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Multicenter Study
. 2012 Nov;143(5):1244-1252.e12.
doi: 10.1053/j.gastro.2012.07.097. Epub 2012 Jul 27.

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

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Free PMC article
Multicenter Study

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

Etienne Patin et al. Gastroenterology. .
Free PMC article

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 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 (P(combined) = 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 (P(combined) = 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.

Conflict of interest statement

Conflicts of interest: The authors disclose no conflicts.

Figures

Figure 1
Figure 1
Manhattan plots of genome-wide analyses of liver fibrosis using (A) the binary F0-1/F3-4 phenotype (949 F0-1/F3-4 patients), (B) the duration F0-1/F3-4 phenotype (872 F0-1/F3-4 patients with available duration of infection) and (C) the QTF phenotype (1,064 patients with available duration of infection). Larger points correspond to SNPs producing a P-value<10−6. All the analyses were performed on 780,650 genotyped or imputed SNPs (Patients & Methods).
Figure 2
Figure 2
Genotype/phenotype relationships for the four SNPs most associated with liver fibrosis in the final combined cohort. (A) Standardized Metavir units (SMU; Patients & Methods) for the three genotypes of SNP rs16851720 (located within RNF7), identified using the QTF phenotype. Bars represent standard errors (SEM) of each mean SMU. Genotype AA was used as the reference (SMU=0). (B) Survival curves for SNP rs4374383 (located within MERTK) identified using the duration F0-1/F3-4 phenotype, in the subsample of transfused patients. (C) Proportions of all HCV-infected patients with Metavir scores of F0 and F4, by genotype at rs2629751 (located within GLT8D2), a replicated SNP identified using the binary F0/F4 phenotype. (D) Survival curves for SNP rs9380516 (located near TULP1), a replicated SNP identified using the duration F0-1/F3-4 phenotype stratified in male patients.

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