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

Abstract

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.

Fig. 1

Enrichment of MAF in groups with increased death ages. MAF, minor allele frequency; group 1, young group (living subjects, the life expectancy was reported as 71.3 year for men in China in 2009, n = 376); group 2 (n = 51), death age = 95; group 3 (n = 121), death ages from 96–100, and group 4 (n = 166), death ages > 100. The p values for group 1 vs 2, group 1 vs 3, and group 1 vs 4 were 0.480, 0.049, and 0.0003 for rs1042718 as well as 0.152, 0.002, and 0.0004 for rs1042719, respectively. *, statistically significant.

Fig. 2

Haplotype structure and cloning strategy of ADRB2-firefly luciferase fusion genes (A) and haplotypic effects on protein production (B). A/G, C/G, G/A, C/A, and G/C were the major/minor alleles for SNPs rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719, respectively; CMV, Human cytomegalovirus promoter region; ADRB2, β2-adrenergic receptor cDNA; Flu, Firefly luciferase cDNA; TK, Herpes simplex virus thymidine kinasepromoter region; Rlu, Renilla luciferase cDNA; a, b and c represented the fusion genes comprising Flu and ADRB2 cDNA harboring haplotypes (C-G), (C-C), and (A-C), respectively; d and e were the constructs to control the transfection. OR, odds ratio; 95% CI, 95% confidence interval; Perm P, permuted p values.