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The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

The Pharmacogenomics Journal volume 8, pages 71–77 (2008)Cite this article

Abstract

Peripheral neuropathy (PN) due to mitochondrial injury complicates HIV therapy with some nucleoside reverse transcriptase inhibitors (NRTIs). Variation in the mitochondrial genome may influence susceptibility to NRTI toxicities. Two non-synonymous mitochondrial DNA polymorphisms, MTND1*LHON4216C (4216C) and MTND2*LHON4917G (4917G) were characterized in HIV-infected participants exposed to NRTIs in a randomized clinical trial. Among 250 self-identified white, non-Hispanic participants, symptomatic PN (⩾ grade 1) developed in 70 (28%). Both 4216C (odds ratio (OR)=1.98 (95% confidence interval (CI) 1.05–3.75); P=0.04) and 4917G (OR=2.93 (95% CI 1.25–6.89); P=0.01) were more frequent in PN cases. These two polymorphisms remained independently associated with PN after adjusting for age, baseline CD4 count, plasma HIV RNA level, and NRTI randomization arm; 4216C (OR=2.0 (95% CI 1.1–4.0) P=0.04) and 4917G (OR=5.5 (95% CI 1.6–18.7) P<0.01). When 4917G individuals were excluded from the analysis, the association with 4216C was no longer seen. The mitochondrial 4917G polymorphism may increase susceptibility to NRTI-associated PN.

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Acknowledgements

The authors sincerely acknowledge their indebtedness to ACTG 384 study team and participants. We also acknowledge Cara Sutcliffe and Ping Mayo in the DNA Core at the Center for Human Genetics Research at Vanderbilt University Medical Center for their invaluable help. Funding Support: Developmental Core Award from the Vanderbilt-Meharry Center for AIDS Research AI54999 (JAC) and a National Institutes of Health Mentored Career Development Award AT002508 (TH). This work was supported in part by the Adult AIDS Clinical Trials Group, funded by the National Institute of Allergy and Infectious Diseases (grant AI38858). Other grant support included Harvard University (Massachusetts General Hospital) (grant A0101), AACTG grant AI27659; Stanford University (A0501), AACTG grant AI27666.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA

    J A Canter, M D Ritchie & D G Murdock

  2. Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN, USA

    D W Haas & T Hulgan

  3. Department of Microbiology and Immunology; Vanderbilt University School of Medicine,

    D W Haas

  4. Vanderbilt University School of Medicine, Nashville, TN, USA

    D W Haas

  5. Division of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    A R Kallianpur

  6. Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, USA

    G K Robbins

  7. Department of Medicine-Infectious Diseases, Stanford University, Stanford, CA, USA

    R W Shafer

  8. Departments of Neurology and Medicine, Washington University School of Medicine, St Louis, MO, USA

    D B Clifford

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Correspondence to J A Canter.

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Canter, J., Haas, D., Kallianpur, A. et al. The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy. Pharmacogenomics J 8, 71–77 (2008). https://doi.org/10.1038/sj.tpj.6500470

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