Iron-Regulatory genes are associated with neuroimaging traits in HIV infection.

Type: Poster
Title: Iron-Regulatory genes are associated with neuroimaging traits in HIV infection.
Authors: Thornton-Wells T, Fennema-Notestine C, Hulgan T, Letendre S, Ellis R, Kallianpur A, for the CHARTER Group
Year: 2015
Publication: Conference on Retroviruses and Opportunistic Infections

Background: HIV-Associated Neurocognitive Disorders (HAND) remain highly prevalent, despite viral suppression with combination antiretroviral therapy. Structural and metabolic changes in the brain may occur early in HIV-infection and represent important endophenotypes of HAND. Since iron dysregulation in the brain is a consistent feature of aging-related neurocognitive disorders, we hypothesized that variants in iron-regulatory genes are associated with neuroimaging traits in HIV-infected persons with or without HAND.

Methods: We genotyped 250 SNPs in 12 iron-related genes and evaluated their associations with magnetic resonance (MR) imaging traits among 243 subjects with neuroimaging data from the CNS HIV Antiretroviral Treatment Effects Research (CHARTER) Study. Structural MR imaging measurements of gray matter (GM) and white matter (WM) volume and MR spectroscopy measurements of brain metabolites were made in 21 regions of interest (ROI). Multivariable regression models of log-transformed neuroimaging variables were adjusted for age, scanner, genetic ancestry, nadir CD4+ T-cell count, and HIV RNA detectability in plasma, as well as trait-specific covariates. Analyses stratified by the presence of neurocognitive impairment (Global Deficit Score, GDS<0.5 or ≥0.5), virus detectability, or comorbidities were also performed, and two levels of correction for multiple statistical tests were applied.

Results: Of 29 common SNPs that were significantly associated with structural and/or metabolic traits after correction for the 37 haplotype blocks represented (p<0.05), 5 SNP associations also survived the most conservative correction (for 37 haplotype blocks and 21 ROI) and demonstrated biologically plausible patterns of association with traits previously linked to aging and/or HAND (Table). Iron-regulatory genes with significant associations included TFRC (in subjects with detectable HIV RNA), SLC40A1 (in subjects with undetectable viral RNA), SLC11A1 (in subjects without neurocognitive impairment), CP and ACO2 (in subjects with comorbidities).

CONCLUSIONS: Iron-regulatory gene variation is associated with specific, aging-related neuroimaging attributes in HIV-infected subjects, such as abnormal WM and subcortical GM volumes, and with regional metabolite levels that reflect brain inflammation and neuronal integrity. Further studies are needed to replicate these findings and assess contributions of these variants to aging-related neuropathologies in HIV infection, including HAND.