TY - JOUR
T1 - Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry
AU - Bustos, Bernabé I.
AU - Pérez-Palma, Eduardo
AU - Buch, Stephan
AU - Azócar, Lorena
AU - Riveras, Eleodoro
AU - Ugarte, Giorgia D.
AU - Toliat, Mohammad
AU - Nürnberg, Peter
AU - Lieb, Wolfgang
AU - Franke, Andre
AU - Hinz, Sebastian
AU - Burmeister, Greta
AU - von Schönfels, Witigo
AU - Schafmayer, Clemens
AU - Völzke, Henry
AU - Völker, Uwe
AU - Homuth, Georg
AU - Lerch, Markus M.
AU - Santos, José Luis
AU - Puschel, Klaus
AU - Bambs, Claudia
AU - Roa, Juan Carlos
AU - Gutiérrez, Rodrigo A.
AU - Hampe, Jochen
AU - De Ferrari, Giancarlo V.
AU - Miquel, Juan Francisco
N1 - Funding Information:
We gratefully acknowledge GSD and GBC affected and unaffected individuals who participated in this study. This work was funded by grants from Fondo de Areas Prioritarias (FONDAP) Center for Genome Regulation (1509000) and Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 1140353 and 1180848 to G.V.D, 1130303 to J.F.M and from the Postdoctoral grant 3160400 to E.R. The Immunohistochemical analysis was supported by the Unidad de Microscopia Avanzada (de Ciencias Biológicas o de Medicina) facility at the Pontificia Universidad Catolica de Chile. The PopGen 2.0 network was supported by a grant from the German Federal Ministry of Education and Research (01EY1103). SHIP-Greifswald is part of the Community Medicine Research net of the University of Greifswald (Germany), which is funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania, and the network “Greifswald Approach to Individualized Medicine” funded by the Federal Ministry of Education and Research (grant 03IS2061A). SHIP-Greifswald genome-wide data have been supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare (Erlangen, Germany) and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/1/28
Y1 - 2019/1/28
N2 -
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
−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 × 10
−8
, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 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.
AB -
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
−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 × 10
−8
, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 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.
UR - http://www.scopus.com/inward/record.url?scp=85060625889&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-35852-z
DO - 10.1038/s41598-018-35852-z
M3 - Article
C2 - 30692554
AN - SCOPUS:85060625889
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 772
ER -