Abstract
BackgroundAIDS develops typically after 7–11 years of untreated HIV-1 infection, with extremes of very rapid disease progression (<2 years) and long-term non-progression (>15 years). To reveal additional host genetic factors that may impact on the clinical course of HIV-1 infection, we designed a genome-wide association study (GWAS) in 404 participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS.MethodsThe association of SNP genotypes with the clinical course of HIV-1 infection was tested in Cox regression survival analyses using AIDS-diagnosis and AIDS-related death as endpoints.ResultsMultiple, not previously identified SNPs, were identified to be strongly associated with disease progression after HIV-1 infection, albeit not genome-wide significant. However, three independent SNPs in the top ten associations between SNP genotypes and time between seroconversion and AIDS-diagnosis, and one from the top ten associations between SNP genotypes and time between seroconversion and AIDS-related death, had P-values smaller than 0.05 in the French Genomics of Resistance to Immunodeficiency Virus cohort on disease progression.ConclusionsOur study emphasizes that the use of different phenotypes in GWAS may be useful to unravel the full spectrum of host genetic factors that may be associated with the clinical course of HIV-1 infection.
Highlights
The clinical course of HIV-1 infection can be highly variable between individuals
After quality control and population stratification, association analysis was performed for 309,494 single nucleotide polymorphisms (SNP) and HIV-1 disease course in 404 HIV-1 infected men who have sex with men (MSM) and DU from the Amsterdam Cohort Studies (ACS) using Cox regression survival analyses with AIDS according to the Centers for Disease Control (CDC) 1993 definition [30] or AIDS-related death, as endpoints
None of the SNP genotypes identified to be associated with AIDS-diagnosis were associated with survival time after AIDS-diagnosis, indicating that their potential effect is at an earlier stage in the course of infection (Table 1)
Summary
The clinical course of HIV-1 infection can be highly variable between individuals. The period of asymptomatic disease after HIV-1 infection in the absence of antiviral therapy is typically 7–11 years [1,2], with extremes of disease progression within 2 years, or virtually no disease progression for more than 15 years [3]. In the Caucasian population, HLA-B5701 and HLA-B27 are most strongly associated with prolonged survival, whereas a variant of HLA-B35 is linked to an accelerated progression to AIDS [4,5,6,7] Another well known example is the 32 base pair deletion in the gene coding for the chemokine receptor CCR5 that serves as a coreceptor for HIV-1. This polymorphism has been associated with reduced susceptibility to infection [8,9] and a slower rate of disease progression [10,11,12]. To reveal additional host genetic factors that may impact on the clinical course of HIV-1 infection, we designed a genome-wide association study (GWAS) in 404 participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS
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