1. ¹Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
2. ²Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN, USA
3. ³Department of Microbiology and Immunology; Vanderbilt University School of Medicine, Nashville, TN, USA
4. ⁴Division of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
5. ⁵Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, USA
6. ⁶Department of Medicine-Infectious Diseases, Stanford University, Stanford, CA, USA
7. ⁷Departments of Neurology and Medicine, Washington University School of Medicine, St Louis, MO, USA

Correspondence: Dr JA Canter, Center for Human Genetics Research, 519 Light Hall, Vanderbilt University Medical Center, Nashville, TN 37212, USA. E-mail: jeff.canter@vanderbilt.edu

Received 18 March 2007; Revised 20 June 2007; Accepted 28 June 2007; Published online 7 August 2007.

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.