基于620份全外显子组数据的阿司匹林药物基因组学分析

Pharmacogenomics study of 620 whole-exome sequencing： focusing on aspirin application

目的探讨阿司匹林药物相关位点在不同种族人群的等位基因频率差异。方法利用复旦大学附属儿科医院2013至2016年因临床诊断不明而进行全外显子组检测的620份测序数据，针对已报道的阿司匹林药物相关位点，与千人基因组计划数据库中的欧洲人群和东亚人群进行等位基因频率的计算及比较，组间比较采用x^2检验。结果620份全外显子组检测数据共涉及38个阿司匹林药物相关的多态性位点，共33个基因。其中10个变异位点（26％）影响药物有效性；28个变异位点（74％）影响药物毒性和（或）不良反应。除去15个公共数据库中记录不全位点，23个阿司匹林药物相关位点中7个位点（rs1050891、rs6065、rs7862221、rs1065776、rs3818822、rs3775291、rs1126643）等位基因频率与千人基因组中的欧洲人群及东亚人群差异均无统计学意义（P均〉0．01）；10个位点（rs2228079、rs1613662、rs4523、rs28360521、rs1131882、rs1007626、rs3856806、rs2768759、rs7572857、rs1126510）与东亚人群差异均无统计学意义（P均〉0．01），与欧洲人群差异均有统计学意义（P均〈0．01）；1个位点（rs2075797）与东亚人群差异有统计学意义（P〈0．01），与欧洲人等位基因频率差异无统计学意义（P〉0．01）；5个位点（rs10279545、rs730012、rs16851030、rs1353411、rs1800069）的等位基因频率（0．019、0．058、0．167、0．452、0．340）与东亚人群（0．100、0．151、0．396、0．568、0．453）和欧洲人群（0．531、0．312、0．037、0．179、0．688）差异均有统计学意义（东亚人群：x^2=21．798、20．400、67．543、16．531、15．807，欧洲人群：x^2=325．799、92．877、144．811、156．471、174．533，P均〈0．01）。结论阿司匹林已报道的药物相关位点中影响药物有效性和影响药物毒性或不良反应占绝大比例，其基因型直接影响临床用药的选择。阿司匹林药物相关位点在种族中存在明显差异性。

Objective To investigate the allele frequencies of aspirin-response-related variants in different population. Method The allele frequencies of reported clinically significant aspirin-response- related variants were evaluated based on 620 whole exome sequencing （WES） data collected from 2013 to 2016 in Children＇s Hospital of Fudan University. Then the local allele frequencies were compared with 1 000 Genomes project database, and X2 test was used. Result Thirty-eight aspirin-response-related variants that had clinical significance had been detected in the 620 WES data. Ten （ 26% ） of them were related with drug efficacy while 28 （74%） were related with toxicity or adverse drug reaction （ADR）. These variants were distributed in 33 genes. There were 23 aspirin-related variants further analysised, and the frequency of 7 （rs1050891, rs6065, rs7862221, rs1065776, rs3818822, rs3775291 and rs1126643） had no significant difference compared with frequency of European and East Asian population of 1 000 Genome project （P 〉 0. 01 for both）, 10 （rs2228079, rs1613662, rs4523, rs28360521, rs1131882, rs1047626, rs3856806, rs2768759, rs7572857 and rs1126510） of them had no significant difference compared with East Asian but were significantly different from European population, 1 （rs2075797） had no significant difference compared with frequency of European and different with frequency of East Asian, and 5 variants （rs10279545, rs730012, rs16851030, rs1353411, rs1800469）were different from frequency of both East Asian（0. 019, 0. 058, 0. 167, 0. 452, 0. 340 vs. O. 100, 0. 151, 0. 396, 0. 568, 0. 453,x^2 = 21. 798, 20. 400, 67. 543, 16.531, 15.807, P all〈0.01） and European population（0.531, 0.312, 0.037, 0.179, 0.688, x^2 = 325.799, 92.877, 144.811, 156.471, 174.533,P all〈0.01）. Conclusion Most variants that have clinical significance in aspirin response are related with drug efficacy or drug toxicity or ADR, indicating the urgency of variants screen in clinical practice. Significant population-specificity is detected in local 620 WES data in aspirin-response-related variants.