Analysis Of Candidate Susceptibility Genes For Migraine In Chinese Han Population

Migraine is a kind of chronic and recurrent vascular headache with extensive clinical and genetic heterogeneity,and its essence is a neurobiological dysfunction encephalopathy.According to the world health organization's 2010 global burden of disease survey,migraine ranks sixth among the world's heaviest disease burdens and is considered one of the 20 most disabling diseases.Our epidemiological investigation has shown that the incidence of migraine in China is 9.3%.An obvious phenomenon is that moderate and severe migraine and chronic migraine related disability and comorbidity problems are prominent,resulting in disability,loss of labor force,limited learning and daily activities,and decline in the quality of life,causing heavy burden on society and families.The etiology of migraine is still not clear and believed having a strong genetic predisposition.Epidemiological studies suggest that genetic factors play an important role in the development of migraine.We have previously found that MTHFR C677T and PRDM16 rs2651899 variants may be risk factors for migraine without aura in Chinese people in a small-scale study.Also,these studies indicated that there was racial differences in the molecular pathogenesis of migraine Recently,several international large-scale GWAS studies have found several migraine related susceptibility genes.Meanwhile,susceptibility locus have been found in the several genes involving different pathway in the pathogenesis of migraine,including estrogen receptor and metabolism,calcitonin gene-related peptide,and 5-hydroxytryptamine receptor.However,Molecular genetic researches on these candidate genes for Han-Chinese migraine have not been conducted so far.Based on the above,we screened the candidate genes of interest in a large sample of Han-Chinese.Objective:1)To study the variation of ESR1,ESR2 and CYP19A1 in Han-Chinese migraine.2)To explore the CALC A and RAMP1 genes involving CGRP metabolism in Han-Chinese migraine;3)To screen multiple migraine related genes discovered by GWAS in recent years and 5-hydroxytryptamine related genes in large-scale sample;to determine whether they are migraine susceptibility genes for Han-Chinese and analyze their effects of interaction on clinical phenotypesMaterials and methods:A case-control study was conducted.And large samples of Han-Chinese clinical migraine gene database were established by collecting migraine patients and control subjects in the headache specialized clinic of the Department of Neurology of the First Affiliated Hospital of Xiamen University.Genotyping was performed using time of flight mass spectrometry in Sequenom's MassARRAY system.Moreover,statistical analysis was performed using binary Logistic regression analysis,haplotype analysis and multifactor dimensionality reduction.Results:1)By employing a case-control approach,8 SNPs in the ESR1,ESR2,and CYP19A1 genes are studied in a cohort of 494 migraine cases and 533 controls.There are significant differences in allelic distributions for rs2234693 and rs9340799 in ESR1 gene between patients with migraine and control subjects.Univariate logistic analysis shows that rs2234693 and rs9340799 are risk factors for migraine,but multivariate analysis reveals that only rs2234693 is significant associated with migraine.In the subgroup analysis,rs2234693 in ESR1 gene is found associated with menstrually related migraine.Further haplotypic analysis shows that rs2234693-rs9340799 TA haplotype serves as risk haplotype for migraine.The GMDR analysis identifies rs2234693 in ESR1 alone to be a crucial candidate in migraine susceptibility.2)Using a case-control approach,rs3781719 and rs145837941 in the CALCA gene and rs3754701 and rs7590387 at the RAMP1 locus was analyzed in a cohort of 504 migraine cases and 529 ethnically matched controls.The CALCA gene rs 145837941 variant was not found in migraine or control group.No significant difference in genotypic and allelic distribution was observed in the other three polymorphisms between migraine cases and controls.All the three SNPs were also not selected as significant factors that independently contributed to susceptibility to migraine in multivariate analysis.In the subgroup analysis,the CALCA rs3781719 seemed to be a significant risk for migraine with aura,but was not statistically significant after FDR correction.Moreover,there was no synergistic relationship between the three SNPs in the multifactor dimensionality reduction analysis for explore locus-locus interactions.3)In the present study,a case-control study was conducted in a cohort of 581 migraine cases and 533 ethnically matched controls among a Chinese population.Eighteen polymorphisms from serotonin receptors and GWASs were selected.The genotypic and allelic distributions of MEF2D rs2274316 and ASTN2 rs6478241 were significantly different between migraine patients and controls.Univariate and multivariate analysis revealed significant associations of polymorphisms in the MEF2D and ASTN2 genes with migraine susceptibility.MEF2D,PRDM16 and ASTN2 were also found to be associated with migraine without aura(MO)and migraine with family history.And MEF2D and ASTN2 also served as genetic risk factors for the migraine without family history.The Generalized Multifactor-Dimensionality Reduction analysis identified that MEF2D and HTR2E constituted the two-factor interaction modelConclusions:1)ESR1 gene plays a role in the migraine process for Han-Chinese.And ESR1 rs2234693 was also a significant risk for migraine without aura,female migraine and menstrually related migraine.2)Variants in CALC A gene and RAMP1 gene were not associated with migraine in the Han-Chinese population.3)The MEF2D,PRDM16 and ASTN2 genes from GWAS are associated with migraine susceptibility,especially MO,among Chinese patients.4)It appears that there is no association with serotonin receptor related genes.