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Abstract: Objective: Evidence of a genetic basis of metabolic risk factors (MRFs) is growing. Studies examining the genetic and environmental basis of the clustering of MRFs, grouped together in the metabolic syndrome (MetS), are however sparse. The aim of this study therefore was to study the heritabilities of the MRFs and the genetic and environmental correlations between the MRFs. Methods: Study participants were 768 Caucasian twins coming from 418 pairs (18–34 years). MRFs were those included in the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS. Multivariate path analysis on the continuous MRFs of the MetS was implemented. Results: Heritabilities ranged between 47.0% and 80.2% (men) and 58.5% and 77.9% (women) for the individual MRFs. Evidence was found for overarching genetic (A) and environmental (E) sources of variance, both however loading mainly on waist circumference. Furthermore, the model included a ‘lipids’ and a ‘blood pressure’-factor both in part attributable to A and E. The majority of the variance however was MRF-specific. Conclusion: Based on our sample of young adults with a low prevalence of the MetS, it can be concluded that both genes and environment contribute significantly to the clustering of the MRFs although the majority of the variation is MRF-specific. Therefore, future QTL searches in young adults may want to focus on MRF-specific loci, rather than ‘cluster-phenotypes’ such as the MetS. [Copyright &y& Elsevier]

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]