title: Mitochondrial DNA subhaplogroups L0a2 and L2a modify susceptibility to peripheral neuropathy in malawian adults on stavudine containing highly active antiretroviral therapy.
abstract: BACKGROUND
  Peripheral neuropathy (PN) is one of the main toxicities associated with stavudine. Genetic variants in mitochondrial DNA (mtDNA) haplogroups have been associated with increased risk of developing PN in European non-Hispanic and black patients on stavudine containing antiretroviral therapy (ART). We investigated mtDNA haplogroups and their role in susceptibility to stavudine-induced peripheral in Malawian patients on ART.
  
  
  METHODS
  Two hundred and fifteen adults on stavudine containing regimens were recruited from the ART clinic at Queen Elizabeth Central Hospital, Blantyre, into a cross-sectional study to investigate the effects of genetic variants in mtDNA of individuals in relation to response to treatment. Patients were categorized according to whether or not they had developed PN after a minimum of 6 months on stavudine containing ART. Whole mtDNA coding regions of each patient were sequenced, and CD4 count, viral load, and creatinine were determined. The mtDNA variation was correlated with clinical characteristics.
  
  
  RESULTS
  Fifty-three (25%) of the participants developed PN after starting stavudine containing ART. Mitochondrial DNA subhaplogroup L0a2 was independently associated with increased risk of PN in a multivariate model (odds ratio, 2.23; 95% confidence interval, 1.14 to 4.39; P = 0.019), and subhaplogroup L2a was independently associated with reduced risk of PN (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.94; P = 0.036).
  
  
  CONCLUSIONS
  Genetic variation in mtDNA confers differential risk of developing PN in patients on stavudine containing ART among Malawians.
authors.affiliation: *Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; and †Department of Pathology, ‡Department of Medicine, and §Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kampira
authors.forename: Johnstone
authors.initials: J
authors.lastname: Kumwenda
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018791:CD4 Lymphocyte Count; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006239:Haplotypes; D006801:Humans; D008295:Malawi / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D018119:Stavudine / Q000627:therapeutic use*; D019562:Viral Load
chemical_list: D004272:DNA, Mitochondrial; D003404:Creatinine; D018119:Stavudine