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Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array.

TitleLipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array.
Publication TypeJournal Article
Year of Publication2016
AuthorsRodriguez S, Gaunt TR, Guo Y, Zheng J, Barnes MR, Tang W, Danish F, Johnson A, Castillo BA, Li YR, Hakonarson H, Buxbaum SG, Palmer T, Tsai MY, Lange LA, Ebrahim S, Smith GDavey, Lawlor DA, Folsom AR, Hoogeveen RC, Reiner A, Keating B
Secondary AuthorsDay INM
JournalEur J Hum Genet
Volume24
Issue1
Pagination106-12
Date Published2016 Jan
ISSN1476-5438
KeywordsAdaptor Proteins, Signal Transducing, Adult, ATP Binding Cassette Transporter, Subfamily G, Member 5, ATP Binding Cassette Transporter, Subfamily G, Member 8, ATP-Binding Cassette Transporters, Body Mass Index, Female, Gallbladder Diseases, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, Lipoproteins, Lipoproteins, HDL, Middle Aged, Obesity, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Risk Factors
Abstract

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 = 6.95 x 10(-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.

DOI10.1038/ejhg.2015.63
Alternate JournalEur J Hum Genet
PubMed ID25920552
PubMed Central IDPMC4681116
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
SP/07/008/24066 / / British Heart Foundation / United Kingdom
N01WH42129-32 / WH / WHI NIH HHS / United States
G0600705 / / Medical Research Council / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
N01WH32100-2 / WH / WHI NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
N01WH32108-9 / WH / WHI NIH HHS / United States
/ / Department of Health / United Kingdom
HHSN268200625226C / / PHS HHS / United States
N01WH42107-26 / WH / WHI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
P20 MD006899 / MD / NIMHD NIH HHS / United States
HHSN268201100012C / / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01WH32122 / WH / WHI NIH HHS / United States
MC_UU_12013/1 / / Medical Research Council / United Kingdom
HHSN268201100007C / / PHS HHS / United States
N01WH32105-6 / WH / WHI NIH HHS / United States
N01WH32111-13 / WH / WHI NIH HHS / United States
N01WH32118-32119 / WH / WHI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
MR/K002767/1 / / Medical Research Council / United Kingdom
HHSN268201100006C / / PHS HHS / United States
MC_UU_12013/5 / / Medical Research Council / United Kingdom
N01WH32115 / WH / WHI NIH HHS / United States
N01WH44221 / WH / WHI NIH HHS / United States
MC_UU_12013/8 / / Medical Research Council / United Kingdom
N01WH24152 / WH / WHI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
PG/07/131/24254 / / British Heart Foundation / United Kingdom