HLA-B*35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum-Induced Liver Injury in Humans

Hepatology. 2019 Jul;70(1):346-357. doi: 10.1002/hep.30660. Epub 2019 May 21.

Abstract

Polygonum multiflorum (PM) is a well-known Chinese herbal medicine that has been reported to induce inflammation-associated idiosyncratic liver injury. This study aimed to identify the genetic basis of susceptibility to PM-drug-induced liver injury (PM-DILI) and to develop biological markers for predicting the risk of PM-DILI in humans. The major histocompatibility complex (MHC) regions of 11 patients with PM-DILI were sequenced, and all human leukocyte antigen (HLA)-type frequencies were compared to the Han-MHC database. An independent replication study that included 15 patients with PM-DILI, 33 patients with other DILI, and 99 population controls was performed to validate the candidate allele by HLA-B PCR sequence-based typing. A prospective cohort study that included 72 outpatients receiving PM for 4 weeks was designed to determine the influence of the risk allele on PM-DILI. In the pilot study, the frequency of HLA-B*35:01 was 45.4% in PM-DILI patients compared with 2.7% in the Han Chinese population (odds ratio [OR], 30.4; 95% confidence interval [CI], 11.7-77.8; P = 1.9 × 10-10 ). In the independent replication study and combined analyses, a logistic regression model confirmed that HLA-B*35:01 is a high-risk allele of PM-DILI (PM-DILI versus other DILI, OR, 86.5; 95% CI, 14.2-527.8, P = 1.0 × 10-6 ; and PM-DILI versus population controls, OR, 143.9; 95% CI, 30.1-687.5, P = 4.8 × 10-10 ). In the prospective cohort study, an asymptomatic increase in transaminase levels was diagnosed in 6 patients, representing a significantly higher incidence (relative risk, 8.0; 95% CI, 1.9-33.2; P < 0.02) in the HLA-B*35:01 carriers (37.5%) than in the noncarriers (4.7%). Conclusion: The HLA-B*35:01 allele is a genetic risk factor for PM-DILI and a potential biomarker for predicting PM-DILI in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asian People / genetics
  • Biomarkers
  • Chemical and Drug Induced Liver Injury / genetics*
  • Drugs, Chinese Herbal / toxicity
  • Fallopia multiflora / toxicity*
  • Female
  • HLA-B35 Antigen / genetics*
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenomic Variants
  • Pilot Projects
  • Prospective Studies
  • Young Adult

Substances

  • Biomarkers
  • Drugs, Chinese Herbal
  • HLA-B*35:01 antigen
  • HLA-B35 Antigen