title: Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual's NRTI-SN risk.
abstract: Nucleoside analog-associated sensory neuropathy (NRTI-SN) attributed to stavudine, didanosine, or zalcitabine (the dNRTIs) and distal sensory polyneuropathy (DSP) attributed to HIV are clinically indistinguishable. As inflammatory cytokines are involved in DSP, we addressed a role for inflammation in NRTI-SN by determining the alleles of immune-related genes carried by patients with and without NRTI-SN. Demographic details associated with risk of various neuropathies were included in the analysis. Alleles of 14 polymorphisms in 10 genes were determined in Australian HIV patients with definite NRTI-SN (symptom onset <6 months after first dNRTI exposure, n = 16), NRTI-SN-resistant patients (no neuropathy despite >6 months on dNRTIs, n = 20), patients with late onset NRTI-SN (neuropathy onset after >6 months of dNRTIs, n = 19), and HIV-negative controls. Carriage of TNFA-1031*2 was highest in NRTI-SN patients, suggesting potentiation of NRTI-SN. Carriage of IL12B (3' UTR)*2 was higher in NRTI-SN-resistant patients than controls or NRTI-SN patients, suggesting a protective role. BAT1 (intron 10)*2 was more common in NRTI-SN than resistant patients, but neither group differed from controls. This marks the conserved HLA-A1, B8, DR3 haplotype. Of the demographic details considered, increasing height was associated with NRTI-SN risk. A model including cytokine genotype and height predicted NRTI-SN status (p < 0.0001, R(2) = 0.54). Late onset NRTI-SN patients clustered genetically with NRTI-SN-resistant patients, so these patients may be genetically "protected." In addition to patient height, cytokine genotype influenced NRTI-SN risk following dNRTI exposure, suggesting inflammation contributes to NRTI-SN.
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia. kcherry@burnet.edu.au
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Cherry
authors.forename: Ann
authors.initials: A
authors.lastname: Rosenow
authors.forename: Jacquita S
authors.initials: JS
authors.lastname: Affandi
authors.forename: Justin C
authors.initials: JC
authors.lastname: McArthur
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wesselingh
authors.forename: Patricia
authors.initials: P
authors.lastname: Price
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D001315:Australia; D001827:Body Height; D016207:Cytokines / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000150:complications* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D009443:Neuritis / Q000235:genetics*; D011110:Polymorphism, Genetic; D020886:Somatosensory Disorders / Q000235:genetics*
chemical_list: D019380:Anti-HIV Agents; D016207:Cytokines