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

doi:10.1371/journal.pone.0138064

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

PLoS One. 2015 Sep 16;10(9):e0138064. doi: 10.1371/journal.pone.0138064. eCollection 2015.

Authors

Clara Breitling¹, Arnd Gross², Petra Büttner¹, Sebastian Weise¹, Dorit Schleinitz³, Wieland Kiess¹, Markus Scholz², Peter Kovacs³, Antje Körner⁴

Affiliations

¹ Center for Pediatric Research (CPL), University Hospital for Children and Adolescents Leipzig, Dept. of Women´s & Child Health, University of Leipzig, Leipzig, Germany.
² Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
³ Integrated Research and Treatment Center Adiposity Diseases (IFB), Medical Faculty, University of Leipzig, Leipzig, Germany.
⁴ Center for Pediatric Research (CPL), University Hospital for Children and Adolescents Leipzig, Dept. of Women´s & Child Health, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center Adiposity Diseases (IFB), Medical Faculty, University of Leipzig, Leipzig, Germany.

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Vesicular Transport / genetics*
Apolipoproteins E / genetics*
Bayes Theorem
Child
Cholesterol, LDL / blood*
Dyslipidemias / blood*
Dyslipidemias / etiology*
Dyslipidemias / pathology
Female
Genetic Predisposition to Disease*
Humans
Male
Obesity / blood
Obesity / complications*
Obesity / pathology
Polymerase Chain Reaction
Polymorphism, Single Nucleotide / genetics*

Substances

Adaptor Proteins, Vesicular Transport
Apolipoproteins E
Cholesterol, LDL
sortilin

Grants and funding

This work was supported by grants from the German Research Council (DFG) for the Clinical Research Center “Obesity Mechanisms” CRC1052/1 C05 and the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001 (IFB AdiposityDiseases), and the European Community’s Seventh Framework Programme (FP7/2007–2013) project Beta-JUDO under grant agreement n° 279153 to A.K. The work of A.G. was supported in part by the German Federal Research Ministry (BMBF), grant PROGRESS (01KI1010I). M.S. was funded by LIFE – Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.