Abstract
OBJECTIVES: To investigate a possible role for functional promoter polymorphisms in tumour necrosis factor (TNF) alpha and beta loci, in modifying the risk of progression to lipodystrophy in HIV-infected patients. Additionally, to investigate whether the effect of antiretroviral therapy-specific factors on lipodystrophy progression may depend on, or interact with, the presence of predisposing host factors.
METHODS: Stored DNA samples of 220 participants in the Western Australian HIV Cohort were typed for promoter polymorphisms at TNF-α (-238G/A and -308G/A), and TNF-β (-250G/C) loci. Results were incorporated into Cox proportional hazards regression analyses (SAS statistical package, SAS Institute, Cary, North Carolina, USA), to assess the effect of variant alleles on the development of clinically apparent lipodystrophy, with adjustment for predictive host and treatment variables. Carriage of the -238G/A TNF-α polymorphism was found in 11.4% of the cohort, all of whom were of white racial origin. Analyses were therefore performed in a limited dataset of 191 white Caucasian participants, to exclude potential confounding attributable to the role of the TNF-α -238G/A polymorphism as a surrogate marker of white racial origin.
RESULTS: Carriage frequency of the TNF-α promoter polymorphism -238G/A was 13.1%. Risk of progression to lipodystrophy was significantly increased in heterozygotes compared with carriers of the wild-type allele (P=0.014, log rank). Cox proportional hazards analyses demonstrated a significant independent effect of TNF-α -238G/A heterozygosity (RR=1.73, P=0.041), which was independent of the effects of age (RR=1.053/year), duration of dual nucleoside reverse transcriptase inhibitor therapy pre-highly active antiretroviral therapy (RR=1.025/month), and time on stavudine (RR=1.081/month). Promoter polymorphisms at TNF-α -308G/A and TNF-β -250G/C were found to not contribute significantly to the Cox proportional hazards regressions. Analyses combining TNF-α -238G/A heterozygosity and treatment-related variables as interaction terms did not suggest synergistic effects of TNF polymorphism and antiretroviral therapy on lipodystrophy progression.
DISCUSSION: In this study, carriage of the TNF-α -238G/A promoter polymorphism independently increased the risk of lipodystrophy progression in a cohort of 191 white Caucasian HAART recipients. The influence of other host and treatment-related variables on lipodystrophy progression were not altered after adjustment for the effect of TNF-α -238G/A polymorphism, indicating that effects of treatment are not contingent on the presence of this host factor.