A newly described genetic mutation in East Asia is associated with risk for cholestasis of pregnancy and protection against hepatitis B infection
Liu Y et al, J Hepatol. 2025;82(5):826-835
This genome-wide association study from China with nearly 100,000 pregnant women identified risk mutations for elevated bile acids and cholestasis of pregnancy. One mutation is located in the NTCP gene, which encodes a bile acid transporter through which hepatitis B viruses (HBV) infect hepatocytes. This mutation confers protection from HBV infection, thus leading to the increased prevalence of this protective mutation in East Asia.
Background and aims: Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. The understanding of the mechanisms underlying ICP and population-level differences remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution.
Methods: The authors conducted the hitherto largest-scale genome-wide association study on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in 3 cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci.
Results: They identified 8 loci for fasting TBA and 4 for ICP, including 10 novel loci. Notably, they discovered an East Asian-specific locus within a 0.4 Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/l and ICP risk by 16.56-fold per risk allele (95% confidence interval: 16.43–16.69, p = 7.06×10-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3000 years.
Conclusions: The authors uncovered a distinct genetic etiology of intrahepatic cholestasis of pregnancy (ICP) in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder.