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

Authors: Zhao L; Yang F; Xu K; Cao H; Zheng GY; Zhang Y; Li J; Cui H; Chen X; Zhu Z; He H; Mo X; Kennedy BK; Suh Y; Zeng Y; Tian XL

Abstract: beta-adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of beta-adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the beta-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 beta2-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 beta2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan.

Keywords: Adenylate Cyclase/genetics/metabolism; Aged, 80 and over; Aging/*genetics/metabolism; Asian Continental Ancestry Group/*genetics; Case-Control Studies; Female; Follow-Up Studies; Genes, Reporter; HEK293 Cells; Haplotypes; Humans; Linkage Disequilibrium; Longevity/*genetics; Luciferases, Renilla; Male; Mitogen-Activated Protein Kinase 1/genetics/metabolism; *Polymorphism, Single Nucleotide; *Protein Biosynthesis; Questionnaires; Receptors, Adrenergic, beta-1/genetics/metabolism; Receptors, Adrenergic, beta-2/*genetics/metabolism; Transfection
Journal: Aging cell
Volume: 11
Issue: 6
Pages: 1094-101
Date: Oct. 2, 2012
PMID: 23020224
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Citation:

Zhao L, Yang F, Xu K, Cao H, Zheng GY, Zhang Y, Li J, Cui H, Chen X, Zhu Z, He H, Mo X, Kennedy BK, Suh Y, Zeng Y, Tian XL (2012) Common genetic variants of the β2-adrenergic receptor affect its translational efficiency and are associated with human longevity. Aging cell 11: 1094-101.


Longevity Variant Associations (p-value):
  • rs740746 (0.556)
  • rs1042718 (0.014)
  • rs1042719 (1.29)
  • rs1042718-rs1042719 (1.86e-05)
  • rs2053044 (0.138)
  • rs1042713 (0.149)
  • rs1042714 (0.558)
  • rs2877709 (0.767)
  • rs9861425 (0.251)
  • rs9844212 (0.901)
  • rs4677882 (0.999)
  • rs4482616 (0.398)
  • rs2291727 (0.003)
  • rs5749998 (0.152)
  • rs2266968 (0.048)
  • rs1892848 (0.218)
  • rs5999521 (0.218)

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