Genetic variation in alcohol dehydrogenase is associated with neurocognition in men with HIV and history of alcohol use disorder: preliminary findings
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.
KeywordsAlcohol dehydrogenase Single-nucleotide polymorphism Cognition HIV-associated neurocognitive disorder Alcohol
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.
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.
- Beck A, Steer R, Brown G (1996) Manual for Beck Depression Inventory II (BDI-II). Psychology Corporation, San AntonioGoogle Scholar
- Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300Google Scholar
- Blackstone K, Iudicello JE, Morgan EE, Weber E, Moore DJ, Franklin DR, Ellis RJ, Grant I, Woods SP (2013) Human immunodeficiency virus infection heightens concurrent risk of functional dependence in persons with long-term methamphetamine use. J Addict Med 7:255–263PubMedPubMedCentralCrossRefGoogle Scholar
- Edenberg HJ, Xuei X, Chen H, Tian H, Wetherill LF, Dick DM, Almasy L, Bierut L, Bucholz KK, Goate A, Hesselbrock V, Kuperman S, Nurnberger J, Porjesz B, Rice J, Schuckit M, Tischfield J, Begleiter H, Foroud T (2006) Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis. Hum Mol Genet 15:1539–1549PubMedCrossRefGoogle Scholar
- Galvan FH, Bing EG, Fleishman JA, London AS, Caetano R, Burnam MA, Longshore D, Morton SC, Orlando M, Shapiro M (2002) The prevalence of alcohol consumption and heavy drinking among people with HIV in the United States: results from the HIV Cost and Services Utilization Study. J Stud Alcohol 63:179–186PubMedCrossRefGoogle Scholar
- Heaton RK, Miller SW, Taylor MJ, Grant I (2004) Revised comprehensive norms for an expanded Halstead Reitan battery: demographically adjusted neuropsychological norms for African American and Caucasian adults. Psychological Assessment Resources, Inc, LutzGoogle Scholar
- Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096PubMedPubMedCentralCrossRefGoogle Scholar
- Hodgkinson CA, Yuan Q, Xu K, Shen PH, Heinz E, Lobos EA, Binder EB, Cubells J, Ehlers CL, Gelernter J, Mann J, Riley B, Roy A, Tabakoff B, Todd RD, Zhou Z, Goldman D (2008) Addictions biology: haplotype-based analysis for 130 candidate genes on a single array. Alcohol Alcohol 43:505–515PubMedPubMedCentralCrossRefGoogle Scholar
- Justice AC, McGinnis KA, Tate JP, Braithwaite RS, Bryant KJ, Cook RL, Edelman EJ, Fiellin LE, Freiberg MS, Gordon AJ, Kraemer KL, Marshall BD, Williams EC, Fiellin DA (2016) Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men. Drug Alcohol Depend 161:95–103PubMedPubMedCentralCrossRefGoogle Scholar
- Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B, Kumar M (2011) Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance. J Neuro-Oncol 17:26–40Google Scholar
- Malaspina L, Woods SP, Moore DJ, Depp C, Letendre SL, Jeste D, Grant I, Group HIVNRP (2011) Successful cognitive aging in persons living with HIV infection. J Neuro-Oncol 17:110–119Google Scholar
- Norman MA, Moore DJ, Taylor M, Franklin D Jr, Cysique L, Ake C, Lazarretto D, Vaida F, Heaton RK, Group H (2011) Demographically corrected norms for African Americans and Caucasians on the Hopkins Verbal Learning Test-Revised, Brief Visuospatial Memory Test-Revised, Stroop Color and Word Test, and Wisconsin Card Sorting Test 64-Card Version. J Clin Exp Neuropsychol 33:793–804PubMedPubMedCentralCrossRefGoogle Scholar
- Pfefferbaum A, Rosenbloom MJ, Sassoon SA, Kemper CA, Deresinski S, Rohlfing T, Sullivan EV (2012) Regional brain structural dysmorphology in human immunodeficiency virus infection: effects of acquired immune deficiency syndrome, alcoholism, and age. Biol Psychiatry 72:361–370PubMedPubMedCentralCrossRefGoogle Scholar
- Saloner R, Marquine MJ, Sundermann EE, Hong S, McCutchan JA, Ellis RJ, Heaton RK, Grant I, Cherner M (2019) COMT Val158Met polymorphism, cardiometabolic risk, and nadir CD4 synergistically increase risk for neurocognitive impairment in men living with HIV. J Acquir Immune Defic Syndr 81:e148–e157PubMedCrossRefGoogle Scholar
- Spitzer R, Williams J, Gibbon M, First M (1995) Structured clinical interview for DSM-IV. American Psychiatric Press, Washington, DCGoogle Scholar
- Sundermann EE, Bishop JR, Rubin LH, Little DM, Meyer VJ, Martin E, Weber K, Cohen M, Maki PM (2015) Genetic predictor of working memory and prefrontal function in women with HIV. J Neuro-Oncol 21:81–91Google Scholar
- Trantham-Davidson H, Centanni SW, Garr SC, New NN, Mulholland PJ, Gass JT, Glover EJ, Floresco SB, Crews FT, Krishnan HR, Pandey SC, Chandler LJ (2017) Binge-like alcohol exposure during adolescence disrupts dopaminergic neurotransmission in the adult prelimbic cortex. Neuropsychopharmacology 42:1024–1036PubMedCrossRefGoogle Scholar
- Wilkinson G, Robertson G (2006) Wide Range Achievement Test-4 (WRAT-4). Lutz, Psychological Assessment Resources IncGoogle Scholar
- World Health Organization (1998) Composite Diagnositic International Interview (CIDI, version 2.1). World Health Organization, GenevaGoogle Scholar