Full sequence mtDNA variation and HIV-SN in the CHARTER cohort.

Type: Poster
Title: Full sequence mtDNA variation and HIV-SN in the CHARTER cohort.
Authors: Holzinger E, Hulgan T, Ellis R, Samuels D, Clifford D, Collier A, Gelman B, Morgello S, Letendre S, Grant I, and the CHARTER Group
Date: 02-28-2011
Abstract:Background: HIV-associated sensory neuropathy (HIV-SN) remains an important complication of combination antiretroviral therapy (CART). Mitochondrial DNA (mtDNA) haplogroups and single nucleotide polymorphisms (SNP) have been associated with risk of symptomatic neuropathy in ART-naïve clinical trial participants. We examined mtDNA variations and HIV-SN in CHARTER. Methods: CHARTER is a U.S.-based prospective observational study of ambulatory HIV-infected adults who underwent a structured interview and standardized clinical examination. HIV-SN was determined by trained examiners as the presence of ≥1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Full mtDNA sequencing was performed using the GeneChip® Human Mitochondrial Resequencing Array 2.0 (Affymetrix), and haplogroups were assigned using published algorithms. Multivariable logistic regression analyses of cross-sectional associations between mtDNA variants at the SNP level, haplogroups and HIV-SN were performed adjusting for age, any d-drug (didanosine, stavudine, zalcitabine) exposure, and CD4 T cell nadir. The first four components of a multidimensional scaling analysis were included in the models to control for potential population stratification. Results: DNA and data were available from 549 persons. The median age was 44 years (range 21-68), median CD4 nadir was 175 cells/mm3 (interquartile range 52-300), 403 (73%) were receiving CART at evaluation, 299 (54%) had any d-drug exposure, and 323 (59%) had HIV-SN. In analyses testing the association of each mtDNA SNP with HIV-SN, the top two significant SNP were at positions 12810A-G (OR=0.27; 95% CI=0.11-0.65; p=0.004) and 489T-C (0.41; 0.21-0.80; p=0.009). These synonymous changes are associated with African haplogroup L1c and European haplogroup J, which were also associated with decreased prevalence of HIV-SN compared with other haplogroups (L1c OR=0.29; 95% CI=0.12-0.71; p=0.007 and J OR=0.42; 0.18-0.998; p=0.05) In the model including haplogroup L1c, age (OR=1.09; 95% CI=1.06-1.12), d-drug use (2.18; 1.45-3.30), and CD4 nadir (0.998; 0.996-0.999) were all significantly associated with HIV-SN (p<0.001 for all), and these associations were similar in other models. Conclusions: In this cohort of heavily CART-treated subjects with intensive neurologic assessments, relatively common mtDNA haplogroups were associated with decreased prevalence of HIV-SN. Of note, the L1c association with HIV-SN was opposite that observed in a HIV-infected clinical trial population followed for symptomatic neuropathy after CART initiation, suggesting that differences in population, phenotype pathophysiology, and/or study design may substantially influence results of genetic association studies in this phenotype. Validation and mechanistic studies are needed.