Oterino Agustin, Toriello Maria, Cayón Amalia, Castillo Jesus, Colas Rafael, Alonson-Arranz Ana, Ruiz-Alegria Carlos, Quintela Estrella, Monton Fernando, Ruiz-Lavilla Nuria, Gonzalez Felix, Pascual Julio
University Hospital Marqués de Valdecilla-Neurology, Santander, Spain.
Headache. 2008 Nov-Dec;48(10):1438-50. doi: 10.1111/j.1526-4610.2008.01294.x.
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.
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.
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).
We found significant association of female hormone metabolism polymorphisms under the perspective of multigene approach.
近年来对偏头痛中的女性激素基因进行了研究。该领域的研究一直存在争议，尤其是关于雌激素受体1（ESR1）基因的研究结果。尚无报告从多基因角度探讨该问题。
我们在一个年龄和性别匹配的730名受试者队列中，研究了5种与女性激素代谢相关的多态性（促卵泡激素受体基因（FSHR）、细胞色素P450 19A1基因（CYP19A1）、雌激素受体1基因（ESR1）、核受体相互作用蛋白1基因（NRIP1）和雌激素受体2基因（ESR2））。使用集合关联法评估基因-基因相互作用的影响，并使用PM Plus软件研究相应的单倍型。为了证实初步结果，我们在一个包含134个家庭的队列中分析了所选标记，其中168个三联体适合在伴有先兆的偏头痛（MA）表型下进行传递不平衡检验（TDT）分析。
对总共356例连续的偏头痛患者（198例MA患者[76%为女性]和158例无先兆偏头痛患者[MO，74%为女性]）以及374名匹配对照（71%为女性）进行了基因分型。在两点分析中，ESR1和ESR2多态性在MA/MO表型下显示出名义上的关联，并且在MA女性中这种关联与FSHR多态性更高（P = 0.004，未校正）。使用SUMSTAT程序，我们观察到ESR2-ESR1-FSHR存在显著的基因-基因相互作用，提示与MA/MO表型相关（P = 0.005；女性中P = 0.003），且仅与MA相关（P = 0.021；女性中P = 0.030）。我们证实在无模型假设下，ESR2-ESR1-FSHR单倍型与偏头痛相互作用（整个样本的经验P = 0.010；女性中P = 0.001），并且仅对MA表型的关联更强（在异质性模型下经验P = 5.0e-4；女性中P = 0.001）。使用基于家系的关联方法证实了这些结果。我们在TDT研究中观察到ESR2和ESR1存在名义上的关联（分别为P = 0.031和0.034），并且使用基于家系的关联检验统计量观察到ESR1存在显著关联。单倍型-TDT分析显示ESR1-ESR2（总体P = 0.009）、ESR2-FSHR（总体P = 0.011）存在进一步的显著基因-基因相互作用，以及ESR2-ESR'1-FSHR基因存在名义上的显著相互作用（总体P = 0.037）。
我们在多基因方法的视角下发现女性激素代谢多态性存在显著关联。
