Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.

Abstract

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.

• Authors: Amit D Joshi, Charlotte Andersson, Stephan Buch, Stefan Stender, Raymond Noordam, Lu-Chen Weng, Peter E Weeke, Paul L Auer, Bernhard Boehm, Constance Chen, Hyon Choi, Gary Curhan, Joshua C Denny, Immaculata De Vivo, John D Eicher, David Ellinghaus, Aaron R Folsom, Charles Fuchs, Manish Gala, Jeffrey Haessler, Albert Hofman, Frank Hu, David J Hunter, Harry L A Janssen, Jae H Kang, Charles Kooperberg, Peter Kraft, Wolfgang Kratzer, Wolfgang Lieb, Pamela L Lutsey, Sarwa Darwish Murad, Børge G Nordestgaard, Louis R Pasquale, Alex P Reiner, Paul M Ridker, Eric Rimm, Lynda M Rose, Christian M Shaffer, Clemens Schafmayer, Rulla M Tamimi, André G Uitterlinden, Uwe Völker, Henry Völzke, Yoshiyuki Wakabayashi, Janey L Wiggs, Jun Zhu, Dan M Roden, Bruno H Stricker, Weihong Tang, Alexander Teumer, Jochen Hampe, Anne Tybjærg-Hansen, Daniel I Chasman, Andrew T Chan, Andrew D Johnson
• Journal: Gastroenterology (Gastroenterology) Vol. 151 Issue 2 Pg. 351-363.e28 (Aug 2016) ISSN: 1528-0012 [Electronic] United States
• PMID: 27094239 (Publication Type: Journal Article, Meta-Analysis)
• Copyright: Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• ABCG8 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 8
• Cholesterol

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 8 (genetics)
• Adult
• Black or African American (genetics)
• Aged
• Case-Control Studies
• Cholesterol (metabolism)
• Female
• Gallstones (genetics)
• Genetic Loci (genetics)
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Hispanic or Latino (genetics)
• Humans
• Lipid Metabolism (genetics)
• Logistic Models
• Male
• Middle Aged
• Odds Ratio
• Phenotype
• Polymorphism, Single Nucleotide
• White People (genetics)