在一项全基因组关联研究的荟萃分析中确定的胆结石疾病的四个易感基因座。
Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
作者信息
Joshi Amit D, Andersson Charlotte, Buch Stephan, Stender Stefan, Noordam Raymond, Weng Lu-Chen, Weeke Peter E, Auer Paul L, Boehm Bernhard, Chen Constance, Choi Hyon, Curhan Gary, Denny Joshua C, De Vivo Immaculata, Eicher John D, Ellinghaus David, Folsom Aaron R, Fuchs Charles, Gala Manish, Haessler Jeffrey, Hofman Albert, Hu Frank, Hunter David J, Janssen Harry L A, Kang Jae H, Kooperberg Charles, Kraft Peter, Kratzer Wolfgang, Lieb Wolfgang, Lutsey Pamela L, Darwish Murad Sarwa, Nordestgaard Børge G, Pasquale Louis R, Reiner Alex P, Ridker Paul M, Rimm Eric, Rose Lynda M, Shaffer Christian M, Schafmayer Clemens, Tamimi Rulla M, Uitterlinden André G, Völker Uwe, Völzke Henry, Wakabayashi Yoshiyuki, Wiggs Janey L, Zhu Jun, Roden Dan M, Stricker Bruno H, Tang Weihong, Teumer Alexander, Hampe Jochen, Tybjærg-Hansen Anne, Chasman Daniel I, Chan Andrew T, Johnson Andrew D
机构信息
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts.
出版信息
Gastroenterology. 2016 Aug;151(2):351-363.e28. doi: 10.1053/j.gastro.2016.04.007. Epub 2016 Apr 16.
BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.
METHODS
We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.
RESULTS
We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.
CONCLUSIONS
In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.
背景与目的
一项针对280例病例的全基因组关联研究（GWAS）确定肝脏胆固醇转运蛋白ABCG8是与胆结石病风险相关的一个基因座，但尚未有其他关于该表型的GWAS研究报告相关结果。我们对有可用既往基因型数据的欧洲血统个体的GWAS进行了大规模荟萃分析，以确定胆结石病的其他遗传风险因素。
方法
我们在10项发现研究（8720例病例和55152例对照）中的每一项中，使用年龄和性别调整的逻辑回归模型获得每个等位基因的比值比（OR）和标准误估计值。我们对研究特异性估计值进行了逆方差加权固定效应荟萃分析，以确定与胆结石病独立相关的单核苷酸多态性。在6489例病例和62797例对照中对关联进行了重复验证。
结果
我们在ABCG8基因座观察到2个单核苷酸多态性的独立关联：rs11887534（OR，1.69；95%置信区间[CI]，1.54 - 1.86；P = 2.44×10⁻⁶⁰）和rs4245791（OR，1.27；P = 1.90×10⁻³⁴）。我们还确定并/或重复验证了TM4SF4中rs9843304的关联（OR，1.12；95% CI，1.08 - 1.16；P = 6.09×10⁻¹¹），SULT2A1中rs2547231（编码一种作用于羟类固醇和胆固醇衍生的甾醇胆汁酸的硫酸化结合酶）的关联（OR，1.17；95% CI，1.12 - 1.21；P = 2.24×10⁻¹⁰），葡萄糖激酶调节蛋白中rs1260326的关联（OR，1.12；95% CI，1.07 - 1.17；P = 2.55×10⁻¹⁰），以及CYP7A1附近rs64717ⱽ17的关联（OR），1.11；95% CI，1.08 - 1.15；P = 8.84×10⁻⁹）。在非裔美国人和西班牙裔美国人血统个体中，rs11887534和rs4245791与胆结石病风险呈正相关，而rs1260326变体的关联则相反。
结论
在这项关于胆结石病的大规模GWAS中，我们在具有胆固醇代谢和转运以及胆汁酸或羟类固醇磺化作用推定功能的基因中确定了4个基因座。
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