Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy.

Kallianpur AR, Jia P, Ellis RJ, Zhao Z, Bloss C, Wen W, Marra CM, Hulgan T, Simpson DM, Morgello S, McArthur JC, Clifford DB, Collier AC, Gelman BB, McCutchan JA, Franklin D, Samuels DC, Rosario D, Holzinger E, Murdock DG, Letendre S, Grant I, CHARTER Study Group
PLoS One. 2014 9 (8): e103123

PMID: 25144566 · PMCID: PMC4140681 · DOI:10.1371/journal.pone.0103123

HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP.

MeSH Terms (16)

Adult Aged Anti-Retroviral Agents Female Genetic Variation Genotype HIV Infections Humans Iron Iron Regulatory Protein 1 Linkage Disequilibrium Male Middle Aged Multivariate Analysis Neuralgia Young Adult

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