EFFECTS OF COMMON GENETIC VARIANTS IN TP53 AND TLR8 ON IMMUNE RESPONSE AND RISK OF CANCER IN PEOPLE WITH HIV/AIDS
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Date
2019-08-23
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Johns Hopkins University
Abstract
Background: Cancer represents a significant source of morbidity and mortality in people living with HIV/AIDS (PLWHA) and risk of most cancer exceeds that observed in the general population. A substantial proportion of cancers in PLWHA may be attributable to infection, with risk largely due to HIV-related immune deficiency and co-infection with oncogenic pathogens. p53 is a tumor suppressor also involved in innate immune signaling via the Toll-like receptor 8 (TLR8). SNPs in both the TP53 (rs1042522) and TLR8 (rs3764880) genes may mediate the innate immune response, with the TP53 G and TLR8 A alleles hypothesized to be jointly protective against cancer.
Methods: Seven hundred and sixty participants enrolled in the Multicenter AIDS Cohort Study (MACS) provided blood samples for ascertainment of SNP genotypes. Outcomes assessed were diagnosis of any cancer, AIDS-defining cancer, non-AIDS-defining cancer, and infection-related cancer up to two years after participants’ last visits. Exact Poisson regression was used to estimate unadjusted and adjusted incidence rate ratios associated with SNP genotypes for each outcome. Joint SNP effects were estimated using an interaction term.
Results: SNPs were found to be jointly protective against any cancer (interaction IRR: 0.46, 95% CI: 0.01-42.71), ADCs (interaction IRR: 0.47, 95% CI: 0.01-48.55), and infection-related cancers (interaction IRR: 0.40, 95% CI: 0.01-39.37) in multivariable models while main effects of SNPs were slightly protective or had no effect for all outcomes.
Discussion: These findings are consistent with a hypothesized synergistic effect of SNPs on the immune response. Weak main SNP effects and strong interaction indicate a protective effect of SNPs only in the presence of each other. Future work will address missing data using imputation and potential effects of sex by adding data collected by the Women’s Interagency HIV Study.
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Cancer, p53, TLR8, HIV, AIDS, infection, immune response