Genome-Wide Association Study Identifies Variants Associated With Progression of Liver Fibrosis From HCV Infection

Abstract

BACKGROUND & AIMS Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We carried out a 2-stage GWA study of liver fibrosis progression related to HCV infection. METHODS We studied well-characterized HCV-infected patients of European descent who had liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of Metavir scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P-values<5×10−5 from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance. RESULTS In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients that received blood transfusions) were associated with fibrosis progression (Pcombined=8.9×10−9 and 1.1×10−9, respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (Pcombined=5.4×10−7), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages. CONCLUSIONS Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

“…The initial association between MERTK rs4374383 and development of fibrosis in chronic HCV disease was observed in a GWAS; in this study, the association was observed only in a sub-group of HCV patients who received blood transfusions [12]. Later, the MERTK SNP significantly added risk to accelerated fibrosis progression rate in the Swiss Hepatitis C Cohort Study [10].…”

“…A large GWAS has shown that a locus in the RNF7 gene is associated with the development of liver fibrosis in chronic hepatitis C [12]. The study reported that in the combined cohort of 2,342 HCV-infected patients rs16851720 was associated with fibrosis progression.…”

“…We did not observe differences in the genotype frequencies between controls and patients with liver fibrosis for the RNF7 rs16851720. To our knowledge, no other studies have addressed the role of this gene polymorphism beyond the published GWAS [12]. In order to evaluate the combined effect of PNPLA3 and RNF7 SNPs genotypes for the risk of HCV fibrosis or cirrhosis, we performed an additional analysis.…”

“…The PNPLA3 gene polymorphism rs738409 was also shown to accelerate liver fibrosis progression rate in HCV-infected patients [10] and contribute to the development of alcoholic liver cirrhosis [11]. Further genetic association studies discovered two other loci harboring RNF7, which is also known as SAG (sensitive to apoptosis gene), and proto-oncogene tyrosine-protein kinase MER (MERTK), which may influence the development of fibrosis in chronic hepatitis C [12]. A metaanalysis of GWAS results on the soluble transferrin receptor (sTfR) and ferritin reported a novel association between sTfR and the variation in the proprotein convertase 7 (PCSK7) gene and the iron overload [13].…”

Immune status and gene polymorphism of cytokines IL-10, IL-4, TNF in patients with chronic hepatitis C depending on the degree of fibrosis

“…При этом на течение и исходы хронических вирусных гепатитов ока-зывает влияние, вероятно, наличие полимор-физма не в одном, а в нескольких генах и опре-деленная их комбинация [22,29].…”