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COMT Val158Met Polymorphism, Cardiometabolic Risk, and Nadir CD4 Synergistically Increase Risk of Neurocognitive Impairment in Men Living With HIV

Saloner, Rowan BSa,b; Marquine, Maria J. PhDb; Sundermann, Erin E. PhDb; Hong, Suzi PhDb; McCutchan, John Allen MDc; Ellis, Ronald J. MD, PhDd; Heaton, Robert K. PhDb; Grant, Igor MDb; Cherner, Mariana PhDb

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15, 2019 - Volume 81 - Issue 5 - p e148–e157
doi: 10.1097/QAI.0000000000002083
Translational Research
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Objective: The Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) results in faster metabolism and reduced bioavailability of dopamine (DA). Among persons living with HIV, Val carriers display neurocognitive deficits relative to Met carriers, presumably due to exacerbation of HIV-related depletion of DA. COMT may also impact neurocognition by modulating cardiometabolic function, which is often dysregulated among persons living with HIV. We examined the interaction of COMT, cardiometabolic risk, and nadir CD4 on neurocognitive impairment (NCI) among HIV+ men.

Methods: Three hundred twenty-nine HIV+ men underwent COMT genotyping and neurocognitive and neuromedical assessments. Cohort-standardized z scores for body mass index, systolic blood pressure, glucose, triglycerides, and high-density lipoprotein cholesterol were averaged to derive a cardiometabolic risk score (CMRS). NCI was defined as demographically adjusted global deficit score of ≥0.5. Logistic regression modeled NCI as a function of COMT, CMRS, and their interaction, covarying for estimated premorbid function, race/ethnicity, and HIV-specific characteristics. Follow-up analysis included the 3-way interaction of COMT, CMRS, and nadir CD4.

Results: Genotypes were 81 (24.6%) Met/Met, 147 (44.7%) Val/Met, and 101 (30.7%) Val/Val. COMT interacted with CMRS (P = 0.02) such that higher CMRS increased risk of NCI among Val/Val [odds ratio (OR) = 2.13, P < 0.01], but not Val/Met (OR = 0.93, P > 0.05) or Met/Met (OR = 0.92, P > 0.05) carriers. Among Val/Val, nadir CD4 moderated the effect of CMRS (P < 0.01) such that higher CMRS increased likelihood of NCI only when nadir CD4 <180.

Discussion: Results suggest a tripartite model by which genetically driven low DA reserve, cardiometabolic dysfunction, and historical immunosuppression synergistically enhance risk of NCI among HIV+ men, possibly due to neuroinflammation and oxidative stress.

aSan Diego Joint Doctoral Program in Clinical Psychology, San Diego State University/University of California, San Diego, CA;

bDepartment of Psychiatry, University of California, San Diego, CA; and

Departments of cMedicine; and

dNeurosciences, University of California, San Diego, La Jolla, CA.

Correspondence to: Rowan Saloner, BS, SDSU/UC San Diego Joint Doctoral Program in Clinical Psychology, University of California, San Diego, HIV Neurobehavioral Research Program, 220 Dickinson Street, Suite B, Mail Code 8231, San Diego, CA 92103-8231 (e-mail: rsaloner@ucsd.edu).

Supported by the NIDA-funded Translational Methamphetamine AIDS Research Center (TMARC) award P50DA026306 (PI: I.G.), NIDA award R01DA026334 (PI: M.C.), and the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study awards N01MH22005, HHSN271201000036C, and HHSN271201000030C. R.S. is supported by NIAAA award T32AA013525, and M.J.M. is supported by NIMH award K23MH105297. The CNS HIV Anti-Retroviral Therapy Effects Research was supported by awards N01 MH22005, HHSN271201000036C, and HHSN271201000030C from the National Institutes of Health. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with Johns Hopkins University; the Icahn School of Medicine at Mount Sinai; University of California, San Diego; University of Texas, Galveston; University of Washington, Seattle; Washington University, St. Louis; and is headquartered at the University of California, San Diego, and includes: Director: Igor Grant, MD; Co-Directors: Scott L. Letendre, MD, Ronald J. Ellis, MD, PhD, and Thomas D. Marcotte, PhD; Center Manager: Donald Franklin, Jr; Neuromedical Component: Ronald J. Ellis, MD, PhD (P.I.) and J. Allen McCutchan, MD; Laboratory and Virology Component: Scott Letendre, MD (Co-P.I.) and Davey M. Smith, MD (Co-P.I.); Neurobehavioral Component: R.K.H. (P.I.), J. Hampton Atkinson, MD, and Matthew Dawson; Imaging Component: Christine Fennema-Notestine, PhD (P.I.), Michael J Taylor, PhD, and Rebecca Theilmann, PhD; Data Management Component: Anthony C. Gamst, PhD (P.I.) and Clint Cushman; Statistics Component: Ian Abramson, PhD (P.I.) and Florin Vaida, PhD; Johns Hopkins University Site: Ned Sacktor (P.I.) and Vincent Rogalski; Icahn School of Medicine at Mount Sinai Site: Susan Morgello, MD (Co-P.I.) and David Simpson, MD (Co-P.I.), Letty Mintz, N.P.; University of California, San Diego Site: J. Allen McCutchan, MD (P.I.); University of Washington, Seattle Site: Ann Collier, MD (Co-P.I.), Christina Marra, MD (Co-P.I.), and Sher Storey, PA-C.; University of Texas, Galveston Site: Benjamin Gelman, MD, PhD (P.I.), Eleanor Head, R.N., B.S.N.; and Washington University, St. Louis Site: David Clifford, MD (P.I.), Muhammad Al-Lozi, MD, and Mengesha Teshome, MD.

Presented at the International Neuropsychological Society (INS) Annual Conference; February 21, 2019; New York, NY.

The authors have no conflicts of interest to disclose.

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.

Received February 01, 2019

Accepted April 08, 2019

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