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Gastroenterology. 2016 Aug;151(2):351-363.e28. doi: 10.1053/j.gastro.2016.04.007. Epub 2016 Apr 16.

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

Author information

1
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. Electronic address: ajoshi@hsph.harvard.edu.
2
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts. Electronic address: ca@heart.dk.
3
Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.
4
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
5
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
6
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minnesota.
7
Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.
8
Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee, Wisconsin; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
9
Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany.
10
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts.
11
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts.
12
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
13
Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee.
14
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
15
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts.
16
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
17
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
18
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
19
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
20
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
21
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
22
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
23
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada.
24
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
25
Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
26
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
27
The Copenhagen General Population Study, Herlev Hospital, Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
28
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
29
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
30
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
31
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
32
Department of General, Abdominal, Thoracic and Transplantation Surgery, University of Kiel, Kiel, Germany.
33
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
34
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
35
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; German Center for Cardiovascular Research, Greifswald, Germany; German Center for Diabetes Research, Greifswald, Germany.
36
National Heart, Lung, and Blood Institute, DNA Sequencing Core Laboratory, Bethesda, Maryland.
37
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
38
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
39
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Herlev, Denmark.
40
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; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: achan@mgh.harvard.edu.
41
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts. Electronic address: johnsonad2@nhlbi.nih.gov.

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.

KEYWORDS:

GWAS; Genetics; Risk Factors; SNP

PMID:
27094239
PMCID:
PMC4959966
DOI:
10.1053/j.gastro.2016.04.007
[Indexed for MEDLINE]
Free PMC Article

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