Common genetic variation in obesity, lipid transfer genes and risk of Metabolic Syndrome: Results from IDEFICS/I.Family study and meta-analysis

As the prevalence of metabolic syndrome (MetS) in children and young adults is increasing, a better understanding of genetics that underlie MetS will provide critical insights into the origin of the disease. We examined associations of common genetic variants and repeated MetS score from early childhood to adolescence in a pan-European, prospective IDEFICS/I.Family cohort study with baseline survey and follow-up examinations after two and six years. We tested associations in 3067 children using a linear mixed model and confirmed the results with meta-analysis of identified SNPs. With a stringent Bonferroni adjustment for multiple comparisons we obtained significant associations(p < 1.4 x 10(-4)) for 5 SNPs, which were in high LD (r(2)> 0.85) in the 16q12.2 non-coding intronic chromosomal region of FTO gene with strongest association observed for rs8050136 (effect size(beta) = 0.31, p(Wald)=1.52 x 10(-5)). We also observed a strong association of rs708272 in CETP with increased HDL (p=5.63 x 10(-40)) and decreased TRG (p=9.60 x 10(-5)) levels. These findings along with meta-analysis advance etiologic understanding of childhood MetS, highlighting that genetic predisposition to MetS is largely driven by genes of obesity and lipid metabolism. Inclusion of the associated genetic variants in polygenic scores for MetS may prove to be fundamental for identifying children and subsequently adults of the high-risk group to allow earlier targeted interventions.