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Copy number variations in “classical” obesity candidate genes are not frequently associated with severe early-onset obesity in children

  • Jan Windholz , Peter Kovacs , Marina Schlicke , Christin Franke , Anubha Mahajan , Andrew P. Morris , Johannes R. Lemke , Jürgen Klammt , Wieland Kiess , Torsten Schöneberg , Roland Pfäffle and Antje Körner EMAIL logo
Published/Copyright: April 28, 2017
Journal of Pediatric Endocrinology and Metabolism
From the journal Journal of Pediatric Endocrinology and Metabolism Volume 30 Issue 5

Abstract

Background:

Obesity is genetically heterogeneous and highly heritable, although polymorphisms explain the phenotype in only a small proportion of obese children. We investigated the presence of copy number variations (CNVs) in “classical” genes known to be associated with (monogenic) early-onset obesity in children.

Methods:

In 194 obese Caucasian children selected for early-onset and severe obesity from our obesity cohort we screened for deletions and/or duplications by multiplex ligation-dependent probe amplification reaction (MLPA). As we found one MLPA probe to interfere with a polymorphism in SIM1 we investigated its association with obesity and other phenotypic traits in our extended cohort of 2305 children.

Results:

In the selected subset of most severely obese children, we did not find CNV with MLPA in POMC, LEP, LEPR, MC4R, MC3R or MC2R genes. However, one SIM1 probe located at exon 9 gave signals suggestive for SIM1 insufficiency in 52 patients. Polymerase chain reaction (PCR) analysis identified this as a false positive result due to interference with single nucleotide polymorphism (SNP) rs3734354/rs3734355. We, therefore, investigated for associations of this polymorphism with obesity and metabolic traits in our extended cohort. We found rs3734354/rs3734355 to be associated with body mass index-standard deviation score (BMI-SDS) (p = 0.003), but not with parameters of insulin metabolism, blood pressure or food intake.

Conclusions:

In our modest sample of severely obese children, we were unable to find CNVs in well-established monogenic obesity genes. Nevertheless, we found an association of rs3734354 in SIM1 with obesity of early-onset type in children, although not with obesity-related traits.

Keywords: children; copy number variations; genetic variants; obesity; SIM1
Corresponding author: Dr. Antje Körner, Pediatric Research Center, University Hospital for Children and Adolescents, University of Leipzig, Liebigstraße 20a, 04103 Leipzig, Germany; Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany; and Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany

Acknowledgments

We thank all the children and their parents who participated in this study. We also gratefully acknowledge the help of the study nurses and physicians for patient care, and the technical assistants for performing these investigations.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by grants from the German Research Foundation for the Clinical Research Center “Obesity Mechanisms” CRC1052/1 C05, by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001, by the European Community’s Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO under grant agreement n° 279153, and the LIFE Child (Leipzig Research Center for Civilization Diseases, Universität Leipzig) funded by the European Union, by the European Regional Development Fund (ERFD) by means of the Free State of Saxony within the framework of the excellence initiative.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Supplemental Material:

The online version of this article (DOI: 10.1515/jpem-2016-0435) offers supplementary material, available to authorized users.

Received: 2016-11-22
Accepted: 2017-3-6
Published Online: 2017-4-28
Published in Print: 2017-5-1

©2017 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Imaging methods for bone mass evaluation during childhood and adolescence: an update
  4. Original Articles
  5. Risk factors for overweight and obesity in children aged 2–6 years
  6. Copy number variations in “classical” obesity candidate genes are not frequently associated with severe early-onset obesity in children
  7. Trends in the prevalence of extreme obesity among Korean children and adolescents from 2001 to 2014
  8. Plasma but not serum brain-derived neurotrophic factor concentration is decreased by oral glucose tolerance test-induced hyperglycemia in children
  9. Environmental and genetic determinants of two vitamin D metabolites in healthy Australian children
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  16. Short Communication
  17. Provider variability in the initial diagnosis and treatment of congenital hypothyroidism
  18. Case Reports
  19. Giant parathyroid adenoma associated with severe hypercalcemia in an adolescent patient
  20. Personalized precision medicine in extreme preterm infants with transient neonatal diabetes mellitus
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https://doi.org/10.1515/jpem-2016-0435
Keywords for this article
children; copy number variations; genetic variants; obesity; SIM1

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Imaging methods for bone mass evaluation during childhood and adolescence: an update
  4. Original Articles
  5. Risk factors for overweight and obesity in children aged 2–6 years
  6. Copy number variations in “classical” obesity candidate genes are not frequently associated with severe early-onset obesity in children
  7. Trends in the prevalence of extreme obesity among Korean children and adolescents from 2001 to 2014
  8. Plasma but not serum brain-derived neurotrophic factor concentration is decreased by oral glucose tolerance test-induced hyperglycemia in children
  9. Environmental and genetic determinants of two vitamin D metabolites in healthy Australian children
  10. Evaluation of vitamin D prophylaxis in 3–36-month-old infants and children
  11. Possible effects of neonatal vitamin B12 status on TSH-screening program: a cross-sectional study from Turkey
  12. Effects of L-thyroxine treatment on heart functions in infants with congenital hypothyroidism
  13. Hyperandrogenism in adolescent girls: relationship with the somatotrophic axis
  14. Plasma kisspeptin and ghrelin levels in puberty variant cases
  15. Genotype-phenotype correlation in paediatric pheochromocytoma and paraganglioma: a single centre experience from India
  16. Short Communication
  17. Provider variability in the initial diagnosis and treatment of congenital hypothyroidism
  18. Case Reports
  19. Giant parathyroid adenoma associated with severe hypercalcemia in an adolescent patient
  20. Personalized precision medicine in extreme preterm infants with transient neonatal diabetes mellitus
  21. Pseudohypoaldosteronism types I and II: little more than a name in common
  22. Primary pigmented nodular adrenocortical disease: literature review and case report of a 6-year-old boy
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