Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression.
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.


RESULTS
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.
Hendrickson
Sher L
SL
Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, USA. hendricksons@mail.nih.gov
Lautenberger
James A
JA
Chinn
Leslie Wei
LW
Malasky
Michael
M
Sezgin
Efe
E
Kingsley
Lawrence A
LA
Goedert
James J
JJ
Kirk
Gregory D
GD
Gomperts
Edward D
ED
Buchbinder
Susan P
SP
Troyer
Jennifer L
JL
O'Brien
Stephen J
SJ
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D044465:White People / Q000235:genetics