Multilocus analyses reveal involvement of the ESR1, ESR2, and FSHR genes in migraine.
OBJECTIVE
Female hormone genes have been investigated in migraine in recent years. Research in this field has been controversial, especially in regard to ESR1 gene findings. None of the reports have yet to approach the problem from a multigenic point of view.


METHODS
We investigated 5 polymorphisms implicated in female hormone metabolism (FSHR, CYP19A1, ESR1, NRIP1, and ESR2) in a cohort of 730 subjects matched for age and sex. The effect of gene-gene interaction was assessed using the set association approach, and the corresponding haplotypes were studied with PM Plus software. To corroborate initial results, we analyzed the selected markers using a cohort of 134 families in which 168 trios were suitable for transmission-disequilibrium test (TDT) analysis under the migraine with aura (MA) phenotype.


RESULTS
A total of 356 consecutive migraine patients (198 with MA [76% females] and 158 migraine without aura [MO, 74% females], and 374 matched controls [71% females]) were genotyped. In the 2-point analyses, the ESR1 and ESR2 polymorphisms showed nominal association under MA/MO phenotype, and this association was higher with the FSHR polymorphism in MA females (P = .004, uncorrected). Using the SUMSTAT program, we observed ESR2-ESR1-FSHR significant gene-gene interaction, suggesting association with the MA/MO phenotype (P = .005; P = .003 in females), and with MA alone (P = .021; P = .030 for females).We corroborated that ESR2-ESR1-FSHR haplotypes interacted for migraine under a model-free hypothesis (empirical P = .010 for the whole sample; P = .001 for females), and the association was stronger for the MA phenotype alone (empirical P = 5.0e-4, under the heterogeneity model; P = .001 for females). These results were corroborated using family-based association approaches. We observed nominal association for ESR2 and ESR1 (P = .031 and .034, respectively) in the TDT study, and significant association for ESR1 using family-based association test statistics. Haplotype-TDT analyses showed further significant gene-gene interaction for ESR1-ESR2 (global P = .009), ESR2-FSHR (global P = .011), and nominally significant interaction for ESR2-ESR1-FSHR genes (global P = .037).


CONCLUSIONS
We found significant association of female hormone metabolism polymorphisms under the perspective of multigene approach.
Oterino
Agustin
A
University Hospital Marqués de Valdecilla-Neurology, Santander, Spain.
Toriello
Maria
M
Cayón
Amalia
A
Castillo
Jesus
J
Colas
Rafael
R
Alonson-Arranz
Ana
A
Ruiz-Alegria
Carlos
C
Quintela
Estrella
E
Monton
Fernando
F
Ruiz-Lavilla
Nuria
N
Gonzalez
Felix
F
Pascual
Julio
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D015331:Cohort Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D004967:Estrogens / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics; D000078723:Nuclear Receptor Interacting Protein 1; D011110:Polymorphism, Genetic / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D011962:Receptors, FSH / Q000235:genetics*; D012737:Sex Factors; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D011960:Receptors, Estrogen; D011962:Receptors, FSH; D019363:Cytochrome P-450 CYP1A1