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Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context.

ABSTRACT: The Gln(27)Glu polymorphism but not the Arg(16)Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln(27)Gln genotype increases risks of cancer, MI and IC, whereas the Glu(27) allele or, equivalently, the Gly(16)Glu(27) haplotype tends to be protective against these diseases. Genetic associations with longevity are of opposite nature at young-old and oldest-old ages highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonistic pleiotropy is associated with an evolutionary-driven advantage of carriers of a derived Gln(27) allele at younger ages and their survival disadvantage at older ages as a result of increased risks of cancer, MI and IC. The ADRB2 gene can play an important systemic role in healthy aging in evolutionary context that warrants exploration in other populations.

SUBMITTER: Kulminski AM

PROVIDER: S-EPMC2895994 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context.

Kulminski Alexander M AM Culminskaya Irina I Ukraintseva Svetlana V SV Arbeev Konstantin G KG Land Kenneth C KC Yashin Anatoli I AI

Mechanisms of ageing and development 20100424 5

The Gln(27)Glu polymorphism but not the Arg(16)Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln(27)Gln genotype increases risks of cancer, MI and IC, whereas the Glu(27) allele or, equivalently, the Gly(16)Glu(27) haplotype te ...[more]

PMID: 20399803

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Project description:BackgroundAsthma is caused by both environmental and genetic factors. The ADRB2 gene, which encodes the beta 2-adrenergic receptor, is one of the most extensively studied genes with respect to asthma prevalence and severity. The Arg16Gly (+46A > G) and Gln27Glu (+79C > G) polymorphisms in the ADRB2 gene cause changes in the amino acids flanking the receptor ligand site, altering the response to bronchodilators and the risk of asthma through complex pathways. The ADRB2 polymorphisms affect beta-adrenergic bronchodilator action and are a tool to identify at-risk populations.ObjectiveTo determine the frequency of these two polymorphisms in allergic asthma patients and healthy subjects and to correlate these data with the occurrence and severity of asthma.MethodsEighty-eight allergic asthma patients and 141 healthy subjects were included in this study. The ADRB2 polymorphisms were analyzed using the amplification-refractory mutation system - polymerase chain reaction (ARMS-PCR) technique. The statistical analysis was performed with the SPSS 21.0 software using the Fisher's Exact and χ2 tests.ResultsThe ADRB2 polymorphisms were associated with asthma occurrence. The Arg16Arg, Gln27Gln and Gln27Glu genotypes were risk factors; the odds ratios were 6.782 (CI = 3.07 to 16.03), 2.120 (CI = 1.22 to 3.71) and 8.096 (CI = 3.90 to 17.77), respectively. For the Gly16Gly and Glu27Glu genotypes, the odds ratios were 0.312 (CI = 0.17 to 0.56) and 0.084 (CI = 0.04 to 0.17), respectively. The haplotype analysis showed that there were associations between the following groups: Arg16Arg-Gln27Gln (OR = 5.108, CI = 1.82 to 16.37), Gly16Gly-Glu27Glu (OR = 2.816, CI = 1.25 to 6.54), Arg16Gly-Gln27Glu (OR = 0.048, CI = 0.01 to 0.14) and Gly16Gly-Gln27Glu (OR = 0.1036, CI = 0.02 to 0.39). The polymorphism Gln27Glu was associated with asthma severity, as the Gln27Gln genotype was a risk factor for severe asthma (OR = 2.798, CI = 1.099 to 6.674) and the Gln27Glu genotype was a protective factor for mild (OR = 3.063, CI = 1.037 to 9.041) and severe (OR = 0.182, CI = 0.048 to 0.691) asthma.ConclusionsThe Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene are associated with asthma presence and severity.

Project description:The recently determined crystal structure of the human beta(2)-adrenergic (beta(2)AR) G-protein-coupled receptor provides an excellent structural basis for exploring beta(2)AR-ligand binding and dissociation process. Based on this crystal structure, we simulated ligand exit from the beta(2)AR receptor by applying the random acceleration molecular dynamics (RAMD) simulation method. The simulation results showed that the extracellular opening on the receptor surface was the most frequently observed egress point (referred to as pathway A), and a few other pathways through interhelical clefts were also observed with significantly lower frequencies. In the egress trajectories along pathway A, the D192-K305 salt bridge between the extracellular loop 2 (ECL2) and the apex of the transmembrane helix 7 (TM7) was exclusively broken. The spatial occupancy maps of the ligand computed from the 100 RAMD simulation trajectories indicated that the receptor-ligand interactions that restrained the ligand in the binding pocket were the major resistance encountered by the ligand during exit and no second barrier was notable. We next performed RAMD simulations by using a putative ligand-free conformation of the receptor as input structure. This conformation was obtained in a standard molecular dynamics simulation in the absence of the ligand and it differed from the ligand-bound conformation in a hydrophobic patch bridging ECL2 and TM7 due to the rotation of F193 of ECL2. Results from the RAMD simulations with this putative ligand-free conformation suggest that the cleft formed by the hydrophobic bridge, TM2, TM3, and TM7 on the extracellular surface likely serves as a more specific ligand-entry site and the ECL2-TM7 hydrophobic junction can be partially interrupted upon the entry of ligand that pushes F193 to rotate, resulting in a conformation as observed in the ligand-bound crystal structure. These results may help in the design of beta(2)AR-targeting drugs with improved efficacy, as well as in understanding the receptor subtype selectivity of ligand binding in the beta family of the adrenergic receptors that share almost identical ligand-binding pockets, but show notable amino acid sequence divergence in the putative ligand-entry site, including ECL2 and the extracellular end of TM7.

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Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context.

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Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context.

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