| Authors: Kallianpur A, Ellis R, Marra C, Simpson D, McArthur J, Clifford D, Gelman B, McCutchan A, Letendre S, Grant I, and the CHARTER Group |
| Abstract:Background: HIV sensory neuropathy (HIV-SN) and neuropathic pain remain prevalent and disabling complications of combination antiretroviral therapy (CART), and CART-associated mitochondrial toxicity is involved in the etiology of HIV-SN. Hemochromatosis (HFE) gene SNPs that affect iron transport alter susceptibility to HIV-SN during mitochondrial-toxic CART. We hypothesized that other iron-regulatory genes modulate risk of HIV-SN and neuropathic pain. Methods: We evaluated the impact of SNPs in key iron-regulatory genes on painful HIV-SN in 560 HIV-infected subjects from a genome-wide study (GWS) of the CHARTER Cohort. Participants in this prospective, observational study of neurological complications during CART underwent structured, in-person interviews to ascertain distal neuropathic pain (DNP), paresthesias and numbness and neurological examinations for HIV-SN signs. Genotypes at candidate loci were determined from GWS sequence data, obtained using the Affymetrix Human SNP Array 6.0. SNP associations with neuropathic endpoints were assessed by multivariate logistic regression. Results: The GWS was informative at loci of interest in >99% of subjects [21% female; mean age 44 yrs (range 21-68); 43% black; 44% white]. We studied 82 SNPs in 19 iron-regulatory genes: HFE, HFE2, SLC40A1, SLC11A1, HAMP, TF, TFRC, TFR2, BMP2, BMP6, CP, SLC11A2, FXN, FTMT, FTH1, ACO1, ACO2, B2M and ATP13A2. Of 559 evaluable subjects, 331 (59%) had ≥1 HIV-SN sign; 160 (29%) met a more stringent definition of HIV-SN (≥2 signs), 281 (50%) reported paresthesias, numbness, or DNP, and 168 (30%) had DNP. SNPs in HFE, SLC11A1, ATP13A2, BMP6 and CP were associated with reduced risk of HIV-SN signs [adjusted odds ratios (ORs) 0.42-0.65, all P<0.05]; a BMP2 SNP conferred increased risk (OR 1.6, P<0.05). Severe HIV-SN in blacks and/or whites was associated with other SNPs in SLC11A1 and SLC40A1 (ORs 0.40-0.66, all P<0.05) and in HFE2, TF, CP and BMP2 (ORs 2.1-9.2, all P<0.05). SNPs in SLC11A1, SCL40A1, TF, BMP6, CP and the mitochondrial iron-transporter gene FXN were associated with neuropathic symptoms and DNP (ORs 0.49-5.0, all P<0.05). Conclusions: In the CHARTER GWS, SNPs in 10 genes encoding cellular and mitochondrial iron-regulatory proteins are associated with HIV-SN, DNP or other symptoms, independent of other factors. Iron transport pathways, critical to mitochondrial function, axonal transport, and control of apoptosis, may be important modulators of neuropathy morbidity during CART |
