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 × 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.
Highlights
Gallstone disease (GSD) is a complex gastrointestinal disorder defined by the presence of gallstones in the gallbladder, most of the time made of cholesterol compounds[1]
We tested for genetic association with GSD by performing a logistic regression analysis adjusted by age, since other known associated covariates such as sex, body mass index (BMI; cases = 29.44 ± 4.28, controls = 29.66 ± 3.94, one-way ANOVA P = 0.376) and native American ancestry proportion, did not differ significantly between cases and controls
We report that common genetic variants within the ABCG8 and TRAF3 genes confer risk to GSD and gallbladder cancer (GBC) in the admixed Chilean population
Summary
Gallstone disease (GSD) is a complex gastrointestinal disorder defined by the presence of gallstones in the gallbladder, most of the time made of cholesterol compounds[1]. The most important genetic risk factor is the ATP-binding cassette, sub-family G (WHITE), member 8, ABCG8 gene[10], an hepatic sterolin transporter where the associated polymorphism (p.D19H, rs11887534) is linked to a gain-of-function responsible for the hyper secretion of cholesterol-saturated bile[11]. A meta-analysis involving 8,720 GSD cases and 55,152 controls identified four additional risk factors, including the Transmembrane 4 L six family member 4, TM4SF4 gene (rs9843304), the Sulfotransferase family 2 A member 1 SULT2A1 gene (rs2547231), the glucokinase regulator, GCKR gene (rs1260326) and the cytochrome P450 family 7 subfamily A member 1, CYP7A1 gene (rs6471717)[15] None of these novel risk factors have been studied in the Chilean population. We hypothesized that a high-density GWAS for GSD in admixed Latinos could identify population specific variants, define the GSD genetic landscape and reveal novel pathological mechanisms
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