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Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection.

ABSTRACT: Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10^-04) and rs8099917 (P value = 5.5 × 10^-04). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10^-05). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10^-04). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.

SUBMITTER: Vergara C

PROVIDER: S-EPMC7657970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Cytokines are proteins that mediate innate and adaptive immunity responses. It is hypothesized that interferon lambda 3 (IFNL3) levels can influence the outcome of chronic hepatitis B virus (HBV) infection. Polymorphisms in IFN genes have been associated with response to infection. OBJECTIVES:This study was carried-out to investigate the association of IFNL3 gene polymorphisms (rs12979860 and rs8099917) with HBV susceptibility, in chronic HBV-infected patients. PATIENTS AND METHODS:In this case-control study, we determined IFNL3 single nucleotide polymorphisms (SNPs) (rs12979860 and rs8099917) in 221 individuals, with chronic HBV infection, and 200 healthy individuals, who were voluntary blood donors, with negative test for HBV. Alleles and genotypes analyses were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS:The frequencies of the rs12979860 and rs8099917 genotypes were not significantly different between the HBV-infected and the control groups (CC:CT:TT of 30.3%:48.0%:21.7% vs. 33.0%:49.0%:18.0%, P > 0.05, and GG:GT:TT of 5.8%:39.4%:54.8% vs. 5.0%:41.0%:54.0%, P > 0.05, respectively). Also, the frequencies of the alleles were not significantly different between both groups (C:T of 54.3%:45.7% vs. 57.5%:42.5%, P > 0.05, and G:T of 25.6%:74.4% vs. 25.5%:74.5%, P > 0.05, respectively) and the chronic HBV infection. There were no significant differences between patients, with at least one rs12979860C and or rs8099917T alleles compared to the healthy controls (rs12979860: CT + CC:TT, OR = 1.26, 95%CI = 0.78 - 2.04, P = 0.341 and rs8099917: GT + TT:GG, OR = 1.03, 95%CI = 0.70 - 1.51, P = 0.877, respectively). CONCLUSIONS:Our study showed no correlation between rs12979860 and rs8099917 SNPs and chronic HBV infection. Further studies, with larger sample sizes and different ethnicities, are necessary to validate our findings.

Project description:BackgroundHepatitis C virus (HCV) infection is a public health concern worldwide. Several factors, including genetic polymorphisms, may be evolved in the progression of HCV infection to liver diseases. Interferon lambdas (IFNLs) modulate the immune response during viral infections. IFNLs induce antiviral activity, interfering in the viral replication by promoting the expression of several genes that regulate immunological functions. The interferon lambda-4 (IFNL4) rs12979860 polymorphism, which is characterized by a C to T transition in intron 1, is associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in the development of HCV-associated liver diseases, including hepatocellular carcinoma (HCC).AimTo investigate the association of IFNL4 rs12979860 polymorphism with fibrosis, cirrhosis, and HCC in patients with chronic HCV infection.MethodsThis study was comprised of 305 chronic HCV-infected patients (53 fibrosis, 154 cirrhosis, and 98 HCC cases). The control group was comprised of 260 HCV-negative healthy individuals. The IFNL4 rs12979860 polymorphism was genotyped using the TaqMan assay. Fibrosis was diagnosed based on liver biopsy findings, while cirrhosis was diagnosed through clinical, laboratory, anatomopathological, and/or imaging data. HCC was diagnosed through imaging tests, tumor, and/or anatomopathological markers.ResultsThe T allele was observed in the three groups of patients (fibrosis, cirrhosis, and HCC) at a significantly higher frequency when compared with the control group (P = 0.047, P < 0.001, and P = 0.01, respectively). Also, genotype frequencies presented significant differences between the control group and cirrhosis patients (P < 0.001) as well as HCC patients (P = 0.002). The risk analysis was performed using the codominant and dominant T allele models. In the codominant model, it was observed that the CT genotype showed an increased risk of developing cirrhosis in comparison with the CC genotype [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.55-4.15; P < 0.001] as well as with HCC (OR = 2.54; 95%CI: 1.44-4.56; P = 0.001). A similar result was observed in the comparison of the TT vs CC genotype between the control group and cirrhosis group (OR = 2.88; 95%CI: 1.44-5.77; P = 0.001) but not for HCC patients. In the dominant T allele model, the CT + TT genotypes were associated with an increased risk for progression to cirrhosis (OR = 2.60; 95%CI: 1.63-4.19; P < 0.001) and HCC (OR = 2.45; 95%CI: 1.42-4.31; P = 0.001).ConclusionThese findings suggest that the T allele of IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients.

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Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection.

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