Anthropometric and metabolic characterization of study samples.

<p>Quantitative variables are presented as median (interquartile range). Obesity is defined as BMI SDS>1.88.</p><p>Anthropometric and metabolic characterization of study samples.</p

Inclusion probabilities of covariables and Bayesian effect sizes.

<p>We present probabilities for inclusion of specified covariables and resulting effect sizes and corresponding standard deviations (SD) averaged over all models containing the covariable. Only covariables with an inclusion probability greater than 0.5% are shown.</p><p>Inclusion probabilities of covariables and Bayesian effect sizes.</p

Results of Bayesian model analysis.

<p>Possible models of HDL-C, LDL-C, TG can contain up to 15 covariables (age, sex, BMI SDS, dominant and recessive effect of six SNPs). We present most probable models, corresponding posterior probabilities and Bayes factors. Models are ranked according to their plausibility. A cumulative probability of 95% served as cut-off for model presentation.</p><p>Results of Bayesian model analysis.</p

Genetic Contribution of Variants near <i>SORT1</i> and <i>APOE</i> on LDL Cholesterol Independent of Obesity in Children

<div><p>Objective</p><p>To assess potential effects of variants in six lipid modulating genes (<i>SORT1</i>, <i>HMGCR</i>, <i>MLXIPL</i>, <i>FADS2</i>, <i>APOE</i> and <i>MAFB</i>) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation.</p><p>Results</p><p>Expression of selected genes increased 10¹ to >10⁴ fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near <i>SORT1</i> with TC and LDL-C and for rs4420638 near <i>APOE</i> with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C.</p><p>Conclusion</p><p>We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near <i>SORT1</i> and <i>APOE</i> influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.</p></div

Bayesian Model.

<p>We present the structure of the Bayesian model analysed. Black arrows represent possible impacts of considered covariables (SNPs, age, BMI SDS, sex) on the distribution means of lipid phenotypes. Grey arrows refer to the covariance between the lipids which is accounted for in the model.</p

Inclusion probabilities of covariables for each lipid phenotype.

<p>For each SNP, results are given for the recessive (first number) and dominant part (second number). Results for inclusion probabilities are rounded to integers of percentage. Effect estimates are illustrated by the shade of grey as indicated. Results rounded to zero are omitted. Results for the lipid phenotypes LDL-C, HDL-C and TG are presented. TC is omitted due to high correlation with LDL-C.</p

mRNA expression profiles of target genes during human adipogenesis.

<p>Fold change of gene expression for <i>SORT1</i>, <i>HMGCR</i>, <i>MLXIPL</i>, <i>FADS2</i>, <i>APOE</i> and <i>MAFB</i> mRNA during human adipocyte differentiation of SGBS cells. Data shown are averaged over 3 independent experiments, each performed in triplicates and results are given in mean±SEM. For all candidates, <i>p</i><0.001 was achieved by one-way ANOVA test with Dunnet´s posthoc test.</p

Association of genotypes with BMI SDS and lipid phenotypes.

<p>We present numbers of cases available for the corresponding analysis (N), beta-coefficients, their standard errors (SE), 95% confidence intervals (CI) and uncorrected <i>p</i>-values. Since standardized values were analysed, beta-coefficients and standard errors have unit 1. BMI SDS was analysed with the additive model adjusted for age and sex. Lipid phenotypes were logarithmized and analysed with the additive model adjusted for age, sex and BMI SDS. Associations significant after correction for multiple testing (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0138064#sec005" target="_blank">methods</a> section) are printed in bold.</p><p>Association of genotypes with BMI SDS and lipid phenotypes.</p