The relationship between human leukocyte antigen-DP/DQ gene polymorphisms and the outcomes of HCV infection in a Chinese population

Hepatitis C virus (HCV) infection remains a major public health concern, although there has been significant progress in the treatment of HCV infection due to the presence of direct antiviral drugs (DAAs). Based on the estimation of the World Health Organization (WHO), there are 130–150 million people infected with HCV globally, and about 30% of infected people will be spontaneously clear, while the others will develop chronic infection, and further progress to cirrhosis and hepatocellular carcinoma (HCC) [1]. In China, the average prevalence of HCV infection is about 3.2%, a total of about 29 million hepatitis C virus carriers [1]. The pathogenesis of HCV infection and chronicity are elusive, but biological characteristics of HCV, host immunity, genetic background and environmental behavior factors are deemed to be interactively involved with the complex pathogenesis [2‐4].

The innate and adaptive immune response after the infection of HCV, which varies across individuals, affect the susceptibility and chronicity to HCV infection [5, 6]. The human leukocyte antigen (HLA) system, as the major histocompatibility complex (MHC) in human, plays an important role in specific immune response and immune regulation through the interaction with natural killer (NK) cells, T- and B- lymphocytes and cytokines [7, 8]. HLA molecules are categorized into three basic groups: class I, class II, and class III, which genes are located close together on the short arm of chromosome 6 [9].

It is globally recognized that HLA class II molecules, categorized into three sub-regions: HLA-DR, −DQ and -DP, are key determinants in the immune response to HCV infection through the effective presentation of T-cells to viral antigens [10, 11]. Researchers have recently discovered that variation in HLA class II genes are determinants of the susceptibility and chronicity of HCV infection. For example, a comparative review showed that HLA DR*13 alleles were protective against HCV infections in several populations [12]. Katayoun et al. conducted a genome wide association study (GWAS) and found the HLA-DRB1 * 0301 alleles were significantly associated with viral clearance, and DQA1 * 0201 and DQB1 * 0602 alleles are significantly associated with HCV persistence [13].

It has been studied that the single nucleotide polymorphism (SNP) rs9277535 of HLA-DP is associated with systemic lupus erythematosus (SLE) susceptibility, cervical cancer susceptibility, and persistent hepatitis B virus (HBV) infection, the SNP rs7453920 of HLA-DQ is also suggested to be associated with ankylosing spondylitis (AS) susceptibility, persistent HBV infection [14‐19]. However, the evidence is sparse about whether above two SNPs is related to HCV in a Chinese population. Therefore, we investigate the relationship of the HLA-DP rs9277535 and -DQ rs7453920 with the susceptibility and chronicity of HCV infection in the Chinese population.

It is well known that HCV is a serious public health problem. Studies on the relationship between HLA Class II gene polymorphisms and the susceptibility and chronicity of HCV infection help us better understand the complicated mechanism. The current research found that HLA-DP rs9277535 A and -DQ rs7453920 A allele significantly increased the risk of HCV chronicity and HCV infection in Chinese Han population, respectively.

The HLA determinant as the principal component of immunogenicity factors has been found associated with HCV infection [20, 21]. HLA-DQ belongs to HLA Class II molecules play crucial roles in the regulation of immune responses [22]. HLA-DQ molecules, which are induced when HLA-DQ genes are expressed, play a regulatory role by binding to exogenous antigens and presenting exogenous substances to CD4+ T lymphocytes [23, 24]. A previous study detected genetic variants of rs2856718 in intron region of HLA-DQ genes also strongly associated with the susceptibility of HCV infection in Chinese population [25]. The current study found that the individuals carrying HLA-DQ rs7453920 A allele had a statistically significantly higher risk of HCV infection. It is possible that rs7453920 variation may alter the expression of the HLA-DQ gene with alternation of non-coding RNA sequences, further affecting the recognition and presentation of exogenous antigen peptide, thus leading to effects on the secretion of cytokines and the differentiation of T-cells. The study of Xu et al. showed that the rs7453920G allele was a risk factor for HBV infection, while rs7453920A allele served as a protective factor in chronic Hepatitis C [26]. Furthermore, rs7453920A allele could predict the better prognosis in liver transplant recipients, and was associated with decreased risk of ankylosing spondylitis (AS) [27]. The explanation of this could be that HBV and HCV have remarkable differences in the molecular virology and specific immune responses, although both of them are hepatotrophic factors and tend to produce liver diseases. For instance, HLA DQB1*0301and HLA DRB1*11 play a protective role in HCV infections, but the opposite in persistent HBV infection [12].

Previous research has shown that low viral diversity and strong CD4+ T-cell response targeting a broad range of virus antigenic epitopes are connection with spontaneous viral clearance (SVC), while infectious agents can lead to incompetent T-cell response and persistent infection through a variety of complex mechanisms [28]. Furthermore, the epitopes of CD4+ T-cell are highly promiscuous and can often be restricted by a variety of different HLA class II molecules [29]. Genetic association studies showed that HLA class II-restricted epitopes goes unrecognized by T-cells may be one of the possible mechanisms of HCV to avoid immune clearance [30]. A meta-analysis confirmed that DQB1*02, DQB1*03, DRB1*04 and DRB1*11 were associated with spontaneous hepatitis C virus clearance [31]. The current study revealed that the individuals carrying HLA-DP rs9277535 A allele had a statistically significantly higher risk of chronic HCV infection. Previous research has shown that HLA-DP rs9277535A allele might protect against chronic HBV infection in Japanese, Korean, Taiwanese, and Thai populations, but might increase the risk of chronic HBV infection in Han Chinese and Saudi Arabian populations [32]. Other studies have found rs9277535A allele that could decrease SLE susceptibility, however, was associated with increased cervical cancer susceptibility in Chinese females [17, 18]. Rs9277535 may be the binding site of some microRNA (miRNA), where 3′-UTR region of HLA- DPB1 gene is found. Research indicates that miRNA affects the stability and translation of messenger RNA (mRNA) by base-pairing with complementary sequences within mRNA molecules [33]. Thus, rs9277535 may affect the regulatory function of miRNA by disrupting microRNA-mRNA interaction, resulting in the deregulation of the expression and stability of HLA mRNA.

The study indicated that the association between HLA-DP/DQ and the susceptibility and chronicity of HCV infection was likely to be more pronounced among people less than 50 years old, PBD population and HD population. It was indicated in the previous research that chronic HD patients were with renal failure and compromised immune systems, and were less likely to clear HCV and other infection [34‐36]. Therefore, we can deduce that HD patients carrying HLA-DP rs7453920 A allele were more prone to gain the genetic benefit because of severe alterations in immune systems. The current research also suggested that the haplotype AA showed a higher risk of HCV infection than the most frequent haplotype GG, which was consistent with the rs7453920 effect but failed to show in rs9277535 effect. This indicates that the effects of HLA-DP and HLA-DQ may not be independent, which has been proposed in a recent study [37]. Therefore, further fine mapping studies are recommended.

The studies generate the genetic evidence of association between HLA Class II gene polymorphisms and the outcome of HCV infection, which may facilitate scientists and clinicians to identify new targets for therapy and personalized medical-based strategy along with other SNP information. There are some limitations in this study. First, the participants of this study were drug addicts, HD and PBD, which have impaired immune function and thus may not represent all subjects with HCV persistent infection and spontaneous clearance in the general population. Second, the clinical information including the infection time of HCV and immunization status for each individual was not sufficient, demonstrating potential biases arising from unmeasured confounding variables. Finally, the sample size of HCV persistent infection group (n = 370) and spontaneous clearance group (n = 194) were relatively small, further research on a large scale is therefore necessary.

In conclusion, this study found that HLA-DQ rs7453920 A allele may be a genetic factor of HCV infection, while HLA-DP rs9277535 A allele may be for chronic HCV infection in the Chinese Han population.