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

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  • Santiago Rodriguez
  • Tom R. Gaunt
  • Yiran Guo
  • Jie Zheng
  • Michael R. Barnes
  • Weihang Tang
  • Fazal Danish
  • Andrew Johnson
  • Berta A. Castillo
  • Yun R. Li
  • Hakon Hakonarson
  • Sarah G. Buxbaum
  • Michael Y. Tsai
  • Leslie A. Lange
  • Shah Ebrahim
  • George Davey Smith
  • Debbie A. Lawlor
  • Aaron R. Folsom
  • Ron Hoogeveen
  • Alex Reiner
  • Brendan Keating
  • Ian Nm Day
<mark>Journal publication date</mark>01/2016
<mark>Journal</mark>European Journal of Human Genetics
Issue number1
Number of pages7
Pages (from-to)106-112
Publication StatusPublished
Early online date29/04/15
<mark>Original language</mark>English


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.European Journal of Human Genetics advance online publication, 29 April 2015; doi:10.1038/ejhg.2015.63.