Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy.
Title | Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | 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, J McCutchan, A, Franklin, D, Samuels, DC, Rosario, D, Holzinger, E, Murdock, DG, Letendre, S, Grant, I |
Corporate Authors | CHARTER Study Group |
Journal | PLoS One |
Volume | 9 |
Issue | 8 |
Pagination | e103123 |
Date Published | 2014 |
ISSN | 1932-6203 |
Keywords | Adult, Aged, Anti-Retroviral Agents, CHARTER, Female, Genetic Variation, Genotype, HIV Infections, Humans, Internal, Iron, Iron Regulatory Protein 1, Linkage Disequilibrium, Male, Middle Aged, Multivariate Analysis, Neuralgia, Young Adult |
Abstract | 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. |
DOI | 10.1371/journal.pone.0103123 |
Alternate Journal | PLoS One |
PubMed ID | 25144566 |
PubMed Central ID | PMC4140681 |
Grant List | HHSN271201000036C / / PHS HHS / United States P30 MH075673 / MH / NIMH NIH HHS / United States HHSN271201000036C / MH / NIMH NIH HHS / United States 1R01 MH 095621 / MH / NIMH NIH HHS / United States N01 MH22005 / MH / NIMH NIH HHS / United States N01 MH022005 / MH / NIMH NIH HHS / United States R01 MH095621 / MH / NIMH NIH HHS / United States |