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Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER

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Abstract

HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CNS HIV Antiretroviral Therapy Effects Research (CHARTER). CHARTER is a USA-based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp–dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups, and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G [odds ratio (95 % confidence interval) = 0.27 (0.11–0.65); p = 0.004] and T489C [odds ratio (95 % confidence interval) = 0.41 (0.21–0.80); p = 0.009]. These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups were associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups [odds ratio (95 % confidence interval) = 0.29 (0.12–0.71); p = 0.007 and odds ratio (95 % confidence interval) = 0.42 (0.18–1.0); p = 0.05, respectively]. In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.

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Acknowledgments

The CNS HIV Antiretroviral Therapy Effects Research (CHARTER) group is affiliated with the Johns Hopkins University; Mount Sinai School of Medicine; University of California, San Diego; University of Texas, Galveston; University of Washington, Seattle; and Washington University, St. Louis and is headquartered at the University of California, San Diego and includes Director: Igor Grant, M.D.; Co-Directors: Scott L. Letendre, M.D., Ronald J. Ellis, M.D., Ph.D., Thomas D. Marcotte, Ph.D.; Center Manager: Donald Franklin, Jr.; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D., Terry Alexander, R.N.; Laboratory, Pharmacology and Immunology Component: Scott Letendre, M.D. (P.I.), Edmund Capparelli, Pharm.D.; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Steven Paul Woods, Psy.D., Matthew Dawson; Virology Component: Davey M. Smith, M.D. (P.I.), Joseph K. Wong, M.D.; Imaging Component: Christine Fennema-Notestine, Ph.D. (Co-P.I.), Michael J. Taylor, Ph.D. (Co-P.I.), Rebecca Theilmann, Ph.D.; Data Management Component: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman; Statistics Component: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D.; Johns Hopkins University site: Justin McArthur (P.I.), Mary Smith; Mount Sinai School of Medicine site: Susan Morgello, M.D. (Co-P.I.) and David Simpson, M.D. (Co-P.I.), Letty Mintz, N.P.; University of California, San Diego site: J. Allen McCutchan, M.D. (P.I.), Will Toperoff, N.P.; University of Washington, Seattle site: Ann Collier, M.D. (Co-P.I.) and Christina Marra, M.D. (Co-P.I.), Trudy Jones, M.N., A.R.N.P.; University of Texas, Galveston site: Benjamin Gelman, M.D., Ph.D. (P.I.), Eleanor Head, R.N., B.S.N.; and Washington University, St. Louis site: David Clifford, M.D. (P.I.), Muhammad Al-Lozi, M.D., Mengesha Teshome, M.D.

Conflict 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.

Funding

The CNS HIV Antiretroviral Therapy Effects Research study is supported by awards (N01 MH22005, HHSN271201000027C, and HHSN271201000030C) from the National Institutes of Health.

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Authors and Affiliations

  1. Vanderbilt University, A2200 MCN 1161 21st Ave South, Nashville, TN, 37232, USA

    Emily R. Holzinger, Todd Hulgan, David C. Samuels, David W. Haas, Asha R. Kallianpur & Doug Selph

  2. University of California-San Diego, San Diego, CA, USA

    Ronald J. Ellis, J. Allen McCutchan, Donald R. Franklin, Debralee Rosario, Scott Letendre & Igor Grant

  3. The Pennsylvania State University, University Park, PA, USA

    Marylyn D. Ritchie

  4. Scripps Research Institute, La Jolla, CA, USA

    Cinnamon S. Bloss

  5. Washington University, St. Louis, MO, USA

    David B. Clifford

  6. University of Washington, Seattle, WA, USA

    Ann C. Collier & Christina M. Marra

  7. University of Texas Medical Branch, Galveston, TX, USA

    Benjamin B. Gelman

  8. Johns Hopkins University, Baltimore, MD, USA

    Justin C. McArthur

  9. Mount Sinai School of Medicine, New York, NY, USA

    Susan Morgello & David M. Simpson

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  1. Emily R. Holzinger
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  2. Todd Hulgan
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Holzinger, E.R., Hulgan, T., Ellis, R.J. et al. Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. J. Neurovirol. 18, 511–520 (2012). https://doi.org/10.1007/s13365-012-0133-y

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