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Background  The present study was undertaken to find out the role of estrogen pathway related gene polymorphisms in susceptibility to migraine in Northern Indian population. Aromatase,  CYP19A1  (rs10046 and rs4646); estrogen receptors,  ESR1  (rs2234693, rs1801132, rs2228480 and rs9340799) and  ESR2  (rs1271572 and rs1256049) polymorphisms were selected for the present study.    Methodology/Principal Findings  The patients were recruited in two cohorts – primary (207) and replicative (127) along with 200 healthy controls and genotyped for various polymorphisms. Logistic regression analysis was applied for statistical analyses. The results were validated in the replicative cohort and pooled by meta analysis using Fisher's and Mantel-Haenszel test. Furthermore, Benjamini – Hochberg false discovery rate test was used to correct for multiple comparisons.  CYP19A1  rs10046 and  CYP19A1  rs4646 polymorphisms were found to confer risk and protective effect, respectively. Out of four  ESR1  polymorphisms, only rs2234693 variant allele was significantly associated in migraine with aura. No significant associations were observed for  ESR2  polymorphisms. Significant haplotypes were identified for  CYP19A1  and  ESR1  polymorphisms. Gene- gene interactions of genotypes as well as haplotypes were observed for  CYP19A1 -  ESR1  showing both risk and protective combinations.    Conclusion  We strongly suggest  CYP19A1  polymorphisms to be the major contributing factors in migraine susceptibility instead of genetic variants of estrogen receptors.

Potential Role of Aromatase over Estrogen Receptor Gene Polymorphisms in Migraine Susceptibility: A Case Control Study from North India