Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
复制标题
DOI：
10.1053/j.gastro.2016.04.007
复制
发表时间：
2016-08
期刊：
影响因子：
29.4
通讯作者：
Johnson AD
中科院分区：
文献类型：
--
作者：
Joshi AD;Andersson C;Buch S;Stender S;Noordam R;Weng LC;Weeke PE;Auer PL;Boehm B;Chen C;Choi H;Curhan G;Denny JC;De Vivo I;Eicher JD;Ellinghaus D;Folsom AR;Fuchs C;Gala M;Haessler J;Hofman A;Hu F;Hunter DJ;Janssen HL;Kang JH;Kooperberg C;Kraft P;Kratzer W;Lieb W;Lutsey PL;Darwish Murad S;Nordestgaard BG;Pasquale LR;Reiner AP;Ridker PM;Rimm E;Rose LM;Shaffer CM;Schafmayer C;Tamimi RM;Uitterlinden AG;Völker U;Völzke H;Wakabayashi Y;Wiggs JL;Zhu J;Roden DM;Stricker BH;Tang W;Teumer A;Hampe J;Tybjærg-Hansen A;Chasman DI;Chan AT;Johnson AD
一项对280例患者进行的全基因组关联研究发现，肝脏胆固醇转运体ABCG8是一个与胆石病风险相关的基因座，但尚未有其他任何该表型的全基因组关联研究报告。我们对具有欧洲血统的个体的GWASs进行了大规模荟萃分析，以确定胆结石疾病的其他遗传风险因素。在10个发现研究(8720个病例和55,152个对照)中，我们使用年龄和性别调整的Logistic回归模型获得了每个等位基因的优势比(OR)和标准误差估计。我们对研究的特异性估计进行了逆方差加权固定效应荟萃分析，以确定与胆结石疾病独立相关的单核苷酸多态(SNPs)。关联在6489例患者和62797名对照中重复。我们观察到ABCG8基因座上的两个SNP独立关联：rs11887534(OR=1.69；95%可信区间：1.54~1.86；P=2.44×10−60)和rs4245791(OR=1.27；P=1.90×10−34)。我们还鉴定和/或复制了TM4SF4中的rs9843304(OR=1.12；95%CI，1.08-1.16；P=6.09×10−11)，SULT2A1中的rs2547231(编码作用于羟基类固醇和胆固醇衍生的类固醇胆汁酸的磺基偶联酶)，(OR=1.17，95%CI，1.12-1.21；P=2.24×10−10)，GCKR中的rs1260326(编码葡萄糖激酶调节因子)(OR=1.12；95%CI，1.07-1.17；P=2.5 5×10−10)和编码胆固醇转化为初级胆汁酸的酶(编码一种催化胆固醇转化为初级胆汁酸的酶)(OR=1.11；95%CI，1.0 8~1.15；P=8.84×10−9)。在非裔美国人和西班牙裔美国人血统的个体中，rs11887534和rs4245791与胆结石疾病的风险正相关，而rs1260326变异的关联则相反。在这一大规模的胆石性疾病中，我们在4个基因上发现了与胆固醇代谢和转运、胆汁酸或羟基类固醇的磺酰化有关的功能。
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. 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 (SNPs) that were independently associated with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. We observed independent associations for 2 SNPs 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 sulfo-conjugation 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 GCKR (encodes a glucokinase regulator) (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 positively associated with gallstone disease risk, while the association for the rs1260326 variant was inverse. 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 hydoxysteroids.