Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array.
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.
Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Santiago
S
Rodriguez
Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
Tom R
TR
Gaunt
Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.|BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, China.
Yiran
http://orcid.org/0000-0002-6549-8589
Y
Guo
Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Jie
J
Zheng
William Harvey Research Institute National Institute for Health Biomedical Research Unit, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
Michael R
http://orcid.org/0000-0001-9097-7381
MR
Barnes
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
Weihang
W
Tang
Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Fazal
F
Danish
National Heart, Lung and Blood Institute, The Framingham Heart Study, Framingham, MA, USA.
Andrew
A
Johnson
Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
Berta A
BA
Castillo
Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
Yun R
http://orcid.org/0000-0002-8077-4975
YR
Li
Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
Hakon
H
Hakonarson
Jackson Heart Study, Jackson State University, Jackson, MS; School of Health Sciences, Department of Epidemiology and Biostatistics, Jackson State University, Jackson, MS, USA.
Sarah G
http://orcid.org/0000-0002-4886-3564
SG
Buxbaum
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
Tom
T
Palmer
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Michael Y
MY
Tsai
Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, USA.
Leslie A
LA
Lange
Department of Non-communicable Disease Epidemiology, The London School of Hygiene & Tropical Medicine, London, UK.
Shah
S
Ebrahim
MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
George
G
Davey Smith
MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
Debbie A
DA
Lawlor
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
Aaron R
AR
Folsom
Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Ron
R
Hoogeveen
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Alex
A
Reiner
Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
Brendan
B
Keating
Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Ian N M
IN
Day
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D015992:Body Mass Index; D005260:Female; D005705:Gallbladder Diseases / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D008075:Lipoproteins, HDL / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human; D008074:Lipoproteins; D008075:Lipoproteins, HDL