Autophagy Related Gene ATG5 Genetic Variants and Hepatitis B Virus Infection Susceptibility

Abstract

Hepatitis B is a severe liver inflammation caused by Hepatitis B virus (HBV). Host genetic factors influence HBV acquisition and outcome. Moreover, HBV has been demonstrated to utilize an autophagy process to promote its replication. Various autophagy-related (ATG) genes regulate the process at different stages and among them; ATG5 is a key regulatory gene that promotes autophagosome formation by interacting with ATG12 and ATG16L1 to form a complex with E3 like activity. Single Nucleotide Polymorphisms (SNPs) in the ATG5 gene have been strongly linked to a variety of diseases like asthma, Paget disease of bone and thyroid carcinoma. Moreover, a non-synonymous SNP (nsSNP), E122D in ATG5 has been shown to impair its interaction with ATG12 leading to the disruption of autophagosome formation. However, until now, SNPs in ATG5 gene have not been studied for their association with HBV infection susceptibility. In this study, we have predicted deleterious nsSNPs (M129V, A95D, and I65V) and analyzed their impact on the structure and function of the ATG5 protein through a computational approach. In addition, we selected non-coding SNPs (rs2245214, rs12212740, and rs510432) of ATG5 gene and genotyped those in 550 HBV infected patients and 250 healthy individuals. We found a strong association of the nsSNP M129V (rs34793250 (T/C), OR=3.35 (T vs. C), p=0.01) and the non-coding SNPs (rs2245214 (C/G), OR=1.30 (C vs. G), p=0.02 and rs510432 (G/A), OR=1.66 (GG vs. GA), p=0.01) with HBV infection susceptibility. Therefore, these SNPs could be utilized as biomarkers for HBV risk analysis in our population after validation. Further, the influence of these SNPs on the patients treatment response could be investigated to develop better therapeutic strategies based on the host genotype. newline