Genetic association of polymorphisms at the intergenic region between PRDM1 and ATG5 with hepatitis B virus infection in Han Chinese patients

Abstract

Chronic hepatitis B virus (HBV) infection is related to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC), and the interplay between the virus and host immune response leads to different outcomes of the infection. PR domain zinc finger protein 1 (PRDM1) and autophagy‐related protein 5 (ATG5) are involved in immune response and HBV infection. An intergenic region between PRDM1 and ATG5 (PRDM1‐ATG5 region) has been identified, and single‐nucleotide polymorphisms (SNPs) in this region were shown to be involved in immune regulation. This study investigated the functionally relevant rs548234, rs6937876, and rs6568431 polymorphisms at the PRDM1‐ATG5 region in a Han Chinese population (403 patients with chronic HBV infection [171 chronic hepatitis, 119 cirrhosis, and 113 HCC], 70 infection resolvers, and 196 healthy controls). The frequencies of the rs6568431 allele A in HBV patients (P = .005) and genotype CA in infection resolvers (P = .005) were significantly higher than in healthy controls. In the dominant model, HCC patients had significantly higher frequencies of rs548234 genotypes CC + TC than cirrhosis patients (P = .009). Rs548234 was an independent factor for HCC in comparison with either cirrhosis (P = .005) or all chronic HBV infection without HCC (P = .018). Functional annotation showed evidence of the role of the SNPs in gene regulation. In conclusion, through this study it is revealed for the first time that rs6568431 may be associated with susceptibility to HBV infection and that rs548234 may be associated with HCC risk in chronic HBV infection, supporting the presence of HBV‐related disease‐causing regulatory polymorphisms in the PRDM1‐ATG5 intergenic region.

ATG5: A central autophagy regulator implicated in various human diseases

“…There was an increased risk of production of anti‐DNA autoantibodies in the case of patients carrying the variant allele of rs2245214. Intergenic region variants rs548234, rs6937876, and rs6568431 of PRDM1‐ATG5 studied recently were found to be associated with chronic HBV infection 186 . ATG5 variant rs6568431 was also reported to be significantly associated with cerebral palsy where low levels of ATG5 were found in cerebral palsy patients carrying this variant 187 .…”

“…The E122D mutation in ATG5 disrupts its conjugation with ATG12 and inhibits autophagy and this results in the development of ataxia, emphasizing the effect of mutations on the functions of this protein and the manifestation of the disease 192 . Recently, Zhang and colleagues 186 identified 15 genetic variants in the different regions of the ATG5 gene in acute myocardial infarction patients using the direct DNA‐sequencing technique. In these patients, they found one novel deletion variant (g.106326168_70delTCT) in the promoter region of ATG5 , which affects the binding of a transcription factor and hence decreases its transcriptional activity 186 .…”

“…Recently, Zhang and colleagues 186 identified 15 genetic variants in the different regions of the ATG5 gene in acute myocardial infarction patients using the direct DNA‐sequencing technique. In these patients, they found one novel deletion variant (g.106326168_70delTCT) in the promoter region of ATG5 , which affects the binding of a transcription factor and hence decreases its transcriptional activity 186 . Overall, these genetic studies illustrate the therapeutic significance of autophagy, which could be modulated for better treatment management strategies for different disorders by targeting ATG5 .…”

Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

“…The formation of Atg5-deficient autophagosomes in response to sorafenib promoted the interaction of p62 with RIPK leading to cell death by necroptosis [108]. Several ATG5 variants were associated with the disease progression and HCC risk in chronic HBV infection [109,110]. A Chinese comparative study comprising around 1000 HCC cases vs. 1000 healthy controls showed that in an allelic model, ATG variants ATG5 rs17067724, ATG10 rs1864183, ATG10 rs10514231, ATG12 rs26537, and ATG16L1 rs4663402 were significantly associated with the risk of HCC, in which the ATG10 10514231 was the strongest factor.…”

Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

“…Noteworthy, in advanced lung adenocarcinoma, two genetic variants in the ATG10 gene, rs10036653, and rs1864182, were reported to be associated with primary or acquired resistance to a tyrosine kinase inhibitor, gefitinib [78]. Moreover, ATG5 genetic variants rs510432 and rs548234 are linked to the HCC progression based on chronic HBV infection [79,80].…”