Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barretts Esophagus, and Gastroesophageal Reflux
Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barretts Esophagus, and Gastroesophageal Reflux
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DOI：
10.1093/jnci/djt303
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发表时间：
2013-11-01
影响因子：
10.3
通讯作者：
MacGregor, Stuart
中科院分区：
文献类型：
--
作者：
Ek, Weronica E.;Levine, David M.;MacGregor, Stuart
食管腺癌(EA)是一种越来越常见的癌症，其存活率较低。Barretts食道(BE)是电针的主要先兆，每年有0.12%~0.5%的BE患者进展为电针。BE通常发生在慢性胃食道反流(GERD)的背景下，GERD是EA的危险因素之一。我们使用全基因组关联数据来研究GERD、BE和EA背后的遗传结构。我们应用一种方法，通过同时考虑所有单核苷酸多态(SNPs)来估计GERD、BE和EA之间的解释方差(阵列遗传力，h(G)(2))和遗传相关性(r(G))。我们还使用预测方法估计了GERD、BE和EA之间的多基因重叠。所有检验都是双侧的，除了使用单侧检验的方差解释估计的情况外。我们估计了具有统计学意义的遗传方差，可解释为BE(h(G)(2)35%；标准差[SE]6%；单侧P110(9))和EA(h(G)(2)25%；SE 5%；单侧P210(7))。BE和Ea的遗传相关很高(r(G)1.0；SE 0.37)。我们还估计了BE和EA之间在统计学上显著的多基因重叠(单侧P110(6))，这表明，连同高度的遗传相关性，共同的基因是BE和EA发展的基础。反之，GERD的结果没有统计学意义。我们已经证明，BE和EA的风险受到许多小效应的种系遗传变异的影响，共同的多基因效应导致了这两种疾病的风险。
Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barretts esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(g)(2)) and the genetic correlation (r(g)) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.We estimated a statistically significant genetic variance explained for BE (h(g)(2) 35%; standard error [SE] 6%; one-sided P 1 10(9)) and for EA (h(g)(2) 25 %; SE 5%; one-sided P 2 10(7)). The genetic correlation between BE and EA was found to be high (r(g) 1.0; SE 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P 1 10(6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.