TY - JOUR
T1 - Lipids, obesity and gallbladder disease in women
T2 - Insights from genetic studies using the cardiovascular gene-centric 50K SNP array
AU - Rodriguez, Santiago
AU - Gaunt, Tom R.
AU - Guo, Yiran
AU - Zheng, Jie
AU - Barnes, Michael R.
AU - Tang, Weihang
AU - Danish, Fazal
AU - Johnson, Andrew
AU - Castillo, Berta A.
AU - Li, Yun R.
AU - Hakonarson, Hakon
AU - Buxbaum, Sarah G.
AU - Palmer, Tom
AU - Tsai, Michael Y.
AU - Lange, Leslie A.
AU - Ebrahim, Shah
AU - Smith, George Davey
AU - Lawlor, Debbie A.
AU - Folsom, Aaron R.
AU - Hoogeveen, Ron
AU - Reiner, Alex
AU - Keating, Brendan
AU - Day, Ian N M
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/ejhg.2015.63
DO - 10.1038/ejhg.2015.63
M3 - Article
C2 - 25920552
AN - SCOPUS:84951574146
SN - 1018-4813
VL - 24
SP - 106
EP - 112
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -