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

被引：68

作者：

Joshi, Amit D. ^{[1
,4
,5
,6
]}

Andersson, Charlotte ^{[7
]}

Buch, Stephan ^{[8
]}

Stender, Stefan ^{[9
]}

Noordam, Raymond ^{[11
,12
]}

Weng, Lu-Chen ^{[15
]}

Weeke, Peter E. ^{[10
,16
]}

Auer, Paul L. ^{[18
,19
]}

Boehm, Bernhard ^{[20
]}

Chen, Constance ^{[1
]}

Choi, Hyon ^{[21
]}

Curhan, Gary ^{[22
,23
,24
]}

Denny, Joshua C. ^{[16
,17
]}

De Vivo, Immaculata ^{[1
,2
,22
,23
]}

Eicher, John D. ^{[7
,25
]}

Ellinghaus, David ^{[26
]}

Folsom, Aaron R. ^{[15
]}

Fuchs, Charles ^{[22
,23
,28
,29
]}

Gala, Manish ^{[1
,4
]}

Haessler, Jeffrey ^{[19
]}

Hofman, Albert ^{[12
]}

Hu, Frank ^{[2
,3
]}

Hunter, David J. ^{[1
,2
]}

Janssen, Harry L. A. ^{[13
,14
,30
]}

Kang, Jae H. ^{[22
,23
]}

Kooperberg, Charles ^{[19
]}

Kraft, Peter ^{[1
,2
]}

Kratzer, Wolfgang ^{[20
]}

Lieb, Wolfgang ^{[27
]}

Lutsey, Pamela L. ^{[15
]}

Murady, Sarwa Darwish ^{[13
,14
]}

Nordestgaard, Borge G. ^{[31
,32
,33
]}

Pasquale, Louis R. ^{[22
,23
]}

Reiner, Alex P. ^{[19
]}

Ridker, Paul M. ^{[29
,34
,35
]}

Rirnribi, Eric ^{[2
,3
,22
,23
]}

Rose, Lynda M. ^{[29
,34
,35
]}

Shaffer, Christian M. ^{[16
]}

Schafmayer, Clemens ^{[36
]}

Tamimi, Rulla M. ^{[2
,22
,23
]}

Uitterlinden, Andre G. ^{[11
,12
]}

Volker, Uwe ^{[37
]}

Volzke, Henry ^{[38
,39
,40
]}

Wakabayashi, Yoshiyuki ^{[41
]}

Wiggs, Janey L.

Zhu, Jun ^{[41
]}

Roden, Dan M. ^{[16
]}

Stricker, Bruno H. ^{[11
,12
]}

Tang, Weihong ^{[15
]}

Teumer, Alexander ^{[38
]}

机构：

[1] Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA

[2] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[3] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA

[4] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Dept Med, Boston, MA 02114 USA

[6] Harvard Med Sch, Boston, MA USA

[7] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA

[8] Tech Univ Dresden, Univ Hosp Dresden, Med Dept 1, Dresden, Germany

[9] Rigshosp, Ctr Heart, Dept Clin Biochem, Copenhagen, Denmark

[10] Rigshosp, Ctr Heart, Dept Cardiol, Copenhagen, Denmark

[11] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[12] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[13] Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands

[14] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA

[15] Vanderbilt Univ, Dept Med, Nashville, TN USA

[16] Vanderbilt Univ, Depat Biomed Informat, Nashville, TN USA

[17] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA

[18] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[19] Ulm Univ Hosp, Dept Internal Med 1, Ulm, Germany

[20] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA

[21] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA

[22] Brigham & Womens Hosp, Boston, MA USA

[23] Harvard Med Sch, Boston, MA USA

[24] Brigham & Womens Hosp, Dept Med, Div Renal, 75 Francis St, Boston, MA 02115 USA

[25] NHLBI, Populat Sci Branch, NIH, Framingham, MA USA

[26] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[27] Univ Kiel, Inst Epidemiol, Kiel, Germany

[28] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[29] Harvard Med Sch, Boston, MA USA

[30] Toronto Western & Gen Hosp, Univ Hlth Network, Toronto Ctr Liver Dis, Toronto, ON, Canada

[31] Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark

[32] Herlev Hosp, Dept Clin Biochem, Herlev, Denmark

[33] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[34] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA

[35] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA

[36] Univ Kiel, Dept Gen Abdominal Thorac & Transplantat, Kiel, Germany

[37] Univ Med Greifswald, Interfaculty Inst Genet & Funct Gen, Dept Funct Gen, Greifswald, Germany

[38] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[39] German Ctr Cardiovasc Res, Greifswald, Germany

[40] German Ctr Diabet Res, Greifswald, Germany

[41] NHLBI, DNA Sequencing Core Lab, Bldg 10, Bethesda, MD 20892 USA

来源：

GASTROENTEROLOGY | 2016年 / 151卷 / 02期

基金：

美国国家卫生研究院;

关键词：

Genetics; Risk Factors; SNP; GWAS; GENE-EXPRESSION; CHOLESTEROL TRANSPORTER; BILIRUBIN LEVELS; DNA METHYLATION; CANDIDATE GENES; ANALYSES REVEAL; EQTL ANALYSIS; RISK-FACTOR; CANCER; HEALTH;

D O I：

10.1053/j.gastro.2016.04.007

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 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 x 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 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 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 x 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.

引用

页码：351 / +

页数：41

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