Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry

Bustos, B. I.; Perez-Palma, E.; Buch, S.; Azocar, L.; Riveras, E.; Ugarte, G. D.; Toliat, M.; Nuernberg, P.; Lieb, W.; Franke, A.; Hinz, S.; Burmeister, G.; von Shoenfels, W.; Schafmayer, C.; Voelzke, H.; Voelker, U.; Homuth, G.; Lerch, M. M.; Santos, J. L.; Puschel, K.; Bambs, C.; Gutierrez, R. A.; Hampe, J.; De Ferrari, G. V.; Miquel, J. F.

doi:10.1101/265728

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bioRxiv · 10.1101/265728

Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry

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Abstract

BackgroundLatin 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.\n\nMethodsWe 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<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.\n\nResultsWe 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.\n\nConclusionsWe 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.

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Bustos, B. I., Perez-Palma, E., Buch, S., Azocar, L., Riveras, E., Ugarte, G. D., Toliat, M., Nuernberg, P., Lieb, W., Franke, A., Hinz, S., Burmeister, G., von Shoenfels, W., Schafmayer, C., Voelzke, H., Voelker, U., Homuth, G., Lerch, M. M., Santos, J. L., Puschel, K., Bambs, C., Gutierrez, R. A., Hampe, J., De Ferrari, G. V., Miquel, J. F.. 2018-02-20. Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry. https://doi.org/10.1101/265728

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