A Genome-Wide Association Study on Chronic HBV Infection and Its Clinical Progression in Male Han-Taiwanese

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.家族聚集性慢性乙型肝炎表面抗原（hepatitis B surface antigen，HBsAg）携带者的现象较为普遍。乙型肝炎病毒（hepatitis B virus，HBV）的家族内传播被认为是HBsAg携带者出现家族聚集的原因之一。此外，遗传与性别因素也被证实与此相关。我们开展了一项三阶段全基因组关联研究（genome-wide association study），以筛选与慢性HBV感染易感性相关的遗传因素。本研究共纳入1065名男性对照与1623名男性HBsAg携带者。其中304名健康对照与321名病例分别通过Illumina HumanHap550基因微珠芯片、Illumina HumanHap610基因微珠芯片完成全基因组基因分型。我们发现，rs9277535（位于HLA-DPB1基因，P=4.87×10^-14）、rs9276370（位于HLA-DQA2基因，P=1.9×10^-12）、rs7756516与rs7453920（分别位于HLA-DQB2基因，对应P值依次为1.48×10^-11与6.66×10^-15）与持续性HBV感染存在显著关联。位于HLA-DPA3基因邻近区域的新型单核苷酸多态性（single nucleotide polymorphism，SNP）rs9366816同样表现出显著关联（P=2.58×10^-10）。上述5个SNP构成的“T-T-G-G-T”单倍型（haplotype）进一步证实了其与疾病的关联（P=1.48×10^-12；比值比（odds ratio，OR）=1.49）。由rs7756516与rs9276370构成的“T-T”单倍型在重症疾病亚组中分布更为广泛，且与治疗无持续应答显著相关（P=0.0262）。而“G-C”单倍型则与治疗持续应答相关（P=0.0132；OR=2.49）。本研究证实，在中国台湾汉族男性人群中，HLA-DPB1、HLA-DQA2与HLA-DQB2基因位点与持续性HBV感染显著相关。此外，HLA-DQA2与HLA-DQB2基因区域还与疾病临床进展及治疗应答存在关联。