title: 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.
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
authors.forename: Rasmi
authors.initials: R
authors.lastname: Thomas
authors.forename: Chloe L
authors.initials: CL
authors.lastname: Thio
authors.forename: Richard
authors.initials: R
authors.lastname: Apps
authors.forename: Ying
authors.initials: Y
authors.lastname: Qi
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Gao
authors.forename: Darlene
authors.initials: D
authors.lastname: Marti
authors.forename: Judy L
authors.initials: JL
authors.lastname: Stein
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Soderberg
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.forename: W Keith
authors.initials: WK
authors.lastname: Hoots
authors.forename: Steven
authors.initials: S
authors.lastname: Wolinsky
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
mesh_terms: D015331:Cohort Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059867:HLA-DP alpha-Chains / Q000235:genetics*; D059868:HLA-DP beta-Chains / Q000235:genetics*; D006509:Hepatitis B / Q000235:genetics*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D044469:Racial Groups / Q000235:genetics*
chemical_list: D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen