Genetic variant in the hepatobiliary cholesterol transporter is associated with increased gallstone risk in the obese and with gallbladder cancer in general population

Introduction Gallstone disease (GD) is prevalent but typically remains symptom-free. Nevertheless, complications such as choledocholithiasis or gallbladder cancer can arise from gallstones. Both genetic predisposition as well as exogenous factors are known to modulate the gallstone risk. Here we analyse the link between the gallstone-associated variant p.D19H in the hepatobiliary sterol transporter ABCG8 and the development of gallstone-related complications.

Methods Prospectively we recruited three cohorts of adult patients: 65 with gallbladder cancer, 170 obese individuals awaiting bariatric surgery, and 72 patients who required endoscopic retrograde cholangiopancreatography (ERCP) for recurring choledocholithiasis. Our control cohort included 172 adults without a history of gallstones. The ABCG8 p.D19H polymorphism was identified through TaqMan assays.

Results The minor allele frequency (MAF) of the examined variant was notably higher (P=0.02) in cases with gallstones or gallbladder cancer (MAF=8.4%) compared to the control group (MAF=4.0%). The highest presence of the risk allele was observed in patients with gallbladder cancer (18.5%) and obese patients with gallstone disease (17.5%), succeeded by those with choledocholithiasis (13.9%). Specifically, this variant was linked with an elevated risk of gallbladder cancer development (OR 2.54, 95% CI 1.04-5.93, P=0.02). It also amplified the risk of GD in obese individuals due for bariatric surgery (OR=2.70, 95%CI 1.05–6.49, P=0.03), but it did not influence the risk for choledocholithiasis.

Conclusions The prevalent ABCG8 risk variant elevates the risk of gallbladder cancer and also intensifies the risk of gallstones in the obese. Individuals carrying the p.D19H variant might benefit from personalized preventative strategies.

Publication History

Article published online:
23 January 2024