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. 2010 Sep 21;5(9):e12862.
doi: 10.1371/journal.pone.0012862.

Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

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Free PMC article

Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

Sher L Hendrickson et al. PLoS One. .
Free PMC article

Abstract

Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression.

Methodology/principal findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl-CoA isomerase (PECI) on chromosome 6.

Conclusions: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Association of SNPs within the PECI gene region of chromosome 6 with AIDS 1987.
A Manhattan plot (a.) and corresponding QQ plot (b.) for 10012 SNPs in NEMP genes showing the additive model that implicates SNPs in the PECI gene region exceeding the GT significance threshold (horizontal line, 9.2×10−6). A gene view of PECI showing SNPs tested and corresponding linkage disequilibrium as inferred by D' between SNPs (c.) and a bar-plot of genotypes of PECI versus the AIDS-1987 diagnosis in years past seroconversion (d.) are shown.
Figure 2
Figure 2. Association of SNPs within the ACSM4 gene region of chromosome 12 with AIDS 1987.
Shown as a a) Manhattan plot for time to AIDS-1987 (genetic model-recessive, GT significance threshold is shown as a horizontal line at 9.2×10−6), b) QQ plot, c) gene view of ACSM4 showing SNPs tested and corresponding linkage disequilibrium as inferred by D' between SNPs, and d) Kaplan-Meier plot of time to AIDS-1987 showing the three ACSM4 genotypes and the p-value for the recessive model.
Figure 3
Figure 3. The effect of rs629362 (a) and rs626080 (b) in PECI on progression to AIDS-defining illness (ADI) Kaposi Sarcoma (KS).

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