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

TitelFour Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
MedientypJournal Article
Jahr der Veröffentlichung2016
AutorenJoshi AD, Andersson C, Buch S, Stender S, Noordam R, Weng L-C, 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 HLA, Kang JH, Kooperberg C, Kraft P, Kratzer W, Lieb W, Lutsey PL, Murad SDarwish, 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
JournalGastroenterology
Volume151
Ausgabe2
Pagination351-363.e28
Datum der Veröffentlichung2016 Aug
ISSN1528-0012
SchlüsselwörterAdult, African Americans, Aged, ATP Binding Cassette Transporter, Subfamily G, Member 8, Case-Control Studies, Cholesterol, European Continental Ancestry Group, Female, Gallstones, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Lipid Metabolism, Logistic Models, Male, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide
Zusammenfassung

<p><b>BACKGROUND & AIMS: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>

DOI10.1053/j.gastro.2016.04.007
Alternate JournalGastroenterology
PubMed ID27094239
PubMed Central IDPMC4959966
Grant ListU01 HG008672 / HG / NHGRI NIH HHS / United States
K24 DK098311 / DK / NIDDK NIH HHS / United States
R01 EY022305 / EY / NEI NIH HHS / United States
R01 EY015473 / EY / NEI NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
U01 HG006378 / HG / NHGRI NIH HHS / United States
Z99 HL999999 / / Intramural NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States