Universität zu Köln

Bustos, Bernabe I., Perez-Palma, Eduardo ORCID: 0000-0003-0546-5141, Buch, Stephan, Azocar, Lorena, Riveras, Eleodoro, Ugarte, Giorgia D., Toliat, Mohammad, Nuernberg, Peter, Lieb, Wolfgang, Franke, Andre, Hinz, Sebastian, Burmeister, Greta, von Schoenfels, Witigo, Schafmayer, Clemens, Voelzke, Henry, Voelker, Uwe, Homuth, Georg, Lerch, Markus M. ORCID: 0000-0002-9643-8263, Luis Santos, Jose, Puschel, Klaus, Bambs, Claudia, Carlos Roa, Juan, Gutierrez, Rodrigo A., Hampe, Jochen ORCID: 0000-0002-2421-6127, De Ferrari, Giancarlo V. and Francisco Miquel, Juan (2019). Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry. Sci Rep, 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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Abstract

Latin Americans and Chilean Amerindians have the highest prevalence of 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 genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P < 1 x 10(-5) in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 x 10(-8), OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 x 10(-7), OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bustos, Bernabe I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez-Palma, Eduardo UNSPECIFIED orcid.org/0000-0003-0546-5141 UNSPECIFIED Buch, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Azocar, Lorena UNSPECIFIED UNSPECIFIED UNSPECIFIED Riveras, Eleodoro UNSPECIFIED UNSPECIFIED UNSPECIFIED Ugarte, Giorgia D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Lieb, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Hinz, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Burmeister, Greta UNSPECIFIED UNSPECIFIED UNSPECIFIED von Schoenfels, Witigo UNSPECIFIED UNSPECIFIED UNSPECIFIED Schafmayer, Clemens UNSPECIFIED UNSPECIFIED UNSPECIFIED Voelzke, Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Voelker, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Homuth, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Lerch, Markus M. UNSPECIFIED orcid.org/0000-0002-9643-8263 UNSPECIFIED Luis Santos, Jose UNSPECIFIED UNSPECIFIED UNSPECIFIED Puschel, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Bambs, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Carlos Roa, Juan UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutierrez, Rodrigo A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hampe, Jochen UNSPECIFIED orcid.org/0000-0002-2421-6127 UNSPECIFIED De Ferrari, Giancarlo V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Francisco Miquel, Juan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-158831
DOI:	10.1038/s41598-018-35852-z
Journal or Publication Title:	Sci Rep
Volume:	9
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; NF-KAPPA-B; BILIARY-TRACT CANCERS; GALLBLADDER CANCER; POPULATION; INFLAMMATION; CHOLECYSTECTOMY; SUSCEPTIBILITY; EPIDEMIOLOGY; PREVALENCE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15883