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Hematopoietically-expressed homeobox protein HHEX (Homeobox protein HEX) (Homeobox protein PRH) [HEX] [PRH] [PRHX]


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

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.

MeSH Terms

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

The risk allele load accelerates the age-dependent decline in beta cell function.

Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function. In the present study we examined the effect of these genes' risk alleles on the age-dependent decline in insulin secretion. The SNPs rs7903146 (TCF7L2), rs7754840(CDKAL1), rs7923837 (HHEX) and rs13266634 (SLC30A8) were genotyped in 1,412 non-diabetic patients, who were subsequently grouped according to their number of risk alleles. All participants underwent an OGTT. Insulin secretion was assessed by validated indices and proinsulin conversion by calculating AUC(proinsulin)/AUC(insulin). The number of risk alleles revealed a Gaussian distribution, with most participants carrying four risk alleles. Stratification into groups with low (LAL, up to three alleles), median (MAL, four alleles) and high (HAL, five to eight alleles) allele load resulted in MAL and HAL participants displaying significantly lower insulin secretion and proinsulin conversion than LAL participants (p <or= 0.0014 and p = 0.0185, respectively). In the overall cohort, age was negatively associated with insulin secretion and proinsulin conversion (both p < 0.0001). MAL and HAL participants showed a significantly more pronounced decline in insulin secretion with increasing age than LAL participants (p <or= 0.0325; analysis of covariance), and after stratification for BMI this relationship was maintained in obese, but not non-obese, participants. Proinsulin conversion decreased with increasing age in MAL and HAL, but not LAL, participants (p <or= 0.0003 vs p = 0.2). The risk allele load significantly accelerates the age-dependent decline in beta cell function, and this might be of particular importance in obese people.

MeSH Terms

  • Adult
  • Aging
  • Analysis of Variance
  • Blood Glucose
  • Body Mass Index
  • DNA
  • Diabetes Mellitus, Type 2
  • Female
  • Gene Frequency
  • Genome, Human
  • Genotype
  • Germany
  • Glucose Tolerance Test
  • Humans
  • Insulin-Secreting Cells
  • Male
  • Polymorphism, Single Nucleotide
  • Risk Assessment