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Genetic Architecture of the APM1 Gene and Its Influence on Adiponectin Plasma Levels and Parameters of the Metabolic Syndrome in 1,727 Healthy Caucasians

¹ GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany
² Department of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
³ First Department of Internal Medicine, St. Johann Spital, Paracelsus Private Medical University Salzburg, Salzburg, Austria
⁴ Department of Neurology, Paracelsus Private Medical University Salzburg, Salzburg, Austria
⁵ Institute for Medical Statistics and Epidemiology & Institute for Psychiatry and Psychotherapy, Clinic "Rechts der Isar," Technical University, Munich, Germany
⁶ Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

Address correspondence and reprint requests to Florian Kronenberg MD, Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria. E-mail: florian.kronenberg{at}i-med.ac.at

Key Words: CCA, common carotid artery • HWE, Hardy-Weinberg equilibrium • LD, linkage disequilibrium • MAF, minor allele frequency • SAPHIR, Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk • SNP, single nucleotide polymorphism

The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease.

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