Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms

PLoS Genet. 2011 Apr;7(4):e1002025. doi: 10.1371/journal.pgen.1002025. Epub 2011 Apr 14.

Abstract

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p = 2.61 × 10(-19)), ARPC1A (rs740160; p = 1.56 × 10(-16)), TRIM4 (rs17277546; p = 4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p = 4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin-Related Protein 2-3 Complex / genetics
  • Actin-Related Protein 2-3 Complex / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aged
  • Aging / blood*
  • Aging / genetics
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Bcl-2-Like Protein 11
  • Cytochrome P-450 CYP2C9
  • Dehydroepiandrosterone Sulfate / blood*
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Expression
  • Genome-Wide Association Study
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Linkage Disequilibrium
  • Liver / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Young Adult

Substances

  • ARPC1A protein, human
  • Actin-Related Protein 2-3 Complex
  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • BMF protein, human
  • Bcl-2-Like Protein 11
  • HHEX protein, human
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • ZKSCAN5 protein, human
  • Dehydroepiandrosterone Sulfate
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Sulfotransferases
  • alcohol sulfotransferase