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

TitleThe mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy.
Publication TypeJournal Article
Year of Publication2008
AuthorsCanter JA, Haas DW, Kallianpur AR, Ritchie MD, Robbins GK, Shafer RW, Clifford DB, Murdock DG, Hulgan T
JournalPharmacogenomics J
Volume8
Issue1
Pagination71-7
Date Published2008 Feb
ISSN1470-269X
KeywordsAdult, Antiretroviral Therapy, Highly Active, DNA, DNA, Mitochondrial, Female, Gene Frequency, Genotype, Haplotypes, Humans, Male, Middle Aged, Mitochondria, NADH Dehydrogenase, Peripheral Nervous System Diseases, Polymorphism, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Treatment Outcome
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 (> or = 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.

DOI10.1038/sj.tpj.6500470
Alternate JournalPharmacogenomics J.
PubMed ID17684475
Grant ListAI 002508 / AI / NIAID NIH HHS / United States
AI 27659 / AI / NIAID NIH HHS / United States
AI 27666 / AI / NIAID NIH HHS / United States
AI 54999 / AI / NIAID NIH HHS / United States