Genetic Determinants of Viral Clearance in HCV-Infected Populations

The World Health Organization estimates there are 170 million persons with HCV infection worldwide, and an estimated 4 million persons are infected in the United States. Persistent HCV infection can cause cirrhosis and hepatocellular cancer. Long term disease consequences do not occur in persons who spontaneously recover. It is not known why 10-40% recover from hepatitis C (and are not at increased risk of cirrhosis and cancer), but that knowledge would contribute to efforts to treat and/or prevent HCV infection. The overall purpose of this study is to investigate the host genetic basis for recovery from hepatitis C virus (HCV) infection. There is strong evidence that host genetic differences determine HCV recovery. After accidental exposure to the same HCV inoculum, some persons recover while others develop persistent infection. Recovery from HCV infection is an outstanding phenotype for genetic studies since both viral exposure and viral recovery can be ascertained with high sensitivity and specificity and since there are no known viral or environmental determinants.

The study group is comprised of an ethnically and geographically diverse international population. All cohorts comprising this study group of 3350 individuals are well characterized. This case-control study is comprised of approximately 40% clearance individuals who are matched by age and HIV status within their respective cohorts at a ratio of 1:1 or 1:2 with HCV chronically infected individuals.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 3434
• Subject Sample Telemetry Report (SSTR)

• BioProject
• BioSample
• MeSH

Cases will be determined as HCV clearance subjects based upon inability to detect HCV RNA using tests (at least one test sensitive to 50 copies/ml) in two consecutive visits separated by six or more months in a person with HCV antibodies. This individual will have attained this clearance state in absentia of treatment.

Controls will be determined as HCV persistence subjects as defined by detection of HCV RNA in serum or plasma at more than one time point in a person with HCV antibodies

We have found strong associations between HCV recovery and polymorphisms in some immune response genes. For example, we were the first to show genetic evidence that inhibitory signaling from human leukocyte antigen C (HLA-C) molecules affected the outcome of infection by interaction with the NK cell killer immunoglobulin-like receptor (KIR). We have also gained new insights through a recently completed haplotype scan of candidate genes. Nonetheless, much of the host genetic basis for HCV recovery remains unexplained. Moreover, since there are no experimental models of HCV recovery, a substantial amount of the pathogenesis is unknown and cannot be anticipated in candidate gene studies.

Enrollees were selected for this study from several international pre-existing cohorts screened for HCV due to high-risk behaviors or circumstances. All subjects have been HCV-infected; some include persons co-infected with HIV or HBV. Subjects have acquired HCV infection either by transfusion of blood or blood products, through injection drug use or mucosal exposure.

• Primary Phenotype: Hepatitis C

• Principal Investigator
  • David Thomas, MD. Johns Hopkins School of Medicine, Division of Infectious Disease, Baltimore, MD, USA.
• Institute
  • CIDR. Center for Inherited Disease Research, MD, USA.
• Funding Source
  • X01. National Institutes of Health, Bethesda, MD, USA.
• Genotyping Center
  • Johns Hopkins University Center for Inherited Disease Research (CIDR), Baltimore, MD, USA.
• Funding Source for Genotyping
  • HHSN268200782096C. NIH contract "High throughput genotyping for studying the genetic contributions to human disease". National Institutes of Health, Bethesda, MD, USA.