Research Center for Exercise and Health, Department of Biomedical Kinesiology, Faculty of Kinesiology and Rehabilitation Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.
Eur J Hum Genet. 2011 Feb;19(2):208-15. doi: 10.1038/ejhg.2010.173. Epub 2010 Nov 10.
Muscle strength is important in functional activities of daily living and the prevention of common pathologies. We describe the two-staged fine mapping of a previously identified linkage peak for knee strength on chr12q12-14. First, 209 tagSNPs in/around 74 prioritized genes were genotyped in 500 Caucasian brothers from the Leuven Genes for Muscular Strength study (LGfMS). Combined linkage and family-based association analyses identified activin receptor 1B (ACVR1B) and inhibin β C (INHBC), part of the transforming growth factor β pathway regulating myostatin - a negative regulator of muscle mass - signaling, for follow-up. Second, 33 SNPs, selected in these genes based on their likelihood to functionally affect gene expression/function, were genotyped in an extended sample of 536 LGfMS siblings. Strong associations between ACVR1B genotypes and knee muscle strength (P-values up to 0.00002) were present. Of particular interest was the association with rs2854464, located in a putative miR-24-binding site, as miR-24 was implicated in the inhibition of skeletal muscle differentiation. Rs2854464 AA individuals were ∼2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n=266) selected from the Baltimore Longitudinal Study of Aging and a Flemish Policy Research Centre Sport, Physical Activity and Health study. However, no genotype-related difference in ACVR1B mRNA expression in quadriceps muscle was observed. In conclusion, we applied a two-stage fine mapping approach, and are the first to identify and partially replicate genetic variants in the ACVR1B gene that account for genetic variation in human muscle strength.
肌肉力量对于日常生活中的功能活动和预防常见疾病非常重要。我们描述了先前鉴定的与膝关节力量相关的连锁峰在 chr12q12-14 上的两阶段精细映射。首先，在来自 Leuven Genes for Muscular Strength 研究（LGfMS）的 500 名白种人兄弟中，对 74 个优先基因内/周围的 209 个标签 SNP 进行了基因分型。结合连锁和基于家庭的关联分析，鉴定出了激活素受体 1B（ACVR1B）和抑制素βC（INHBC），它们是调节肌肉生长抑制素（一种肌肉质量的负调节剂）信号的转化生长因子β途径的一部分，用于后续研究。其次，根据其可能对基因表达/功能产生功能影响的可能性，在 LGfMS 兄弟姐妹的扩展样本中对这两个基因中的 33 个 SNP 进行了基因分型。在 ACVR1B 基因型和膝关节肌肉力量之间存在很强的关联（P 值低至 0.00002）。特别有趣的是与 rs2854464 的关联，该 SNP 位于一个假定的 miR-24 结合位点，因为 miR-24 被牵连到抑制骨骼肌肉分化中。位于 rs2854464 的 AA 个体比 G-等位基因携带者强约 2%。在从巴尔的摩纵向研究老龄化和佛兰德政策研究中心体育、身体活动和健康研究中选择的独立复制样本（n=266）中也观察到 A-等位基因的增强效应。然而，在股四头肌中未观察到 ACVR1B mRNA 表达的基因型相关差异。总之，我们应用了两阶段精细映射方法，首次鉴定并部分复制了 ACVR1B 基因中的遗传变异，这些变异解释了人类肌肉力量的遗传变异。
