Evaluation of candidate genes associated with hepatitis A and E virus infection in Chinese Han population

Hepatitis A and E virus (HAV and HEV) infections are heavy public health problems in developed and developing countries. It is estimated that over ten millions people have been infected by these two viruses every year worldwide [1, 2]. Both HAV and HEV are mainly transmitted via the fecal-oral route either by the contaminated food or water ingestion or via person-to-person contact. Although the disease of hepatitis A or hepatitis E is usually mild or asymptomatic, the higher incidences of fulminant hepatitis could be occurred in the HAV-infected elders and HEV-infected women in pregnant [3, 4].

In the past decade, Genome-wide association studies (GWAS) have been carried out rapidly and contributed to identify susceptible loci for many kinds of infectious diseases, such as malaria, tuberculosis, hepatitis B and C [5‐7]. In a US study, Zhang et al. recently reported that Mexican Americans carrying the functional T allele of TGFβ1 rs1800469 and T allele of XRCC1 rs1799782 were more prone to be infected by HAV, while the minor allele (T) of ABCB1 rs1045642 was associated with lower risk for anti-HAV seropositivity [8]. TGF-β1 is a multifunctional cytokine and involved in the pathogenesis of liver injury during acute HAV infection. Moreover, it has been reported that TT genotype of TGFB1 rs1800469 is significantly associated with higher plasma levels of TGF-β1 [9]. XRCC1 is a major DNA repair gene so it has ability to repair DNA damage, which may be a requisite for risk of many infectious diseases [10]. Recently, the results from a 10-year cohort study indicated that XRCC1 gene may be responsible for hepatocellular transformation in Chinese chronic hepatitis B patients [11]. ABCB1 gene encodes one member of the ATP-binding cassette super family of membrane transporters. Up-regulated expression of ABCB1 in human hepatocytes in viral hepatitis may render the cells resistant to oxidative damage [12].

In another study, Zhang et al. further reported that rs5110-C/A in APOA4 and rs7412-C/T in APOE were significantly associated with protection against HEV infection in non-Hispanic blacks in United States [13]. Both APOA4 and APOE genes were recognized for their importance in lipoprotein metabolism and cardiovascular disease. However, more and more studies indicated that these two genes are not only play the key roles in lipid transport, but also involved in immunoregulation, which in turn can influence susceptibility to and the natural history of infectious disease [14, 15].

However, the associations of these loci with HAV or HEV infections have not been evaluated in other populations. Owing to its long history, large population, environmental pollution, and poor hygiene, both hepatitis A and E outbreaks and sporadic incidents are the major public health problems in China [16, 17]. Additionally, accumulative evidences demonstrated that the seroprevalence of HAV and HEV infections are very high in Han ethnic areas (~ 60% and ~ 20% for anti-HAV IgG and anti-HEV IgG, respectively) [16]. Given the additional evidences of genetic associations will improve our understanding of genetic factors and mechanisms truly influencing HAV or HEV infection, we performed the present study to evaluate the single-nucleotide polymorphisms (SNPs) recently reported to be associated with HAV or HEV infection in Chinese Han population.

In this study, we attempted to evaluate the GWAS-associated SNPs from ABCB1, CYP2E1, CAT, TGFB1 and XRCC1 with HAV infection, and SNPs from APOA4 and APOE with HEV infection in Chinese Han populations, respectively. However, the conflicting results were observed in the present study. First, our results found that rs1045642 C to T variation was associated with the decreased risk of HAV infection in Chinese Han persons, while the results from US study indicated that individuals with T allele of rs1045642 were less prone to be infected by HAV [8]. Second, we observed that rs1001581A to G variation in XRCC1 was significantly associated with protection against HAV infections, whereas this association was not observed in US population. Lastly, Zhang et al. reported that variants in APOA4 and APOE were significantly associated with the lower odds of anti-HEV seropositivity [13]. However, our results only suggested that rs7412 C to T variation in APOE was associated with decreased risks of HEV infection in Chinese Han males.

Several factors could contribute to the differences between our present study and the previous US study. One factor could be ascribed to the genetic heterogeneity of virus. HAV and HEV could be divided into six genotypes (I-VI) and four major genotypes (1–4), respectively [18, 19]. Both HAV and HEV genotypes exhibited a particular geographic distribution [20‐22]. Although subgenotype IA HAV constitutes a major fraction of genotype I strains circulating in US and China, the virus strains from the US and China could be further divided into different clusters [23, 24]. In addition, genotype 3 HEV is the main genotype circulating in US, while genotype 4 HEV strain is the dominant genotype in China [25‐27]. Thus, the effects of the genetic variation of viruses on the risk of infection in different ethnicities should be investigated in future. Additionally, although the allele frequencies of tested polymorphisms were similar between two studies, the genetic differences among ethnicities might be as the other explanation for the present results (Additional file 3: Table S3) [28, 29]. Therefore, replication studies in different racial/ethnic groups are encouraged.

To our knowledge, this is the first replication study to explore the associations between GWAS-associated SNPs and HAV or HEV infection in China. However, there are several general limitations should be considered. First, although the number of study participants met the requirement for analysis, independent replications in larger population should be conducted in future. Second, our study only sought to replicate the limited SNPs in a Chinese Han population because we felt such a replication would be a critical first step to understanding these results. Greater genome coverage and more informative markers including APOE isoforms are required in order to realize true genetic determinants of hepatitis A and E infections. Last, it is well known that HAV or HEV infections are significantly associated with environmental and social factors. Thus, gene-gene and gene-environment interaction on the risks of virus infection should be further discussed.

Summary, our present study suggested that ABCB1 and XRCC1 genes variants were significantly associated with the lower risk of HAV infection. Additionally, Chinese Han males with rs7412 C to T variation in APOE are less prone to be infected by HEV. In order to further understand the effects of host genetic factors on HAV or HEV infection in different ethnic populations, more studies using a large-scale association analysis should be warranted in future.