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Gastroenterology. 2018 Dec 26. pii: S0016-5085(18)35421-0. doi: 10.1053/j.gastro.2018.12.014. [Epub ahead of print]

Multi-Ancestry Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.

Author information

1
Johns Hopkins University, School of Medicine, Baltimore, MD. USA.
2
RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA. USA.
3
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. USA.
4
Liver Unit IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
5
Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD. USA.
6
Johns Hopkins University, School of Medicine, Baltimore, MD. USA; Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD. USA.
7
Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. USA.
8
Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Francisco.CA. USA.
9
University of Southampton, Southampton General Hospital, Southampton, UK.
10
Department of Internal Medicine and Digestive Diseases, CHU Purpan, UMR 152, IRD Toulouse 3 University, France.
11
South West Liver Unit, Plymouth, PL6 8DH, UK.
12
Rho, Inc., Chapel Hill, NC.USA.
13
SUNY Downstate College of Medicine, Brooklyn, NY. USA.
14
University of California and Vitalant Research Institute, San Francisco, CA, USA.
15
UCL Institute for Liver and Digestive Health, The Royal Free Hospital, Pond St, Hampstead, London NW3 2QG.
16
University of Colorado, Aurora, Colorado, 90045, United States.
17
Department of Genetics, Stanford University School of Medicine, Stanford, CA. USA.
18
Johns Hopkins University, School of Medicine, Baltimore, MD. USA; Universidad Pontificia Bolivariana. Medellin, Colombia.
19
Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD. USA. Electronic address: pduggal@jhu.edu.

Abstract

BACKGROUND & AIMS:

Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry.

METHODS:

We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina arrays and statistically imputed to 1000 Genomes Project. For each ancestry group, the association of single nucleotide polymorphisms with HCV clearance was tested by log-additive analysis and then a meta-analysis was performed.

RESULTS:

In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2; P=5.99x10-50) and the MHC locus 6p21.32 (P=1.15x10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P=1.80x10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared to individuals carrying none or 1 of the clearance-associated variants.

CONCLUSIONS:

In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.

KEYWORDS:

GWAS; SNP; cytokine; risk

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