Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ∼53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10 -7, ß=-0.146) and TTC39B rs686030:C>A (P=6.95x10 -7, ß=0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10 -47, ß=0.734), ABCG8 rs4299376:G > T (P=2.40 × 10 -18, ß=0.278), ABCG5 rs6544718:T>C (P=2.08 × 10 -14, ß=0.044) and ABCG5 rs6720173:G>C (P=3.81 × 10 -12, ß = 0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.
Bibliographical noteFunding Information:
Data Access for the NHLBI Candidate gene Association Resource (CARe). The NHLBI initiated the CARe to create a shared genotype/phenotype resource for analyses of the association of genotypes with phenotypes relevant to the mission of the NHLBI. The resource comprises nine cohort studies funded by the NHLBI including: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Cleveland Family Study (CFS), Coronary Artery Risk Development in Young Adults (CARDIA), Framingham Heart Study (FHS), Jackson Heart Study (JHS), Multi-Ethnic Study of Atherosclerosis (MESA) and the Sleep Heart Health Study (SHHS). A database of genotype and phenotype data was created that includes records for ~ 41 000 study participants with ~ 50 000 SNPs from >2000 selected candidate genes. Data from individual cohorts such as ARIC are available to the approved investigators upon submission of data requests through the dbGaP portal.
ARIC: The ARIC study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. BWHHS: The BWHHS is supported by funding from the British Heart Foundation (BHF) and the Department of Health Policy Research Programme (England). HumanCVD genotyping of the BWHHHS was funded by the BHF (PG/07/131/24254).
WHI: The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The UK Medical Research Council (MRC) and the University of Bristol provide core funding for the MRC Centre of Causal Analyses in Translational Epidemiology (MRC grant G0600705). This work was also supported by the MRC project grant MR/K002767/1.
The CARe Consortium wishes to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research (NHLBI contract number HHSN268200960009C). The following nine parent studies have contributed parent study data, ancillary study data and DNA samples through the Massachusetts Institute of Technology—Broad Institute (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the ARIC study, the CHS, the CFS, the Cooperative Study of Sickle Cell Disease (CSSCD), the CARDIA study, the FHS, the JHS, the MESA and the SHHS.
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