ADRB1
Beta-1 adrenergic receptor (Beta-1 adrenoreceptor) (Beta-1 adrenoceptor) [ADRB1R] [B1AR]
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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
The human trabecular meshwork and ciliary body, which express beta-adrenergic receptors (ADRB1 and ADRB2), control aqueous humor dynamics. We investigated associations of ADRB polymorphisms with open-angle glaucoma (OAG), because ADRB gene polymorphisms alter receptor function. We studied 240 Japanese controls and 505 Japanese OAG patients including 211 with primary open-angle glaucoma (POAG), and 294 with normal-tension glaucoma (NTG). Associations of four polymorphisms (Ser49Gly and Arg389Gly in the ADRB1 gene; Arg16Gly and Gln27Glu in the ADRB2 gene) were compared between patients and controls. Age, intraocular pressure (IOP), and visual field defects at diagnosis were examined for associations with polymorphisms. The Arg389Gly polymorphism in the ADRB1 gene showed significantly different allele and genotype frequencies in patients with NTG than in controls (p = 0.004 and 0.006, respectively). Other polymorphisms did not show a significant frequency difference. In POAG patients, carriers of Gly16 in the ADRB2 gene were significantly younger at diagnosis than noncarriers (p<0.001). The IOP at diagnosis was significantly higher in OAG patients carrying 27Glu in the ADRB2 gene than in patients without this allele (p<0.001). Clinical characteristics of OAG patients did not differ significantly in relation to other polymorphisms. Certain polymorphisms of the ADRB1 and ADRB2 genes influence the pathophysiology of OAG in Japanese patients.
MeSH Terms
- Aged
- Aging
- Asian Continental Ancestry Group
- Case-Control Studies
- Female
- Gene Frequency
- Genes, Dominant
- Genes, Recessive
- Genetic Predisposition to Disease
- Genotype
- Glaucoma, Open-Angle
- Heterozygote
- Humans
- Intraocular Pressure
- Male
- Middle Aged
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Receptors, Adrenergic, beta-1
- Receptors, Adrenergic, beta-2