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

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.

Copy number variants in lipid metabolism genes are associated with gallstones disease in men

“…Although these genes are involved in lipid and glucose metabolism, as well as in inflammatory response processes, which are strongly related to the etiology of the disease [1,9], the signals reported exhibit modest to low effect sizes (OR < 2) conferring minimal risk to the carriers [10]. Moreover, we have recently reported ethnicspecific genome-wide associations in a high-risk admixed Latin American population with no evident replication of the aforementioned meta-analysis signals [6], reflecting the complex genetic composition of GSD.…”

“…Initially, a total of 5568 individuals were collected through three independent studies: (i) The PopGen Population Genetics Biobank (POPGEN) from Kiel, Germany, comprising 2274 individuals of European origin; (ii) The Study of Health in Pomerania second follow-up (SHIP-2) from Greifswald, Germany, with 2059 individuals of European origin; and (iii) The Chilean Latin American cohort (ANCORA) from Santiago, Chile, comprising 1235 individuals [6]. POPGEN and SHIP-2 dataset were conceived as population based cohorts designed to study complex and prevalent diseases in German populations, including cardiovascular, neurodegenerative, and metabolic disorders such as GSD.…”

“…For all three datasets, written informed consent was obtained from all participants and the corresponding ethics committees approved study protocols. Further specific details regarding study design and recruitment for POPGEN [18], SHIP-2 [19], and ANCORA [6] datasets are provided in their original publications.…”

“…GSD has a moderate to strong genetic component [2,3] with an estimated heritability (i.e., the fraction of cases explained by additive genetic factors) above 25% in Europeans [4] and as high as 50% in admixed Latin American populations [2,5]. To date, the strongest and most consistently replicated common genetic variants associated with GSD reside in the ATP-binding cassette subfamily G member 5/8 ABCG5/8 gene (rs11887534; hg19, chr2:44066247G>C) [3,6] and in the UDP glucuronosyltransferase family 1 member A1 UGT1A1 gene (rs6742078; hg19, chr2:234672639G>T), with the latter significantly associated with GSD only in men [7]. Both variants explain from~50 down to 29% of the heritability observed for European and Latin populations [5], respectively, which suggests that additional variants remain to be discovered.…”

A Six-Year Retrospective Follow-up of 502 Patients with Laparoscopic Cholelithotomy for Gallstone Recurrence: Success or Prospect

“…The gallbladder is a pear-shaped elastic sac located under the ribcage and below the liver. This organ concentrates and stores bile 1 . With the advent of minimally invasive surgery and increasing clinical application of laparoscopy, laparoscopic cholelithotripsy has been widely used to remove gallstones.…”