Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry.

TitelVariants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry.
MedientypJournal Article
Jahr der Veröffentlichung2019
AutorenBustos BI, Pérez-Palma E, Buch S, Azócar L, Riveras E, Ugarte GD, Toliat M, Nürnberg P, Lieb W, Franke A, Hinz S, Burmeister G, von Schönfels W, Schafmayer C, Völzke H, Völker U, Homuth G, Lerch MM, Santos JLuis, Puschel K, Bambs C, Roa JCarlos, Gutiérrez RA, Hampe J, De Ferrari GV, Miquel JFrancisco
JournalSci Rep
Volume9
Ausgabe1
Pagination772
Datum der Veröffentlichung2019 Jan 28
ISSN2045-2322
Zusammenfassung

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 × 10 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 × 10, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 10, 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.

DOI10.1038/s41598-018-35852-z
Alternate JournalSci Rep
PubMed ID30692554
Grant List1180848 / / Fondo Nacional de Desarrollo Cient&amp;#x00ED;fico y Tecnol&amp;#x00F3;gico (National Fund for Scientific and Technological Development) /
1140353 / / Fondo Nacional de Desarrollo Cient&amp;#x00ED;fico y Tecnol&amp;#x00F3;gico (National Fund for Scientific and Technological Development) /
1130303 / / Fondo Nacional de Desarrollo Cient&amp;#x00ED;fico y Tecnol&amp;#x00F3;gico (National Fund for Scientific and Technological Development) /