凝血因子V基因的单核苷酸多态性与不明原因复发流产的相关性

Association of coagulation factor V gene polymorphism with unexplained recurrent spontaneous abortion among ethnic Hans from Wenzhou area

目的探讨温州地区汉族女性凝血因子V基因单核苷酸多态性与不明原因复发性流产（unexplained recurrent spontaneous abortion,URSA）的相关性。方法应用目标区域捕获测序法检测96例URSA女性（URSA组）和103名正常妊娠史女性（对照组）凝血因子V基因的单核苷酸多态性，并采用飞行时间质谱验证。比较两组基因型频率、等位基因频率并分析连锁不平衡性和位点与凝血因子V表达水平相关性。结果检出19个已知多态性位点，未检出凝血因子VLeiden突变。URSA组rs9287090A等位基因频率（6．77％）、rs1046712T等位基因频率（3．12％）和rs1800594G等位基因频率（10．94％）低于对照组的16．50％、13．11％和18．45％。经Bonferroni法和FDR法多重检验校正，rs9287090和rsl046712等位基因频率在两组间具有统计学差异（校正后P〈0．05）。与野生型比较，URSA组rs9287090 GA、AA基因型频率和rs1046712GT、TT基因型频率均低于对照组，多重检验校正后差异无统计学意义（校正后P〉0．05）。rs6022和rs6029完全连锁不平衡（r2=1，D’=1），rs6022A等位基因频率和rs6029T等位基因频率分布在URSA组高于对照组，校正后差异无统计学意义（校正后P〉0．05）。A-T-T单倍型（rs6022-rs6029-rs6028）在URSA组分布频率显著高于对照组，差异有统计学意义（75．00％VS．65．50％，OR=1．578，95％CI：1．021～2．438，X2=4．248，P〈0．05）。结论温州地区汉族人群中URSA存在凝血因子V遗传易感性，rs9287090A等位基因、rsl046712T等位基因和rsl800594G等位基因可能是URSA保护等位基因，rs6022A等位基因和rs6029T等位基因可能是URSA易感等位基因。

Objective To assess the association of coagulation factor V gene polymorphisms with unexplained recurrent spontaneous abortion （URSA） among ethnic Han Chinese from Wenzhou area. Methods Ninety-six patients with URSA and 103 females with a history of normal pregnancy were recruited. Genotypes of coagulation factor V gene were determined through target sequence capture and high-throughput sequencing. The results were confirmed with a MassARRAY system. Allelic and genotypic frequencies between the two groups were compared. Results Nineteen single nucleotide polymorphism （SNPs）, except coagulation factor V Leiden, were identified in the two groups. The frequencies of rs9287090 allele A, rs1046712 allele T and rs1800594 allele G of the URSA group were lower than those of the control group （6.77%vs. 16.50%, 3.12% vs. 13.11%, 10.94% vs. 18.45%, respectively）. After Bonferroni and false discovery rate correction, rs9287090 and rs1046712 were significantly associated with URSA （corrected P〈0. 05）. Although genotypic distribution of rs9287090 and rs1046712 also differed between the two groups, the corrected P value showed no significance （corrected P〉0.05）. A complete linkage disequilibrium （r2= 1, D＇= 1） of rs6022 and rs6029 was observed for the haplotype block rs6022- rs6029-rs6028. The frequencies of rs6022 allele A and rs6029 allele T were higher in the URSA group with corrected insignificance （75.00% vs. 65.53%, corrected P 〉0.05）. Furthermore, significantly more A-T- T haplotype was found in the URSA group （75.00% vs. 65. 50%, OR= 1. 578, 95%CI： 1. 021 2. 438, X2=4. 248, P〈0. 05）. Conclusion The decreased rate of rs9287090 allele A, rs1046712 allele T, and rs1800594 allele G may contribute to the susceptibility to URSA among ethnic Han Chinese from Wenzhou area. The rs6022 allele A and rs6029 allele T may also predispose to URSA.