Genetic Contribution of Variants near SORT1 and APOE on LDL Cholesterol Independent of Obesity in Children

Clara Breitling, Arnd Gross, Petra Büttner, Sebastian Weise, Dorit Schleinitz, Wieland Kiess, Markus Scholz, Peter Kovacs, Antje Körner, Clara Breitling, Arnd Gross, Petra Büttner, Sebastian Weise, Dorit Schleinitz, Wieland Kiess, Markus Scholz, Peter Kovacs, Antje Körner

Abstract

Objective: To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) 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.

Results: Expression of selected genes increased 10(1) to >10(4) 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 SORT1 with TC and LDL-C and for rs4420638 near APOE 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.

Conclusion: We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.

Conflict of interest statement

Competing Interests: A.K. declares on behalf of all authors there are no competing interests that could be perceived to bias their work, acknowledging all financial support and any other relevant financial or non-financial competing interests.

Figures

Fig 1. Bayesian Model.
Fig 1. Bayesian Model.
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.
Fig 2. Inclusion probabilities of covariables for…
Fig 2. Inclusion probabilities of covariables for each lipid phenotype.
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.
Fig 3. mRNA expression profiles of target…
Fig 3. mRNA expression profiles of target genes during human adipogenesis.
Fold change of gene expression for SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB 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, p<0.001 was achieved by one-way ANOVA test with Dunnet´s posthoc test.

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