Genome-wide association study link novel loci to endometriosis.
Genome-wide association study link novel loci to endometriosis.
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DOI：
10.1371/journal.pone.0058257
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ward K
中科院分区：
文献类型：
--
作者：
Albertsen HM;Chettier R;Farrington P;Ward K
子宫内膜异位症是一种常见的妇科疾病，其病因复杂，其定义是子宫内膜腺体和间质在子宫外的存在。子宫内膜异位症是周期性和慢性盆腔疼痛、生育能力下降和生活质量下降的常见原因。子宫内膜异位症的诊断和治疗从症状出现起平均延迟 7-10 年。缺乏及时和非侵入性的诊断工具是目前识别和治疗子宫内膜异位症的最大障碍。双胞胎和家庭研究表明，家庭中的相对风险有所增加。为了确定导致子宫内膜异位症的遗传因素，我们对欧洲队列进行了两阶段全基因组关联研究 (GWAS)，其中包括 2,019 例经手术确诊的子宫内膜异位症病例和 14,471 例对照。我们在联合分析中确定的 P<5×10−8 相关的三个 SNP 属于两个位点：1p36.12 上的 LINC00339-WNT4（rs2235529；P = 8.65×10−9，OR = 1.29，CI = 1.18–1.40）和 RND3-RBM43 上2q23.3（rs1519761； P = 4.70×10−8，OR = 1.20，Cl = 1.13–1.29，以及rs6757804； P = 4.05×10−8，OR = 1.20，Cl = 1.13–1.29）。使用调整后的 Bonferoni 显着性阈值 4.51×10−7，我们在荟萃分析中确定了两个与子宫内膜异位症相关的额外位点：6p22.3 上的 RNF144B-ID4（rs6907340；P = 2.19×10−7，OR = 1.20，Cl = 1.12–1.28），以及 10q11.21 上的 HNRNPA3P1-LOC100130539（rs10508881；P = 4.08×10−7，OR = 1.19，Cl = 1.11–1.27）。与之前提出的与 WNT4 的关联一致，我们的研究表明 WNT4 周围有一个 150 kb 的区域，其中还包括 LINC00339 和 CDC42。对记录的不孕症、初潮年龄和家族史的单变量分析未显示与这些 SNP 标记的等位基因关联。我们研究中患者的临床数据显示，诊断平均延迟 8.4 年，并证实子宫内膜异位症严重程度与不孕之间存在很强的相关性 (n = 1182，P<0.001，OR = 2.18)。子宫内膜异位症的全基因组关联分析（GWAS）在病例诊断上具有很高的确定性，并且对人群亚结构进行了严格的处理。我们的研究结果拓宽了对子宫内膜异位症中起作用的遗传因素的理解。
Endometriosis is a common gynecological condition with complex etiology defined by the presence of endometrial glands and stroma outside the womb. Endometriosis is a common cause of both cyclic and chronic pelvic pain, reduced fertility, and reduced quality-of-life. Diagnosis and treatment of endometriosis is, on average, delayed by 7–10 years from the onset of symptoms. Absence of a timely and non-invasive diagnostic tool is presently the greatest barrier to the identification and treatment of endometriosis. Twin and family studies have documented an increased relative risk in families. To identify genetic factors that contribute to endometriosis we conducted a two-stage genome-wide association study (GWAS) of a European cohort including 2,019 surgically confirmed endometriosis cases and 14,471 controls. Three of the SNPs we identify associated at P<5×10−8 in our combined analysis belong to two loci: LINC00339-WNT4 on 1p36.12 (rs2235529; P = 8.65×10−9, OR = 1.29, CI = 1.18–1.40) and RND3-RBM43 on 2q23.3 (rs1519761; P = 4.70×10−8, OR = 1.20, Cl = 1.13–1.29, and rs6757804; P = 4.05×10−8, OR = 1.20, Cl = 1.13–1.29). Using an adjusted Bonferoni significance threshold of 4.51×10−7 we identify two additional loci in our meta-analysis that associate with endometriosis:, RNF144B-ID4 on 6p22.3 (rs6907340; P = 2.19×10−7, OR = 1.20, Cl = 1.12–1.28), and HNRNPA3P1-LOC100130539 on 10q11.21 (rs10508881; P = 4.08×10−7, OR = 1.19, Cl = 1.11–1.27). Consistent with previously suggested associations to WNT4 our study implicate a 150 kb region around WNT4 that also include LINC00339 and CDC42. A univariate analysis of documented infertility, age at menarche, and family history did not show allelic association with these SNP markers. Clinical data from patients in our study reveal an average delay in diagnosis of 8.4 years and confirm a strong correlation between endometriosis severity and infertility (n = 1182, P<0.001, OR = 2.18). This GWAS of endometriosis was conducted with high diagnostic certainty in cases, and with stringent handling of population substructure. Our findings broaden the understanding of the genetic factors that play a role in endometriosis.
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DOI：
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