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Genetic variation in alcohol dehydrogenase is associated with neurocognition in men with HIV and history of alcohol use disorder: preliminary findings

  • Rowan SalonerEmail author
  • Emily W. Paolillo
  • Maulika Kohli
  • Sarah S. Murray
  • David J. Moore
  • Igor Grant
  • Mariana Cherner
Article

Abstract

The co-occurrence of HIV and alcohol use disorder (AUD) amplifies risk for neural injury and neurocognitive deficits. However, the substantial neurocognitive heterogeneity across HIV+/AUD+ individuals suggests inter-individual differences in vulnerability to the neurotoxicity of comorbid HIV/AUD. Genetic variation in alcohol dehydrogenase (ADH), which metabolizes ethanol, may contribute to inter-individual neurocognitive variability. We evaluated associations between five ADH single-nucleotide polymorphisms (SNPs) and neurocognition in men stratified by HIV and lifetime AUD status. Neurobehavioral assessments were administered to 153 men. Three-way ANOVAs examined the interaction of HIV, AUD, and ADH SNPs on global and domain-specific demographically corrected T scores. Follow-up ANCOVAs adjusted for age, estimated verbal IQ, depression, and remote non-alcohol substance use disorders. HIV/AUD groups differed globally and for verbal fluency, working memory, executive function, and processing speed T scores specifically, with HIV+/AUD+ exhibiting the poorest performance. ADH4 (rs1126671) was associated with large effects on working memory (d = − 1.16, p = .001) and executive function (d = − 0.77, p = .028) selectively in HIV+/AUD+, which remained significant in ANCOVA models. ADH1A (rs3819197) moderated the deleterious effects of HIV+/AUD+ on processing speed such that HIV+/AUD+ related to slower information processing in A allele carriers but not GG homozygotes (ps < 0.03). Preliminary findings suggest genetic variation in the ADH pathway moderates the deleterious neurocognitive effects of comorbid HIV/AUD. Differential metabolism of heavy ethanol exposure may compromise neurocognition under conditions of neurobiological stress, such as in HIV infection. The functional effects on ethanol metabolism of ADH SNPs examined in this study remain poorly understood, warranting further examination of pharmacokinetic mechanisms mediating ADH gene-neurobehavior relationships in HIV.

Keywords

Alcohol dehydrogenase Single-nucleotide polymorphism Cognition HIV-associated neurocognitive disorder Alcohol 

Notes

Acknowledgments

Data for this study were collected as part of a NIDA-funded research program that includes the Translational Methamphetamine AIDS Research Center (TMARC), supported by award P50DA026306 and the program projects on NeuroAIDS Effects of Methamphetamine and NeuroAIDS Effects of Methamphetamine & HCV, supported by award R01DA012065, as well as by award R01DA026334: COMT Genotype and Risky Decision-Making in HIV and Methamphetamine Dependence. Stipend support to RS is funded by NIA award F31AG064989. Stipend support to EWP is funded by NIAAA award F31AA027198. Stipend support to MK is funded by NIAAA award T32AA013525.

The Translational Methamphetamine AIDS Research Center (TMARC) is supported by Center award P50DA026306 from the National Institute on Drug Abuse (NIDA) and is affiliated with the University of California, San Diego (UCSD), the Sanford-Burnham Medical Discovery Institute (SBMDI), and the University of California, Irvine (UCI). The TMARC comprises: Administrative Coordinating Core (ACC) – Executive Unit: Director – Igor Grant, M.D.; Co-Directors – Ronald J. Ellis, M.D., Ph.D., Scott L. Letendre, M.D., and Cristian L. Achim, M.D., Ph.D.; Center Manager – Mariana Cherner, Ph.D.; Associate Center Managers – Erin E. Morgan, Ph.D. and Jared Young, Ph.D.; Data Management and Information Systems (DMIS) Unit: Anthony C. Gamst, Ph.D. (Unit Chief), Clint Cushman, B.A. (Unit Manager); ACC – Statistics Unit: Florin Vaida, Ph.D. (Unit Chief), Ian S. Abramson, Ph.D., Reena Deutsch, Ph.D., Anya Umlauf, M.S.; ACC – Participant Unit: J. Hampton Atkinson, M.D. (Unit Chief), Jennifer Marquie-Beck, M.P.H. (Unit Manager); Behavioral Assessment and Medical (BAM) Core – Neuromedical and Laboratory Unit (NLU): Scott L. Letendre, M.D. (Core Co-Director/NLU Chief), Ronald J. Ellis, M.D., Ph.D.; BAM Core – Neuropsychiatric Unit (NPU): Robert K. Heaton, Ph.D. (Core Co-Director/NPU Chief), J. Hampton Atkinson, M.D., Thomas D. Marcotte, Ph.D., Erin E. Morgan, Ph.D., Matthew Dawson (NPU Manager); Neuroimaging (NI) Core: Gregory G. Brown, Ph.D. (Core Director), Thomas T. Liu, Ph.D., Miriam Scadeng, Ph.D., Christine Fennema-Notestine, Ph.D., Sarah L. Archibald, M.A., John R. Hesselink, M.D., Mary Jane Meloy, Ph.D., Craig E.L. Stark, Ph.D.; Neuroscience and Animal Models (NAM) Core: Cristian L. Achim, M.D., Ph.D. (Core Director), Marcus Kaul, Ph.D., Virawudh Soontornniyomkij, M.D.; Pilot and Developmental (PAD) Core: Mariana Cherner, Ph.D. (Core Director), Stuart A. Lipton, M.D., Ph.D.; Project 1: Arpi Minassian, Ph.D. (Project Director), William Perry, Ph.D., Mark A. Geyer, Ph.D., Jared W. Young, Ph.D.; Project 2: Amanda B. Grethe, Ph.D. (Project Director), Susan F. Tapert, Ph.D., Assawin Gongvatana, Ph.D.; Project 3: Erin E. Morgan, Ph.D. (Project Director), Igor Grant, M.D.; Project 4: Svetlana Semenova, Ph.D. (Project Director).; Project 5: Marcus Kaul, Ph.D. (Project Director).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Disclaimer

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.

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Copyright information

© Journal of NeuroVirology, Inc. 2020

Authors and Affiliations

  1. 1.Joint Doctoral Program in Clinical PsychologySan Diego State University/University of California San DiegoSan DiegoUSA
  2. 2.Department of Psychiatry, HIV Neurobehavioral Research ProgramUniversity of California San DiegoSan DiegoUSA
  3. 3.Department of PathologyUniversity of California San DiegoLa JollaUSA

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