Sapkota Yadav, Fassbender Amelie, Bowdler Lisa, Fung Jenny N, Peterse Daniëlle, O Dorien, Montgomery Grant W, Nyholt Dale R, D'Hooghe Thomas M
QIMR Berghofer Medical Research Institute,Brisbane,Queensland,Australia.
Department of Development and Regeneration,Organ Systems,KU Leuven,Leuven,Belgium.
Twin Res Hum Genet. 2015 Oct;18(5):518-25. doi: 10.1017/thg.2015.61. Epub 2015 Sep 4.
Endometriosis is a complex disease that affects 6-10% of women in their reproductive years and 20-50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant (p < .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with 'All' (p = .066) and 'Grade_B' (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.
子宫内膜异位症是一种复杂的疾病，影响6%-10%处于生育年龄的女性以及20%-50%的不孕女性。针对子宫内膜异位症的全基因组和候选基因关联研究已确定了10个独立的风险位点，其中9个（rs7521902、rs13394619、rs4141819、rs6542095、rs1519761、rs7739264、rs12700667、rs1537377和rs10859871）在欧洲人群中具有多态性。在此，我们对来自比利时的998例经腹腔镜检查和组织学确诊的子宫内膜异位症病例以及783例无病对照进行了9个单核苷酸多态性（SNP）位点的重复验证。SNP位点rs7521902、rs13394619和rs6542095与子宫内膜异位症存在名义上显著的（p < 0.05）关联，而7个SNP的效应方向与原始报告一致。值得注意的是，IL1A基因座处的rs6542095与“所有类型”（p = 0.066）和“B级”（p = 0.01）子宫内膜异位症的关联，因为这是在独立人群中的首次成功重复验证。将已发表结果进行荟萃分析后，发现rs7521902、rs13394619、rs6542095、rs12700667、rs7739264和rs1537377具有全基因组显著证据。值得注意的是，GREB1（靠近rs13394619）和CDKN2B-AS1（靠近rs1537377）中的三个编码变体也与子宫内膜异位症存在名义上显著的关联。总体而言，本研究在一个具有独特特征的独立人群中提供了重要的重复验证，并表明大多数最初的全基因组关联研究结果并非仅由偶然因素导致。
