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Mutation analysis of the MCHR1 gene in human obesity

¹ Clinical Research Group, Department of Child and Adolescent Psychiatry, ² Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, 45147 Essen, Germany, ³ Genome Analysis, Institute of Molecular Biotechnology, 07745 Jena, Germany, ⁴ Institute of Pharmacology and Toxicology and ⁵ Institute of Medical Biometry and Epidemiology, University of Marburg, 35039 Marburg, Germany, ⁶ Institute of Anatomy II, Friedrich-Schiller-University, 07743 Jena, Germany, ⁷ Aventis Pharma AG, 65812 Bad Soden a Ts, Germany, ⁸ Treatment Center Insula, 83489 Berchtesgaden, Germany, ⁹ Spessartklinik Bad Orb, 63619 Bad Orb, Germany, ¹⁰ Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6140, USA, ¹¹ Department of Paediatric Endocrinology, Charité Children’s Hospital, Humboldt University, 13353 Berlin, Germany, ¹² GSF National Research Center for Environment and Health, Institute of Epidemiology, 85764 Neuherberg, Germany, ¹³ Danish Epidemiology Science Centre, Institute of Preventive Medicine, Copenhagen University Hospital, DK-1399 Copenhagen, Denmark, ¹⁴ Institute of Human Nutrition, Royal Veterinary and Agricultural University, DK-1958 Frederiksberg Copenhagen, Denmark, ¹⁵ Steno Diabetes Center, DK-2820 Gentofte, Denmark, ¹⁶ Hotel Dieu, Laboratoire de Nutrition, EA, 3502 INSERM ‘Avenir’, 75004 Paris, France, ¹⁷ PsychoBiology Research Unit, University of Leeds, Leeds LS2 9JT, UK and ¹⁸ Department of Pediatrics and Adolescent Medicine, University of Ulm, 89075 Ulm, Germany

(Correspondence should be addressed to J Hebebrand, Rheinische Kliniken Essen, Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany; Email: Johannes.Hebebrand{at}lvr.de)

Objective: The importance of the melanin-concentrating hormone (MCH) system for regulation of energy homeostasis and body weight has been demonstrated in rodents. We analysed the human MCH receptor 1 gene (MCHR1) with respect to human obesity.

Design: This consisted of genomic screening of 13.4 kb encompassing the MCHR1 in extremely obese German children and adolescents and association analyses for two coding single nucleotide polymorphisms (SNPs). To confirm initial positive association results, additional association studies and transmission disequilibrium tests in further German, Danish, French and American samples were conducted. Selected SNPs were investigated using functional in vitro studies and reporter gene assays.

Methods: Single-stranded conformation polymorphism analysis, re-sequencing, PCR-restriction fragment length polymorphism analyses, tetra-primer amplification refractory mutation systems, matrix-assisted laser desorption/ionization time of flight mass spectrometry and reporter gene assays were carried out as well as measuring inositol phosphate formation, inhibition of cAMP formation and activation of p42/44 MAP kinase.

Results: We identified 11 infrequent variations and two SNPs in the MCHR1 coding sequence and 18 SNPs (eight novel) in the flanking sequence. Association and transmission disequilibrium with obesity were detected for several SNPs in independent study groups of German obese children and adolescents and controls. In two German samples, encompassing 4056 and 295 individuals, trends towards association with obesity were detected. Findings in a second epidemiological German sample and in Danish, French and American samples were negative. Functional in vitro studies as well as reporter gene assays revealed no significant results.

Conclusion: Our initial association of MCHR1 alleles/haplotype detected might be related to juvenile-onset obesity, conditional on a particular genetic and/or environmental background. Alternatively, we could not exclude the possibility that the initially detected association represented a false positive finding.

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