Other research has demonstrated that ANKRD6 likely plays a role in human cardiogenesis. In zebrafish, ANKRD6 was found to control fusion of heart precursors, influence gastrulation movements during embryogenesis, and play a critical role in normal heart development. Additionally, ANKRD6 functions in Wnt signaling pathways, which regulate many developmental processes including cell proliferation, cell-fate specification, and morphogenesis in embryos (5). Within the Wnt pathway, ANKRD6 specifically binds with Dishevelled in the planar cell polarity pathway, creating a functional interaction essential for cardiogenesis and gastrulation in vertebrates (15).
Based on its physiology and function in developmental biology, ANKRD6 would appear to play an important role in human neural development, axis formation, and cardiogenesis. Additionally, according to Table 2, all SNPs we found phenotype associations with were located in exons, suggesting that these SNPs may influence the function of the protein. Thus, it is biologically plausible that this gene could influence muscle performance and habitual PA participation through centrally and peripherally mediated mechanisms, which may alter neural and cardiac tissue development, growth, and function. A centrally mediated mechanism for PA regulation has been suggested by studies that involve the candidate gene dopamine receptor 1 (Drd1) (14). Of note, Knab et al. (12) found that the brains of high physically active animals presented with down-regulated Drd1 compared with low physically active animals for 7 different dopamine genes. Furthermore, Rhodes and Garland (23) showed that PA was altered through pharmacological manipulation of Drd1. Although mechanisms explaining how Drd1 regulates PA are not yet known, the existent research suggests that the Drd1 associations with PA in animals are centrally mediated. Thus, it is possible that the ANKRD6 genetic variants may also associate with PA through central mechanisms. Our discussion regarding central and peripheral mechanistic explanations of how ANKRD6 may influence PA and muscle performance are purely speculative, and further prospective studies are necessary to validate our preliminary findings and, if validated, investigate mechanisms for the associations we observed.
Strengths of our study include a large homogenous sample and a highly standardized training intervention. Additionally, although FAMuSS was a multicenter trial and measurements of muscle performance and habitual PA were taken at multiple sites by a variety of different investigators, a manual with standardized measurement techniques and investigator certification was required at each site to minimize measurement variability, and all sites used the same equipment.
One limitation of this study is that FAMuSS was not originally designed to assess habitual PA levels, which were determined using a self-reported questionnaire. However, the PPAQ has been validated in similar subject populations and is considered to provide an accurate estimation of habitual PA in adults (1). Another limitation is that the study involved a young self-selected sample from university communities that may not represent the general population as a whole. However, the sample was an accurate representation of the general college-aged population from which it was studied. Similar to most candidate gene association studies, the significance we found in this study is limited by very low minor allele frequency values of the SNPs examined. However, cell sizes of the individual SNPs will never approach equality in this case because of the low prevalence of the minor allele in the general population. Despite such limitations, Urso (31) recently cited FAMuSS as one of the few initial studies in the field of exercise genomics that followed the model for a quality exercise genomics research study including a large sample size, rigorous exercise intervention, and diverse population. A final limitation of this study is that one of the SNPs, ANKRD6 710 L>X, was not in Hardy-Weinberg equilibrium.
This research was supported by National Institutes of Health-National Institute Neurological Disorder and Stroke Grant R01 NS40606-02 and the University of Connecticut Center for Health, Intervention, and Prevention.
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