A Common HLA-DPA1 Variant is a Major Determinant of Hepatitis B Virus Clearance in Han Chinese

Basic Research Laboratory, SAIC-Frederick, Maryland, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 04/2011; 203(7):943-7. DOI: 10.1093/infdis/jiq154
Source: PubMed


A recent genome-wide study showed that the single nucleotide polymorphisms (SNPs) in the HLA-DP region were associated with chronic hepatitis B virus (HBV) infection in Japanese and Thai persons. We tested the effects of HLA-DP SNPs for all major HBV outcomes in Han Chinese (n = 1742): HBV resistance, clearance, chronic infection, cirrhosis, and hepatocellular carcinoma. HLA - DPA1 rs3077 T was strongly associated with decreased risk of chronic HBV infection (odds ratio, .62; P = .001), consistent with the previous report. We showed for the first time to our knowledge that it is a predictor for HBV clearance (odds ratio, 2.41; P < .001). However, rs3077 was not associated with the development of cirrhosis or hepatocellular carcinoma.

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    • "Genetic variations in STAT4 and HLA-DQ genes were recently identified as host genetic factors in a large-scale genome-wide association study (GWAS) for HBV-related HCC in China [6]. With regard to the genes associated with susceptibility to chronic HBV infection, HLA-DP and HLA-DQ genes were identified by GWAS in Japanese and Thai populations in 2009 [7] and 2011 [8], respectively. In addition, our previous GWAS confirmed and identified the association of SNP markers located on HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535) genes with susceptibility to chronic hepatitis B (CHB) and HBV clearance in Japanese and Korean subjects[9]. "
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    ABSTRACT: Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09∶01 (P = 1.36×10(-6); OR = 1.97; 95% CI, 1.50-2.59) and a new protective allele DPB1*02∶01 (P = 5.22×10(-6); OR = 0.68; 95% CI, 0.58-0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02∶01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55×10(-7); OR = 0.50; 95% CI, 0.39-0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.
    PLoS ONE 02/2014; 9(2):e86449. DOI:10.1371/journal.pone.0086449 · 3.23 Impact Factor
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    • "Among the 706 HBsAg-negative subjects, 202 had previous history of hepatitis B vaccination and were excluded from the subsequent analysis. All study patients/subjects are Chinese, and all blood samples were collected during the period January 2010 to March 2011. All subjects were tested negative for hepatitis C virus and human immunodeficiency virus by the Procleix Ultrio Assay (Novartis Diagnostics, Emeryville, CA). "
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    ABSTRACT: The association between HLA-DP single nucleotide polymorphisms (SNPs) and chronic hepatitis B virus (HBV) infection varies between different populations. We aimed to study the association between HLA-DP SNPs and HBV infection and disease activity in the Chinese population of Hong Kong. We genotyped SNPs rs3077 (near HLA-DPA1) and rs9277378 and rs3128917 (both near HLA-DPB1) in 500 HBV carriers (hepatitis B surface antigen [HBsAg]-positive), 245 non-HBV infected controls (HBsAg- and antibody to hepatitis B core protein [anti-HBc]-negative), and 259 subjects with natural HBV clearance (HBsAg-negative, anti-HBc-positive). Inactive HBV carriers state was defined by HBV DNA levels <2,000 IU/ml and persistently normal alanine aminotransferase level for least 12 months. Compared to the non-HBV infected subjects, the HBV carriers had a significantly lower frequency of the rs3077 T allele (p = 0.0040), rs9277378 A allele (p = 0.0068) and a trend for lower frequency of rs3128917 T allele (p = 0.054). These alleles were associated with an increased chance of HBV clearance (rs3077: OR = 1.41, p = 0.0083; rs9277378: OR = 1.61, p = 0.00011; rs3128917: OR = 1.54, p = 0.00017). Significant associations between HLA-DP genotypes and HBV clearance were also found under different genetic models. Haplotype TAT was associated with an increased chance of HBV clearance (OR = 1.64, p = 0.0013). No association was found between these SNPs and HBV disease activity. HLA-DP SNPs rs3077, rs9277378 and rs3128917 were associated with chronicity of HBV disease in the Chinese. Further studies are required to determine whether these SNPs influence the disease endemicity in different ethnic populations.
    PLoS ONE 06/2013; 8(6):e66920. DOI:10.1371/journal.pone.0066920 · 3.23 Impact Factor
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    • "In the independent case–control study, we inferred that the genotype distributions and the frequencies of two protective alleles A of both sites (rs3077 and rs9277535) in our southwest Chinese populations were similar to those in Asian populations, compared with European and Central American populations (data from HapMap databases). The results of the genetic association in our study were also consistent with the previous study (An et al., 2011; Guo et al., 2011; Hu et al., 2011; Li et al., 2011; Wang et al., 2011). The results of our mini meta-analysis of these two SNPs also indicate HLA-DP rs3077-A and rs9277535-A alleles may be the protective factors for HBV clearance. "
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    ABSTRACT: Hepatitis B virus (HBV) infection is a serious public health problem worldwide. Two common genetic variants (rs3077 and rs9277535) of human leukocyte antigen DP (HLA-DP) have been reported to be associated with persistent HBV infection in populations of Japan and Thailand. To confirm whether the association can be replicated in Chinese populations, an independent case-control study were conducted, and two polymorphisms (rs3077 and rs9277535) were genotyped using the TaqMan SNP genotyping assay in 282 persistent chronic HBV carriers and 64 spontaneously HBV recovered carriers. To provide a more definitive conclusion, a meta-analysis combining and summarizing five studies was performed by random-effects model using the DerSimonian and Laird's method. By using logistic regression analysis with adjustment for covariates, including age, sex, and alcohol consumption, the results of our independent case-control study showed that the minor allele's homozygote (AA genotype) of rs3077 and rs9277535 was significantly associated with decreasing risk/protection of HBV persistent chronic infection (for rs3077: P=0.0017, OR=0.29, 95% CI=0.13-0.62; for rs9277535, P=0.0004, OR=0.26, 95% CI=0.12-0.54). The results of meta-analysis pooling all eligible studies also showed that rs3077-A and rs9277535-A alleles were associated with an increased clearance rate to HBV infection (rs3077: OR=0.57, 95% CI=0.44-0.75; rs9277535: OR=0.56, 95% CI=0.47-0.63). These results further confirmed the strong influence of HLA-DP gene variants on risk of spontaneous HBV clearance from persistent HBV infection. Both A alleles of HLA-DP SNP rs3077 and rs9277535 showed strong protective effects for spontaneous HBV clearance from persistent HBV infection in the Han Chinese population.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 04/2012; 12(6):1222-8. DOI:10.1016/j.meegid.2012.03.026 · 3.02 Impact Factor
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