A new 3 p 25 locus is associated with liver fibrosis progression in HIV / HCV co-infected patients

N=263 words) Background: There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) mono-infection, but this aspect has been little investigated in patients co-infected with HCV and human immunodeficiency virus (HIV). We performed the first genome-wide association study (GWAS) of liver fibrosis progression in patients co-infected with HCV and HIV, using the well-characterized French ANRS CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan) providing a quantitative fibrosis score. After quality control, GWAS was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed SNPs. SNPs with p-values < 10 were investigated in two independent replication cohorts of European patients infected with HCV alone. Results: Two signals of genome-wide significance (p-value < 5x10) were obtained. The first, on chromosome 3p25 and corresponding to rs61183828 (p-value = 3.8x10), was replicated in the two independent cohorts of patients with HCV mono-infection. The cluster of SNPs in linkage disequilibrium with rs61183828 was located close to two genes involved in mechanisms affecting both cell signaling and cell structure (CAV3) or HCV replication (RAD18). The second signal, obtained with rs11790131 (p-value = 9.3x10) on chromosome region 9p22, was not replicated. Conclusion: Our GWAS identified a new locus associated with liver fibrosis severity in patients with HIV/HCV co-infection, on chromosome 3p25. This finding was replicated in patients with HCV mono-infection. These results provide new relevant hypotheses for the pathogenesis of liver fibrosis in patients with HIV/HCV co-infection that may help define new targets for drug development or new prognostic tests, to improve patient care. Page 5 of 47 Hepatology Hepatology This article is protected by copyright. All rights reserved.