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.
Highlights
Hepatitis B virus (HBV) infection is a major global health problem, resulting in 0.5–1.0 million deaths per year [1]
10– 15% develops liver cirrhosis (LC), liver failure and hepatocellular carcinoma (HCC), and the remaining individuals eventually achieve a state of nonreplicative infection, resulting in HBsAg negative and anti-HBc positive, i.e. HBVresolved individuals
The human leukocyte antigen (HLA)-DPA1 and HLA-DPB1 genes were identified as host genetic factors significantly associated with chronic hepatitis B (CHB) infection, mainly in Asian populations [7,8,9,10,11,12], and not in European populations [13]
Summary
Hepatitis B virus (HBV) infection is a major global health problem, resulting in 0.5–1.0 million deaths per year [1]. The prevalence of chronic HBV infection varies. Due to the introduction of vaccination programs, the prevalence of HBV infection in many countries has gradually been decreasing with consequent decreases in HBV-related hepatocellular carcinoma (HCC) [3]. Some HBV carriers spontaneously eliminate the virus, about 10–15% of carriers develop liver cirrhosis (LC), liver failure and HCC [4]. The progression of liver disease was revealed to be associated with the presence of several distinct mutations in HBV infections [5]. 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]
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