title: Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver.
abstract: A genome-wide association study identified single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 located in the 3' untranslated regions of human leukocyte antigen (HLA) class II genes HLA-DPA1 and HLA-DPB1, respectively, as the independent variants most strongly associated with chronic hepatitis B. We examined whether these SNPs are associated with mRNA expression of HLA-DPA1 and HLA-DPB1. We identified gene expression-associated SNPs (eSNPs) in normal liver samples obtained from 651 individuals of European ancestry by integrating genotype (~650 000 SNPs) and gene expression (>39 000 transcripts) data from each sample. We used the Kruskal-Wallis test to determine associations between gene expression and genotype. To confirm findings, we measured allelic expression imbalance (AEI) of complementary DNA compared with DNA in liver specimens from subjects who were heterozygous for rs3077 and rs9277535. On a genome-wide basis, rs3077 was the SNP most strongly associated with HLA-DPA1 expression (p=10(-48)), and rs9277535 was strongly associated with HLA-DPB1 expression (p=10(-15)). Consistent with these gene expression associations, we observed AEI for both rs3077 (p=3.0 × 10(-7); 17 samples) and rs9277535 (p=0.001; 17 samples). We conclude that the variants previously associated with chronic hepatitis B are also strongly associated with mRNA expression of HLA-DPA1 and HLA-DPB1, suggesting that expression of these genes is important in control of HBV.
authors.affiliation: Infections and Immunoepidemiology Branch, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. obrient@mail.nih.gov
authors.forename: T R
authors.initials: TR
authors.lastname: O'Brien
authors.forename: I
authors.initials: I
authors.lastname: Kohaar
authors.forename: R M
authors.initials: RM
authors.lastname: Pfeiffer
authors.forename: D
authors.initials: D
authors.lastname: Maeder
authors.forename: M
authors.initials: M
authors.lastname: Yeager
authors.forename: E E
authors.initials: EE
authors.lastname: Schadt
authors.forename: L
authors.initials: L
authors.lastname: Prokunina-Olsson
mesh_terms: D020413:3' Untranslated Regions; D000483:Alleles; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059867:HLA-DP alpha-Chains / Q000235:genetics* / Q000276:immunology; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008099:Liver / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis*
chemical_list: D020413:3' Untranslated Regions; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen; D012333:RNA, Messenger