A candidate gene study of intermediate histopathological phenotypes in HIV-associated neurocognitive disorders
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A candidate gene study of intermediate histopathological phenotypes in HIV-associated neurocognitive disorders Andrew J. Levine 1 & Virawudh Soontornniyomkij 2 & Eliezer Masliah 3 & Janet S. Sinsheimer 4,5 & Sarah S. Ji 5 & Steve Horvath 5,6 & Elyse J. Singer 1 & Asha Kallianpur 7 & David J. Moore 2 Received: 25 November 2019 / Revised: 13 April 2020 / Accepted: 22 April 2020 # Journal of NeuroVirology, Inc. 2020
Abstract HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and β-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND. Keywords HIV-associated neurocognitive disorder . Genetic . Histopathology . Neuropathology . NeuroAIDS . Synaptodendritic
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13365-020-00846-z) contains supplementary material, which is available to authorized users. * Andrew J. Levine [email protected] 1
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Departments of Human Genetics and Computational Biology, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA
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Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA
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Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA
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