Common variants inABCG8andTRAF3genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry

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 genomewide significance (P<1x10 -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=3.24x10 -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=1.11x10 -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. Conslusions: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.Gallstone disease (GSD) is a complex gastrointestinal disorder defined by the development of gallstones in the gallbladder, most of the time cholesterol compounds. 1 The presence of gallstones are common in the world population (~10-20% of presence in adults) and although their appearance can remain silent throughout life, more than 20% of the patients develop symptoms that include intense abdominal pain, jaundice, fever, nausea and vomiting, requiring medical attention and therefore establishing itself as a clinical condition . 2 Main complications of GSD are acute cholecystitis, acute pancreatitis and bile duct obstruction, 3 and these are generally treated by surgical removal of the gallbladder (cholecystectomy). In Chile, these procedures accounts for more than 40,000 interventions each year, 4 with a net cost of more than US $25 million for the public healthcare system. GSD is also the main risk factor for gallbladder cancer (GBC), a disease that presents a high mortality rates in Chile (38.2 deaths per 100,000 inhabitants). 5 In the vast majority of cases, GBC is an adenocarcinoma characterized by high lethality due to late diagnosis and the ineffectiveness of chemotherapy/radiotherapy. With the removal of the gallbladder and its stones, GBC risk is consid...