title: 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.
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Huiqing
authors.initials: H
authors.lastname: Cao
authors.forename: Gu-Yan
authors.initials: GY
authors.lastname: Zheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
authors.forename: Hanbin
authors.initials: H
authors.lastname: Cui
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Chen
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhu
authors.forename: Hongbo
authors.initials: H
authors.lastname: He
authors.forename: Xianming
authors.initials: X
authors.lastname: Mo
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Tian
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D017930:Genes, Reporter; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008136:Longevity / Q000235:genetics*; D049410:Luciferases, Renilla; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D011795:Surveys and Questionnaires; D014162:Transfection
chemical_list: C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D049410:Luciferases, Renilla; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V