Gastroenterology

Gastroenterology

Volume 143, Issue 5, November 2012, Pages 1244-1252.e12
Gastroenterology

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

https://doi.org/10.1053/j.gastro.2012.07.097Get rights and content

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 performed 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 underwent 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 who 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.

Section snippets

Patient Subjects

The sample used for the primary screen combined data from 2 cohorts of adult patients of European descent from France and Switzerland with chronic HCV infection. We retained only patients who underwent liver biopsy before treatment. The French cohort (ANRS Genoscan Study Group) included patients from the hepatology units of several hospitals in Paris and Marseilles; the inclusion criteria applied, including no coinfection by human immunodeficiency virus (HIV) or hepatitis B virus (HBV), have

Genome-Wide Analyses in the Primary Cohort

GWA analyses were conducted on a filtered primary cohort of 1161 HCV-infected patients (Table 1), with a total of 780,650 SNPs. We first used the binary F0–1/F3–4 phenotype of liver fibrosis and assumed an additive genetic model. No significant deviations from expectations were observed on quantile-quantile plots before and after correction for population stratification (Supplementary Figure 1), attesting to an absence of difference in ancestry between cases and controls (genomic inflation

Discussion

We report the first GWA study investigating liver fibrosis progression in a large sample of more than 2300 HCV-infected patients of European descent. For all patients, liver biopsy data were obtained before treatment. We defined several fibrosis phenotypes on the basis of histologic findings because the METAVIR system grading is not linear21 and because we wished to investigate various and complementary aspects of the fibrosis process. In this context, we also sought to use an additional, more

Acknowledgments

E.P.'s current affiliation is: Human Evolutionary Genetics, CNRS URA3012, Institut Pasteur, Paris, France.

E.P. and Z.K. contributed equally to the work, and P.-Y.B. and L. Abel jointly directed the work.

The authors thank all study subjects, all members of both branches of the Laboratory of Human Genetics of Infectious Diseases for fruitful discussion, and Alain Dessein (INSERM-UMR 906/Université de la Méditerranée, Marseilles), Marija Zeremski, and Ray Peterson (Division of Gastroenterology and

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    Conflicts of interest The authors disclose no conflicts.

    Funding The Swiss Hepatitis C Cohort Study is supported by grants from the Swiss National Science Foundation (3347C0-108782/1), the Swiss Federal Office for Education and Sciences (03.0599), and the European Commission (LSHM-CT-2004-503359; VIRGIL Network of Excellence on Antiviral Drug Resistance). The French cohort and E.P. are supported and sponsored by the National Agency for Research on AIDS and Viral Hepatitis (ANRS Study HC EP 26 Genoscan). E.J. received funding from Rockefeller University Center for Clinical and Translational Science Grant Award number UL1RR0241443. C.M.R., A.H.T., and I.M.J. are supported in part by the Greenberg Medical Research Institute and the Starr Foundation. F.N. is supported by the Swiss National Science Foundation (314730-130498). P.-Y.B. is supported by the Swiss National Foundation (32003B-127613), the Leenaards Foundation, and the Santos-Suarez Foundation.

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