Common variants inABCG8andTRAF3genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry
Authors
Bernabé Bustos, Eduardo Pérez-Palma, Stephan Buch, Lorena Azócar, Eleodoro Riveras, Giorgia Ugarte, Mohammad Toliat, Peter Nürnberg, Wolfgang Lieb, Andre Franke, Sebastian Hinz, Greta Burmeister, Witigo von Schönfels, Clemens Schafmayer, Henry Völzke, Uwe Völker, Georg Homuth, Marcus Lerch, José Luis Santos, Klaus Puschel, Claudia Bambs, Rodrigo Gutiérrez, Jochen Hampe, Giancarlo De Ferrari, Juan Francisco Miquel
Year of publication
2018Journal
UKNVolume
-Issue
-Abstract
Background
Latin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.
Methods
We performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P<1×10 −5 ) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.
Results
We consistently replicated the ABCG8 gene (rs11887534; P=3.24×10 −8 , OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within the TRAF3 gene on chromosome 14 (rs12882491; P=1.11×10 −7 , OR=1.40). ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.
Conclusions
We confirmed ABCG8 and identified TRAF3 both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.