Abstract
HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended treatment schedules, the prevalence of HIV-SN has declined and associated risk factors have changed. With stavudine, rs1799964*C (TNF-1031) associated with HIV-SN in Caucasians and Indonesians but not in South Africans. Here, we investigate associations between HIV-SN and rs1799964*C and 12 other polymorphisms spanning TNF and seven neighboring genes (the TNF-block) in Indonesians (n = 202; 34/168 cases) and South Africans (n = 75; 29/75 cases) treated without stavudine. Haplotypes were derived using fastPHASE and haplotype networks built with PopART. There were no associations with rs1799964*C in either population. However, rs9281523*C in intron 10 of BAT1 (alternatively DDX39B) independently associated with HIV-SN in Indonesians after correcting for lower CD4 T-cell counts and >500 copies of HIV RNA/mL (model p = 0.0011, Pseudo R2 = 0.09). rs4947324*T (between NFKBIL1 and LTA) independently associated with reduced risk of HIV-SN and shared haplotype 1 (containing no minor alleles) associated with increased risk of HIV-SN after correcting for greater body weight, a history of tuberculosis and nadir CD4 T-cell counts (model: p = 0.0003, Pseudo R2 = 0.22). These results confirm TNF-block genotypes influence susceptibility of HIV-SN. However, critical genotypes differ between ethnicities and with stavudine use.
Highlights
HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and its treatment
Indonesian and South African HIV patients treated without stavudine are assessed to identify single nucleotide polymorphisms (SNP) and haplotypes of the Tumor necrosis factor alpha (TNF)-block associated with HIV-SN
The regression model retained greater weight, tuberculosis and a low nadir CD4 T-cell count independently associated with HIV-SN
Summary
HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and its treatment. Carriage of the minor allele at TNF-1031 (rs1799964) associated with increased risk of HIV-SN in Caucasians, Chinese and Malays who had received stavudine [5,6,15], but not in South Africans [16]. We characterized TNF-block haplotypes in multiple ethnicities and showed that the haplotype containing the minor allele of TNF-1031 in Asians and Caucasians was not present in Africans [14,16] This implicates an allele carried in linkage with TNF-1031 in its associations with HIV-SN. Indonesian and South African HIV patients treated without stavudine are assessed to identify single nucleotide polymorphisms (SNP) and haplotypes of the TNF-block associated with HIV-SN. The minor allele of rs9281523 associated with risk of HIV-SN in Caucasian patients who developed a toxic neuropathy following exposure to stavudine [6], but showed no effect in our. Instances where the predominant haplotypes vary, but the same SNP associates with the phenotype provide circumstantial evidence that the SNP contributes directly to the phenotype
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