CIP Genomics Core

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Genotyping and Genetic Epidemiology. The CIP Genetics Core (CIPGC) has been active in both the generation of genotypic data and in the statistical analysis of genetic epidemiological data. In particular, the work of the Genetics Core over the past year has been used by CIP principal investigators to establish findings for 5 manuscripts. Early events in human immunodeficiency virus (HIV) infection are a potent indicator of subsequent viral progression. Specifically, the Core was repsonsible for the statistical analysis which showed that the initial CD8+ T-cell responses determined both viral set points and loss of CD4+ T cells in a cohort of 527 HIV-1-infected individuals. Preservation of the CD8+ T-cell immunodominance patterns through the acute to the chronic phase of infection was significantly associated with slower CD4+ T-cell decline. A reported association between the Duffy antigen/receptor for chemokines (DARC) -46 T/C genotype and HIV infection/progression was not replicated in cohorts that were made available to the CIPGC and this association may be spurious or limited to a specific cohort. Specifically, the -46 single nucleotide polymorphism (SNP) was genotyped by the CIP Genetics Core in a cohort of 381 untreated black South Africans and verified by direct sequencing in several of these samples. Statistical analyses revealed that there was no difference in CD4 counts over time, or in mean HIV viral load and no influence on HIV disease progression among the various DARC genotypes. The CIP Genetics Core was also responsible for the genotyping of tumor cell lines and RT-PCR that helped establish the functional basis for promoter variation in the MSMB gene that results in prostate cancer susceptibility. Sixty-seven different tumor cell lines were characterized both for the MSMB promoter polymorphism and for MSMB expression levels to establish the likely cause of this association with prostrate cancer. Statistical analyses demonstrated that a polymorphism in the HLA-C promoter was strongly associated with HIV viral control while progression was dependent both on promoter variation and KIR genotype in a large (1739) cohort of European descent. The CIP Genetics Core also undertook both the statistical epidemiology and population variation analysis used in demonstrating that spontaneous clearance of hepatitis C virus (HCV) was strongly associated with a polymorphism linked to the IL28B gene. This study demonstrates the strongest host genetic effect yet seen for HCV clearance as well as indicating the therapeutic potential of IL28B in HCV infection.