We examined 904 genes for nuclear-encoded mitochondrial proteins for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1455 European American patients from five US AIDS cohorts. 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.
Antibodies to PECI have been found in patients with autoimmune diabetes 
, breast cancer
, renal cancer 
, and hepatocarcinoma 
and PECI serves as an autoantigen eliciting immune attack against hematopoietic progenitor cells by both T and B cells in acquired aplastic anemia patients 
. PECI is an auxiliary enzyme that catalyzes an isomerization step required for the beta-oxidation of unsaturated fatty acids 
. Cellular energy metabolism is largely sustained by mitochondrial β-oxidation of saturated and unsaturated fatty acids. A recent study in the THESA cohort suggested that intake of poly-unsaturated fats was adversely related to liver function in asymptomatic HIV-infected subjects compared with HIV-uninfected subjects 
. One hypothesis put forth by the THESA study is that polyunsaturated fats, which are susceptible to attack by free radicals and oxidation into lipid peroxides, promote liver damage because of increased oxidative stress in HIV-infected subjects. This hypothesis will need to be further explored to resolve if and how the associations observed between SNPs in PECI
and accelerated AIDS progression here may be related.
ACSM4 is a member of a group of synthases that catalyze the fundamental initial reaction in fatty acid metabolism. This activation of fatty acids allows their participation in both anabolic and catabolic pathways 
. How these functions may relate to AIDS progression remains to be discovered. As ACSM4 associations are weaker and lack a obvious mechanism, we consider these associations preliminary.
AIDS'87 is defined by diagnosis of an AIDS sequela, or “clinical” AIDS, therefore most patients are typically past the earlier CD4 cell count <200 stage. To look for underlying associations between PECI and ASCM4 and AIDS-1987 defining conditions, KS, PCP and opportunistic infections were analyzed for association with significant SNPs in these two genes. These data suggest the connection between PECI and AIDS progression may be through an association to KS.
It should be noted, that although these tests were follow-up to the genes found significant in progression analyses, if a strict Bonferoni criteria considering all tests was used, these results would no longer be significant. We have tried to account for this matter by using two methods, the first (GT) adjusted for the number of genes analyzed in the study multiplied by the two hypotheses and three genetic models, and a second correction (ST) adjusted for the total SNPs (10,012) and the six tests. The precise correction likely falls somewhere between these two measures; as the first is not conservative enough, while the second is likely too strict. P-values as presented are moderate and conclusions must be tempered by the multiple comparisons problem. Replication of these genes in additional cohorts is necessary.We also examined NEMPs that were previously reported as cellular gene products required for HIV-infection in screens using siRNAs 
, mRNA expression 
, or proteomics 
for SNPs associated with AIDS-1987. Out of 1353 cellular factors identified in these studies, 151 are also identified NEMPs. NEMP genes are significantly overrepresented in Chan et al
. 2007, Ryo et al.
2000 and in Ringrose et al.
2008, and a trend is observed in Espeseth et al.
2008 (Table S3
), suggesting a strong link between mitochondrial function and HIV infection. None of the SNPs within the 151 NEMP genes that were identified by the HIV infection studies showed p
-values above the pGT
correction threshold; however, fifty-nine genetic associations from twenty genes produce unadjusted p
≤0.01, with the strongest significance found for quinoid dihydropteridine reductase (QDPR) (rs2535228). SNPs within three of fifteen genes replicated between the original studies were associated with accelerated progression to AIDS-1987 in the current study: NADH Dehydrogenase (Ubiquinone) 1 Beta Subcomplex, 7
), Isocitrate Dehydrogenase 1
) , and Isocitrate Dehydrogenase 3 (NAD+) Alpha
)]. These associations may be real or may be statistical artifacts of multiple tests, therefore they need to be validated in other studies. However, s, the independent replication of these three HIV factors, plus the observation of modest SNP associations for these genes with AIDS progression adds support to a plausible regulatory role of each NEMP-HIV factor occurs in HIV-related pathogenesis.
Our previous studies on mitochondrial DNA that showed European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events 
, and 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.