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Author Notes:

Christine Fennema-Notestine, PhD, University of California, San Diego (UCSD), 9500 Gilman Dr., #0738, La Jolla, CA 92093-0738, Phone: 858-246-0605; Fax: 858-246-0556. Email: fennema@ucsd.edu

This work was supported in part by awards from National Institutes of Health (R01 MH05621, T. Hulgan and A. Kallianpur; K24 MH097673, S.L. Letendre; the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) N01 MH2205 and HHSN271201000036C, to I. Grant; R01 MH107345, R.K. Heaton and S.L. Letendre; and P30 MH62512, R. Heaton). The views expressed in this article are those of the authors and do not reflect the official policy or position of the United States Government. We gratefully acknowledge all individuals who participated in CHARTER studies, as well as all CHARTER study investigators

The authors report no biomedical financial interests or potential conflicts of interest relevant to this manuscript beyond those participating through the NIH funding stated above:

Christine Fennema-Notestine, PhD1,2 has no disclosures to report, other than participating through NIH funding stated above. Tricia A. Thornton-Wells, PhD3 has no disclosures to report, other than participating through NIH funding stated above. Todd Hulgan, PhD4 has no disclosures to report, other than the NIH funding stated above. Scott Letendre, MD5 has no disclosures to report, other than the NIH funding stated above. Ronald J. Ellis, MD, PhD6 has no disclosures to report, other than participating through NIH funding stated above. Donald R. Franklin, Jr., BS1 has no disclosures to report, other than participating through NIH funding stated above. Albert M. Anderson, MD7 has no disclosures to report. Robert K. Heaton, PhD1 has no disclosures to report, other than the NIH funding stated above. Cinnamon S. Bloss, PhD1,8 has no disclosures to report. I. Grant, MD1 has no disclosures to report, other than the NIH funding stated above. Asha R. Kallianpur, MD, MPH9,10 has no disclosures to report, other than the NIH funding stated above.

Subject:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neuroimaging
  • Neurosciences & Neurology
  • Iron-regulatory gene
  • Brain
  • Structural MRI
  • Magnetic resonance spectroscopy (MRS)
  • HIV
  • Association studies in genetics
  • ANTIRETROVIRAL THERAPY
  • ALZHEIMERS-DISEASE
  • COGNITIVE IMPAIRMENT
  • APOE EPSILON-4
  • CSF BIOMARKERS
  • BRAIN
  • MATTER
  • HOMEOSTASIS
  • SPECTROSCOPY
  • METABOLISM

Iron-regulatory genes are associated with Neuroimaging measures in HIV infection

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Tools:

Journal Title:

BRAIN IMAGING AND BEHAVIOR

Volume:

Volume 14, Number 5

Publisher:

, Pages 2037-2049

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The pathogenesis of HIV-associated neurocognitive impairment (NCI) may involve iron dysregulation. In 243 HIV-seropositive adults without severe comorbidities, we therefore genotyped 250 variants in 20 iron-related genes and evaluated their associations with magnetic resonance imaging measures of brain structure and metabolites, including measures previously linked to NCI. Multivariable regression analyses examined associations between genetic variants and neuroimaging measures, adjusting for relevant covariates and multiple testing. Exploratory analyses stratified by NCI (Global Deficit Score ≥ 0.5 vs. <0.5), virus detectability in plasma, and comorbidity levels were also performed. Of 27 variants (in 12 iron-regulatory genes) associated with neuroimaging measures after correction for the 37 haplotype blocks represented, 3 variants survived additional correction for the 21 neuroimaging measures evaluated and demonstrated biologically plausible associations. SLC11A1 rs7576974_T was significantly associated with higher frontal gray matter N-acetylaspartate (p = 3.62e−5). Among individuals with detectable plasma virus, TFRC rs17091382_A was associated with smaller subcortical gray matter volume (p = 3.23e−5), and CP rs4974389_A (p = 3.52e−5) was associated with higher basal ganglia Choline in persons with mild comorbidities. Two other strong associations were observed for variants in SLC40A1 and ACO2 but were not robust due to low minor-allele frequencies in the study sample. Variants in iron metabolism and transport genes are associated with structural and metabolite neuroimaging measures in HIV-seropositive adults, regardless of virus suppression on antiretroviral therapy. These variants may confer susceptibility to HIV-related brain injury and NCI. Further studies are needed to determine the specificity of these findings to HIV infection and explore potential underlying mechanisms.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/rdf).
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