1. Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene.
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Windelinckx, An, De Mars, Gunther, Huygens, Wim, Peeters, Maarten W., Vincent, Barbara, Wijmenga, Cisca, Lambrechts, Diether, Delecluse, Christophe, Roth, Stephen M., Metter, E. Jeffrey, Ferrucci, Luigi, Aerssens, Jeroen, Vlietinck, Robert, Beunen, Gaston P., and Thomis, Martine A.
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MUSCLE strength ,ACTIVIN ,TRANSFORMING growth factors ,GENETIC regulation ,PHYSICAL activity ,HUMAN genetic variation ,CAUCASIAN race ,HEALTH - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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