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.
Highlights
The success of combination antiretroviral therapy in human immunodeficiency virus (HIV) infection has focused attention on addressing long-term complications that reduce quality of life, such as peripheral neuropathy [1]
We previously reported associations between ironloading, single-nucleotide polymorphisms (SNPs) in the hemochromatosis (HFE) gene and reduced risk of HIV sensory neuropathy’’ (HIV-SN) in HIVinfected individuals exposed to D-drug-containing combination antiretroviral therapy (cART) [31]
Polymorphisms in cytoplasmic aconitase (ACO1), beta-2 microglobulin (B2M), CP, TF, and transferrin receptor 1 (TFRC) rs480760, most of which are very common among both blacks and whites, showed statistically significant associations with distal neuropathic pain (DNP) severity in one or both subgroups as well as in the entire study population. This represents the first study to associate key iron-regulatory and iron-transport-pathway genes, which make up the human ferrome and are critical for maintenance of neuronal metabolism and mitochondrial function, with painful neuropathy in HIVinfected subjects
Summary
The success of combination antiretroviral therapy (cART) in human immunodeficiency virus (HIV) infection has focused attention on addressing long-term complications that reduce quality of life, such as peripheral neuropathy [1]. Peripheral neuropathy in HIV infection is a distal symmetric, often painful, sensory polyneuropathy associated with the virus itself and/or to toxic effects of certain antiretroviral drugs, the dideoxy-nucleoside reverse-transcriptase inhibitors HIV-SN may first manifest or worsen upon initiation of cART and is associated with sensory loss, paresthesias, and distal neuropathic pain (DNP) or dysesthesias. Substitution of less toxic antiretroviral drugs lowers the risk of HIV-SN, older D-drugs like stavudine are likely to remain in use in low-resource settings for some time as part of generic, fixed-dose cART regimens, and the study of HIV-SN and DNP remains very relevant [19,20]. Improved understanding of the biological mechanisms underlying painful HIV-SN may lead to better ways of categorizing and therapeutically targeting DNP [21,22,23]
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