129-33. 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] Tzourio
C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alpérovitch A Association
between migraine and endothelin type A receptor (ETA -231 A/G) gene polymorphism. Neurology.
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] Paterna
S, Di Pasquale P, D'Angelo A, Seidita G, Tuttolomondo A, Cardinale A, Maniscalchi
T, Follone G, Giubilato A, Tarantello M, Licata G Angiotensin-converting
enzyme gene deletion polymorphism determines an increase in frequency of migraine
attacks in patients suffering from migraine without aura. Eur
Neurol. 2000;43(3):133-6. 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] Rainero
I, Pinessi L, Salani G, Valfrè W, Rivoiro C, Savi L, Gentile S, Giudice RL, Grimaldi
LM A polymorphism in the interleukin-1alpha gene influences
the clinical features of migraine. Headache. 2002
May;42(5):337-40. 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] Kusumi
M, Ishizaki K, Kowa H, Adachi Y, Takeshima T, Sakai F, Nakashima K Glutathione
S-transferase polymorphisms: susceptibility to migraine without aura. Eur
Neurol. 2003;49(4):218-22. 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] Erdal
ME, Herken H, Yilmaz M, Bayazit YA Association of
the T102C polymorphism of 5-HT2A receptor gene with aura in migraine. J
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] On
Site Link: Migraine with Aura and 5-HT2A Receptors Nyholt
DR, Curtain RP, Gaffney PT, Brimage P, Goadsby PJ, Griffiths LR Migraine
association and linkage analyses of the human 5-hydroxytryptamine (5HT2A) receptor
gene. Cephalalgia. 1996 Nov;16(7):463-7. 5-Hydroxytryptamine
(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.
[Abstract] Kusumi
M, Araki H, Ijiri T, Kowa H, Adachi Y, Takeshima T, Sakai F, Nakashima K Serotonin
2C receptor gene Cys23Ser polymorphism: a candidate genetic risk factor of migraine
with aura in Japanese population. Acta Neurol Scand.
2004 Jun;109(6):407-9. 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.
[Abstract] Johnson
MP, Lea RA, Curtain RP, MacMillan JC, Griffiths LR An
investigation of the 5-HT2C receptor gene as a migraine candidate gene. Am
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] Burnet
PW, Harrison PJ, Goodwin GM, Battersby S, Ogilvie AD, Olesen J, Russell MB Allelic
variation in the serotonin 5-HT2C receptor gene and migraine. Neuroreport.
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] Buchwalder
A, Welch SK, Peroutka SJ Exclusion of 5-HT2A and 5-HT2C
receptor genes as candidate genes for migraine. Headache.
1996 Apr;36(4):254-8. 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] Racchi
M, Leone M, Porrello E, Rigamonti A, Govoni S, Sironi M, Montomoli C, Bussone
G Familial migraine with aura: association study with
5-HT1B/1D, 5-HT2C, and hSERT polymorphisms. Headache.
2004 Apr;44(4):311-7. 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] Juhasz
G, Zsombok T, Laszik A, Gonda X, Sotonyi P, Faludi G, Bagdy G Association
analysis of 5-HTTLPR variants, 5-HT2a receptor gene 102T/C polymorphism and migraine. J
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] Juhasz
G, Zsombok T, Laszik A, Jakus R, Faludi G, Sotonyi P, Bagdy G Despite
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. Neurosci
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] Kotani
K, Shimomura T, Shimomura F, Ikawa S, Nanba E A polymorphism
in the serotonin transporter gene regulatory region and frequency of migraine
attacks. Headache. 2002 Oct;42(9):893-5. BACKGROUND:
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] Yilmaz
M, Erdal ME, Herken H, Cataloluk O, Barlas O YA Significance
of serotonin transporter gene polymorphism in migraine. J
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.
[Abstract] Ogilvie
AD, Russell MB, Dhall P, Battersby S, Ulrich V, Smith CA, Goodwin GM, Harmar AJ,
Olesen J Altered allelic distributions of the serotonin
transporter gene in migraine without aura and migraine with aura. Cephalalgia.
1998 Jan;18(1):23-6. 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] Mochi
M, Cevoli S, Cortelli P, Pierangeli G, Soriani S, Scapoli C, Montagna P A
genetic association study of migraine with dopamine receptor 4, dopamine transporter
and dopamine-beta-hydroxylase genes. Neurol Sci.
2003 Feb;23(6):301-5. 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.
[Abstract] Lea
RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR Evidence
for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility
to typical migraine. Neurogenetics. 2000 Sep;3(1):35-40. Migraine
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] Emin
Erdal M, Herken H, Yilmaz M, Bayazit YA Significance
of the catechol-O-methyltransferase gene polymorphism in migraine. Brain
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] Rebaudengo
N, Rainero I, Parziale A, Rosina F, Pavanelli E, Rubino E, Mazza C, Ostacoli L,
Furlan PM Lack of interaction between a polymorphism
in the dopamine D2 receptor gene and the clinical features of migraine. Cephalalgia.
2004 Jun;24(6):503-7. 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] Maude
S, Curtin J, Breen G, Collier D, Russell G, Shaw D, Clair DS The
-141C Ins/Del polymorphism of the dopamine D2 receptor gene is not associated
with either migraine or Parkinson's disease. Psychiatr
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] Dichgans
M, Förderreuther S, Deiterich M, Pfaffenrath V, Gasser T The
D2 receptor NcoI allele: absence of allelic association with migraine with aura. Neurology.
1998 Sep;51(3):928. [Abstract] Peroutka
SJ, Wilhoit T, Jones K Clinical susceptibility to
migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles. Neurology.
1997 Jul;49(1):201-6. 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] Shepherd
AG, Lea RA, Hutchins C, Jordan KL, Brimage PJ, Griffiths LR Dopamine
receptor genes and migraine with and without aura: an association study. Headache.
2002 May;42(5):346-51. 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] Del
Zompo M, Cherchi A, Palmas MA, Ponti M, Bocchetta A, Gessa GL, Piccardi MP Association
between dopamine receptor genes and migraine without aura in a Sardinian sample. Neurology.
1998 Sep;51(3):781-6. 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] Stochino
ME, Asuni C, Congiu D, Del Zompo M, Severino G Association
study between the phenotype migraine without aura-panic disorder and dopaminergic
receptor genes. Pharmacol Res. 2003 Nov;48(5):531-4. Clinical
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] Marziniak
M, Mössner R, Benninghoff J, Syagailo YV, Lesch KP, Sommer C Association
analysis of the functional monoamine oxidase A gene promotor polymorphism in migraine. J
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] Maassen
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
patients. Am J Med Genet. 1998 Jun 5;77(5):415-20. The
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] MaassenVanDenBrink
A, Vergouwe MN, Ophoff RA, Saxena PR, Ferrari MD, Frants RR 5-HT1B
receptor polymorphism and clinical response to sumatriptan. Headache.
1998 Apr;38(4):288-91. 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] Peroutka
SJ, Price SC, Jones KW The comorbid association of
migraine with osteoarthritis and hypertension: complement C3F and Berkson's bias. Cephalalgia.
1997 Feb;17(1):23-6. 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] Griffiths
LR, Nyholt DR, Curtain RP, Goadsby PJ, Brimage PJ Migraine
association and linkage studies of an endothelial nitric oxide synthase (NOS3)
gene polymorphism. Neurology. 1997 Aug;49(2):614-7. Migraine
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] Iniesta
JA, Corral J, González-Conejero R, Rivera J, Vicente V Prothrombotic
genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular
disease. Headache. 1999 Jul-Aug;39(7):486-9. The
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] Corral
J, Iniesta JA, González-Conejero R, Lozano ML, Rivera J, Vicente V Migraine
and prothrombotic genetic risk factors. Cephalalgia.
1998 Jun;18(5):257-60. 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 Single-nucleotide
polymorphism alleles in the insulin receptor gene are associated with typical
migraine. Genomics. 2001 Dec;78(3):135-49. We
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] Mochi
M, Cevoli S, Cortelli P, Pierangeli G, Scapoli C, Soriani S, Montagna P Investigation
of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura. J
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] Jones
KW, Ehm MG, Pericak-Vance MA, Haines JL, Boyd PR, Peroutka SJ Migraine
with aura susceptibility locus on chromosome 19p13 is distinct from the familial
hemiplegic migraine locus. Genomics. 2001 Dec;78(3):150-4. Migraine
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] Jen
JC, Kim GW, Dudding KA, Baloh RW No mutations in CACNA1A
and ATP1A2 in probands with common types of migraine. Arch
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 g |