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Adenylate cyclase type 6 (EC (ATP pyrophosphate-lyase 6) (Adenylate cyclase type VI) (Adenylyl cyclase 6) (Ca(2 )-inhibitable adenylyl cyclase) [KIAA0422]


Common genetic variants of the β2-adrenergic receptor affect its translational efficiency and are associated with human longevity.

β-adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of β-adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the β-adrenergic signaling pathway are associated with human longevity. We performed a 10-year follow-up study of the Chinese longitudinal healthy longevity survey. The Han Chinese population in this study consisted of 963 long-lived and 1028 geography-matched young individuals. Sixteen SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were selected and genotyped. Two SNPs, rs1042718 (C/A) and rs1042719 (G/C), of ADRB2 in linkage disequilibrium (D' = 1.0; r2 = 0.67) were found to be associated with enhanced longevity in men in two geographically isolated populations. Bonferroni-corrected P-values in a combined analysis were 0.00053-0.010. Men with haplotype A-C showed an increased probability to become centenarians (the frequency of A-C in long-lived and young individuals are 0.332 and 0.250, respectively, OR = 1.49, CI 95% = 1.17-1.88, P = 0.0007), in contrast to those with haplotype C-G (the frequency of C-G in long-lived and young individuals are 0.523 and 0.635, respectively, OR = 0.63, CI 95% = 0.51-0.78, P = 0.000018). The permuted P-values were 0.00005 and 0.0009, respectively. ADRB2 encodes the β2-adrenergic receptor; the haplotype A-C markedly reduced its translational efficiency compared with C-G (P = 0.002) in transfected HEK293 cells. Thus, our data indicate that enhanced production of β2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan.

MeSH Terms

  • Adenylyl Cyclases
  • Aged, 80 and over
  • Aging
  • Asian Continental Ancestry Group
  • Case-Control Studies
  • Female
  • Follow-Up Studies
  • Genes, Reporter
  • HEK293 Cells
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Longevity
  • Luciferases, Renilla
  • Male
  • Mitogen-Activated Protein Kinase 1
  • Polymorphism, Single Nucleotide
  • Protein Biosynthesis
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Surveys and Questionnaires
  • Transfection