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A novel variant marking HLA-DP expression levels predicts recovery from hepatitis B virus infection.

Abstract
Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3' untranslated regions (3'UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3'UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3'UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.
AuthorsRasmi Thomas, Chloe L Thio, Richard Apps, Ying Qi, Xiaojiang Gao, Darlene Marti, Judy L Stein, Kelly A Soderberg, M Anthony Moody, James J Goedert, Gregory D Kirk, W Keith Hoots, Steven Wolinsky, Mary Carrington
JournalJournal of virology (J Virol) Vol. 86 Issue 12 Pg. 6979-85 (Jun 2012) ISSN: 1098-5514 [Electronic] United States
PMID22496224 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • HLA-DP alpha-Chains
  • HLA-DP beta-Chains
  • HLA-DPA1 antigen
  • HLA-DPB1 antigen
Topics
  • Cohort Studies
  • Genetic Variation
  • Genome-Wide Association Study
  • HLA-DP alpha-Chains (genetics)
  • HLA-DP beta-Chains (genetics)
  • Hepatitis B (genetics)
  • Hepatitis B virus (physiology)
  • Humans
  • Racial Groups (genetics)

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