PT  - JOURNAL ARTICLE
AU  - Bernabé I. Bustos
AU  - Eduardo Pérez-Palma
AU  - Stephan Buch
AU  - Lorena Azócar
AU  - Eleodoro Riveras
AU  - Giorgia D. Ugarte
AU  - Mohammad Toliat
AU  - Peter Nürnberg
AU  - Wolfgang Lieb
AU  - Andre Franke
AU  - Sebastian Hinz
AU  - Greta Burmeister
AU  - Witigo von Shönfels
AU  - Clemens Schafmayer
AU  - Henry Völzke
AU  - Uwe Völker
AU  - Georg Homuth
AU  - Marcus M. Lerch
AU  - José Luis Santos
AU  - Klaus Puschel
AU  - Claudia Bambs
AU  - Rodrigo A. Gutiérrez
AU  - Jochen Hampe
AU  - Giancarlo V. De Ferrari
AU  - Juan Francisco Miquel
TI  - Common variants in <em>ABCG8</em> and <em>TRAF3</em> genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry
AID  - 10.1101/265728
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 265728
4099  - http://biorxiv.org/content/early/2018/02/20/265728.short
4100  - http://biorxiv.org/content/early/2018/02/20/265728.full
AB  - 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.