Abstract
It is common to observe the clustering of chronic hepatitis B surface antigen (HBsAg) carriers in families. Intra-familial transmission of hepatitis B virus (HBV) could be the reason for the familial clustering of HBsAg carriers. Additionally, genetic and gender factors have been reported to be involved. We conducted a three-stage genome-wide association study to identify genetic factors associated with chronic HBV susceptibility. A total of 1,065 male controls and 1,623 male HBsAg carriers were included. The whole-genome genotyping was done on Illumina HumanHap550 beadchips in 304 healthy controls and HumanHap610 beadchips in 321 cases. We found that rs9277535 (HLA-DPB1, P = 4.87×10−14), rs9276370 (HLA-DQA2, P = 1.9×10−12), rs7756516 and rs7453920 (HLA-DQB2, P = 1.48×10−11 and P = 6.66×10−15 respectively) were significantly associated with persistent HBV infection. A novel SNP rs9366816 near HLA-DPA3 also showed significant association (P = 2.58×10−10). The “T-T-G-G-T” haplotype of the five SNPs further signified their association with the disease (P = 1.48×10−12; OR = 1.49). The “T-T” haplotype composed of rs7756516 and rs9276370 was more prevalent in severe disease subgroups and associated with non-sustained therapeutic response (P = 0.0262). The “G-C” haplotype was associated with sustained therapeutic response (P = 0.0132; OR = 2.49). We confirmed that HLA-DPB1, HLA-DQA2 and HLA-DQB2 loci were associated with persistent HBV infection in male Taiwan Han-Chinese. In addition, the HLA-DQA2 and -DQB2 complex was associated with clinical progression and therapeutic response.
Highlights
It is common to observe clustering of chronic hepatitis B surface antigen (HBsAg) carriers and hepatocellular carcinoma (HCC) in families of affected individuals [1,2,3,4,5]
Previous candidate gene studies suggested that human leukocyte antigen (HLA), cytokines, DNA repair and others were involved in hepatitis B virus (HBV) clearance or progression to hepatocarcinogenesis [8,9,10]
Based on the Linkage Disequilibrium (LD) block and the trend test P-value, fifteen SNPs were selected for the first replication in an independent cohort of 646 cases and 345 controls (Table S2)
Summary
It is common to observe clustering of chronic hepatitis B surface antigen (HBsAg) carriers and hepatocellular carcinoma (HCC) in families of affected individuals [1,2,3,4,5]. Most of the children born to the mothers with active HBV replications became HBsAg carriers This type of perinatal infection gives little room for genetic roles to participate [3]. The total number of HBsAg carriers was higher in children of male HCC patients (high horizontal transmission) than in children of female HCC patients (high perinatal infection) [5]. The clinical significance of these genes on HBV-related disease progression remained unclear. It could be shielded by multi-factorial problems associated with chronic HBV infection. It is well-known that the prevalence of HBsAg carriers in males is much higher than that in females [6]. We conducted a GWAS in male Taiwan-Han Chinese to examine the differences between non-HBsAg carriers, inactive HBsAg carriers and active HBV related liver diseases
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