Polymorphism rs368234815 of interferon lambda 4 gene and spontaneous clearance of hepatitis C virus in haemodialysis patients: a case-control study

Abstract

Background In non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms. Methods Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. Results The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38–5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45–5.43, 0.002 for rs12980275 and 2.44, 1.27–4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69–24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1. Conclusions In haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.

Paraoxonase 1 gene (PON1) variants concerning hepatitis C virus (HCV) spontaneous clearance in hemodialysis individuals: a case–control study

“…We initially assumed that associations of PON1 SNVs with spontaneous HCV clearance could be related to their epistatic interaction with IFNL4 rs368234815, which is the most powerful influencer of HCV outcome among genes of IFNL3/4 region in HD individuals [ 34 ]. However, the analysis of epistatic gene–gene interaction between tested PON1 SNVs and IFNL4 rs368234815 did not show significance at a P-value below 0.05.…”

“…Spontaneous HCV clearance was assumed to occur in 14%–46% of individuals [ 38 ]. In HD individuals of the Great Poland region, HCV clearance was shown in 42.2% of cases [ 34 ]. For 100 individuals who spontaneously resolved HCV infection (the case group) and 100 who remained persistently HCV infected (controls), a power of about 80% could be shown at an odds ratio of at least 1.5 (Additional file 1 : Table S1).…”

“…The IFNL4 variant rs368234815 was the strongest predictor of spontaneous HCV clearance among other IFNL3/IFNL4 variants [ 34 ]. PON1 SNVs and PON-1 activity distribution did not differ concerning HCV infection in a small group of HD individuals (20 HCV infected, 26 HCV not infected) [ 11 ].…”

Single nucleotide polymorphisms in INFL3-INFL4 region are associated with fibrosis and cirrhosis in Egyptian patients with chronic hepatitis C

“…Additionally, while production of type I and II interferon is reduced during HCV infection and in advanced hepatic disease, IFN-λ receptor production is unaffected [24][25][26]. SNPs in the INFL3-INFL4 region, rs12979860, rs4803217 and rs368234815 were determined as a powerful foreteller of HCV clearance [27][28][29]. Several reports showed the genetic and functional association of these variants with liver fibrosis in different ethnicities [30][31][32].…”