Common genetic variants of the 2-adrenergic receptor affect its translational efficiency and are associated with human longevity

Ling Zhao,1 Fan Yang,1 Ke Xu,1 Huiqing Cao,1 Gu-Yan Zheng,1 Yan Zhang,1 Jianxin Li,2 Hanbin Cui,3 Xiaomin Chen,3 Zhiming Zhu,4 Hongbo He,4 Xianming Mo,5 Brian K. Kennedy,6 Yousin Suh,7 Yi Zeng8,9† and Xiao-Li Tian1†

P = 0.000018). The permuted P-values were 0.00005 and 0.0009, respectively. ADRB2 encodes the b2-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 b2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan.

Yousin Yi and Xiao-Li

Department of Human Population Genetics, Institute of Molecular Peking University,

Yiheyuan Road, Beijing,

, China

Department of Sociology, Peking University,

Yiheyuan Road, Beijing,

, China

Key Laboratory of Ningbo First Hospital and Cardiovascular Center of Ningbo First Hospital, Ningbo University,

Liuting Street, Ningbo, China

Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Chongqing Institute of Hypertension, Third Military Medical University, Chongqing,

, China

Department of Geriatrics, West China Hospital, West China Medical Sichuan University, Chengdu,

, China

Buck Institute for Research on Aging, Novato, CA,

, USA

Departments of Medicine and Genetics, Albert Einstein College of Bronx, NY,

, USA

Center for Healthy Aging and Development Studies, National School of Development, Peking University,

Yiheyuan Road, Beijing,

, China

Center for Study of Aging and Human Development, Medical School of

Introduction

The system is critical to the regulation of vascular tone (Chang et al., 2009), cell growth and apoptosis (Singh et al., 2010), lipid metabolism (Zee et al., 2006), and the immunoresponse (Woszczek et al., 2005). Therefore, it is clinically one of the most common pharmacological targets for treating various cardiovascular diseases and asthma. Because of their protective effects from various types of cardiovascular stresses, beta-receptor blockage was hypothesized to increase longevity (Milne & Hong, 2004). In support, it was recently demonstrated that mice lacking ADCY5, encoding type 5-adenylyl cyclase (AC5), are stress resistant and have experience a 30% increase in median lifespan (Yan et al., 2007). AC5 is a member of adenylyl cyclase (AC) family that is activated by b-adrenergic receptors (bARs) and is responsible for the production of cAMP in vivo (Roth et al., 2002). Null function of AC5 blocks the signaling transduction of bARs. On the other hand, transgenic mice engineered to overexpress a b2AR in cardiac tissue have reduced lifespan, with males displaying a more dramatic phenotype (Gao et al., 2003). These findings establish a role for bAR signaling in mammalian longevity regulation and also suggest that this pathway may underscore sexual dimorphic feature of this complex phenotype. However, a role for bAR signaling in human longevity remains to be established, and it is important to address this question because b-adrenergic agonists and antagonists are widely used in treating various human diseases.

for Healthy Aging and Development Studies, National School of Peking University, 5 Yiheyuan Road, Beijing, 100871, China for Study of Aging and Human Development, Medical School of University, Duke University, BUSSE Building, Durham, NC, 27710, USA

Summary

treatment of cardiovascular diseases and asthma. Genetic mod- ifications of b-adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the b-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-val- ues 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,

Here, we tested for such associations by evaluating the genetic contribution of the b-adrenergic signaling pathway to human longevity in Chinese populations. Sixteen SNPs were selected from the ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 genes, together encoding the key components of the pathway including the b1-adrenergic receptor (b1AR), b2-adrenergic receptor (b2AR), type 5 adenylyl cyclase (AC5), type 6 adenylyl cyclase (AC6), and mitogen-activated protein kinase 1 (MAPK1), respectively. The genotypic frequencies of these genes were compared between long-lived and middle-age individuals. We identified two common genetic variants of ADRB2 that suppress its translation and are predominantly associated with longevity in men. These findings support that bAR signaling is linked to aging and establish this pathway as a candidate to explain the sexually dimorphic nature of human

Xiao-Li Tian, Department of Human Population Genetics, Institute of Molecular Medicine, Peking University,

Yiheyuan Road, Beijing

, China. Tel.: +

; fax: +

; e-mail: tianxiaoli@pku.edu.cn † These authors have contributed equally to the work. Accepted for publication

September

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