The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy.
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.
Canter
J A
JA
Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. jeff.canter@vanderbilt.edu
Haas
D W
DW
Kallianpur
A R
AR
Ritchie
M D
MD
Robbins
G K
GK
Shafer
R W
RW
Clifford
D B
DB
Murdock
D G
DG
Hulgan
T
T
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D004247:DNA / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D004272:DNA, Mitochondrial; D004247:DNA; D009245:NADH Dehydrogenase; C521326:NADH dehydrogenase subunit 2, human