Klimentidis Yann C, Bea Jennifer W, Thompson Patricia, Klimecki Walter T, Hu Chengcheng, Wu Guanglin, Nicholas J Skye, Ryckman Kelli K, Chen Zhao
1Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ; 2University of Arizona Cancer Center, University of Arizona, Tucson, AZ; 3Department of Nutritional Sciences, University of Arizona, Tucson, AZ; 4Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ; 5Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ; 6Department of Epidemiology and Pediatrics, University of Iowa, Iowa City, IA.
Med Sci Sports Exerc. 2016 Jul;48(7):1270-5. doi: 10.1249/MSS.0000000000000889.
Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait.
In this study, we selected 1493 single-nucleotide polymorphisms (SNP) in 155 candidate genes involved in anabolic, catabolic, growth hormone, and other related pathways and examined their association with LM, assessed by dual-energy x-ray absorptiometry, in a sample of 2760 non-Hispanic and Hispanic white postmenopausal women from the Women's Health Initiative (WHI) Observational Study. We assessed the replication of our top findings in a meta-analysis of 20 genome-wide association studies (n = 38,292) conducted by the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Musculoskeletal Working Group.
We identified 32 SNPs that had nominally significant associations with LM in the WHI cohort. In the replication stage, we find that SNP rs2276541 in the activin A receptor, type IIB (ACVR2B), was significantly associated with LM (β = 0.15, P = 2.17 × 10). ACVR2B codes for a receptor for a negative regulator of skeletal muscle, myostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass.
Our findings support a previously proposed role of ACVR2B allelic variation as a determinant of muscle mass and extend prior findings in men and women. Additional large-scale studies will be needed to confirm our findings in different populations.
低瘦体重是慢性病的一个风险因素，是导致残疾和生活质量下降的主要原因，并且是一种可遗传的特征。然而，相对较少的特定遗传因素被确定可能影响这一特征。
在本研究中，我们在155个参与合成代谢、分解代谢、生长激素及其他相关途径的候选基因中选择了1493个单核苷酸多态性（SNP），并在来自妇女健康倡议（WHI）观察性研究的2760名非西班牙裔和西班牙裔白人绝经后妇女样本中，检测它们与通过双能X线吸收法评估的瘦体重的关联。我们在基因组流行病学心脏与衰老研究队列联盟肌肉骨骼工作组进行的20项全基因组关联研究（n = 38,292）的荟萃分析中评估了我们的主要发现的重复性。
我们在WHI队列中鉴定出32个与瘦体重有显著名义关联的SNP。在重复性阶段，我们发现IIB型激活素A受体（ACVR2B）中的SNP rs2276541与瘦体重显著相关（β = 0.15，P = 2.17×10）。ACVR2B编码骨骼肌负调节因子肌肉生长抑制素的受体，并且先前在一项候选基因研究中已被确定为骨骼肌质量的一个决定因素。
我们的发现支持了先前提出的ACVR2B等位基因变异作为肌肉质量决定因素的作用，并扩展了先前在男性和女性中的发现。需要更多大规模研究来在不同人群中证实我们的发现。
