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Multicenter Study
, 22 (18), 2429-39

Mitochondrial DNA Haplogroups Influence AIDS Progression

Affiliations
Multicenter Study

Mitochondrial DNA Haplogroups Influence AIDS Progression

Sher L Hendrickson et al. AIDS.

Abstract

Objective: Mitochondrial function plays a role in both AIDS progression and HAART toxicity; therefore, we sought to determine whether mitochondrial DNA variation revealed novel AIDS restriction genes, particularly as mitochondrial DNA single-nucleotide polymorphisms are known to influence regulation of oxidative phosphorylation, reactive oxygen species production, and apoptosis.

Design: This is a retrospective cohort study.

Methods: We performed an association study of mitochondrial DNA haplogroups among 1833 European American HIV-1 patients from five US cohorts: the Multicenter AIDS Cohort Study, the San Francisco City Clinic Study, Hemophilia Growth and Development Study, the Multicenter Hemophilia Cohort Study, and the AIDS Linked to Intravenous Experiences cohort to determine whether the mitochondrial DNA haplogroup correlated with AIDS progression rate.

Results: Mitochondrial DNA haplogroups J and U5a were elevated among HIV-1 infected people who display accelerated progression to AIDS and death. Haplogroups Uk, H3, and IWX appeared to be highly protective against AIDS progression.

Conclusion: The associations found in our study appear to support a functional explanation by which mitochondrial DNA variation among haplogroups, influencing ATP production, reactive oxygen species generation, and apoptosis, is correlated to AIDS disease progression; however, repeating these results in cohorts with different ethnic backgrounds would be informative. These data suggest that mitochondrial genes are important indicators of AIDS disease progression in HIV-1 infected persons.

Figures

Figure 1
Figure 1
A) An ARGARRAY display [37] of categorical and survival analyses for AIDS progression in 34 Caucasian mitochondrial haplogroups. A phylogenetic tree showing the relationship between haplogroups is shown on the left [29]. Each major haplogroup was analyzed, and then successively more definitive subgroups within the haplogroups were analyzed separately. The haplogroups known to contain uncoupling SNPs are in red type in the phylogenetic tree. B) Individual SNP genotypes within the U and J Mitochondrial haplogroups. Locations of SNP in coding genes of the mitochondria are given. *=non-synonymous substitution. Significant values are shown in color (non-grey). Hazardous hazard and odds ratios are indicated by orange and red squares, while significant protection is show in green and blue. In AIDS progression Categorical analyses, 2= dichotomous categorical analysis, M=multipoint categorical analysis. The AIDS association tests illustrated on the horizontal are non-independent. However, the hypothesis study groups: AIDS progression in MSM patients and AIDS progression in patients with hemophilia can be considered independent although tests within each hypothesis study group are related. The five associations IWX, U5a, Uk, J, and H3 did not replicate between MSM cohorts and hemophilia cohorts perhaps as a result of fewer study participants among the hemophiliacs (N=158 versus MSM N=615).
Figure 2
Figure 2
Representative Kaplan-Meier plots for significant results. a) J haplogroup and AIDS’87 progression in sexual transmission cohorts, b) SNP 13708 from the J haplogroups and AIDS’87 progression in sexual transmission cohorts, c) Haplogroup U5a and drop to CD4< 200 cells/μL, and d) SNP 3010, which is in haplogroups J1 and H1 and time to death in sexual transmission cohorts. RH, p-values and numbers shown in the lower left of each graph are from Cox Proportional Models controlling for confounding variables (nuclear ARG genotype, age).
Figure 3
Figure 3
Frequencies of Uk in categorical analyses for Uk using dichotomous (a, c) and multipoint (b, d) models to CD4<200 cells/μL (a,b) and AIDS’93 (c,d). *Odds rations shown for multipoint models are Common Odds Ratios.

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