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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4238-4242
Copyright © 2004 by The Endocrine Society

Special Feature

Ala12Ala Genotype of the Peroxisome Proliferator-Activated Receptor {gamma}2 Protects against Atherosclerosis

Theodora Temelkova-Kurktschiev, Markolf Hanefeld, Giulia Chinetti, Christophe Zawadzki, Stephan Haulon, Agata Kubaszek, Carsta Koehler, Wolfgang Leonhardt, Bart Staels and Markku Laakso

Center for Clinical Studies, Technical University Dresden (T.T.-K., M.H., C.K., W.L.), Dresden, Germany; UR 545, Institut National de la Santé et de la Recherche Médicale, Institut Pasteur de Lille and Université de Lille II (G.C., B.S.), Lille, France; Equipe d’Accueil 2693, Université de Lille II (C.Z.), Lille, France; Chirurgie Vasculaire (S.H.), Lille, France; and Department of Medicine, University of Kuopio (A.K., M.L.), Kuopio, Finland

Address all correspondence and requests for reprints to: Dr. Theodora Temelkova-Kurktschiev, Center for Clinical Studies, Technical University Dresden, Fiedlerstrasse 34, 01307 Dresden, Germany. E-mail: theodora{at}gwtonline-zks.de.

A mutation in the peroxisome proliferator-activated receptor {gamma}2 (PPAR{gamma}2) gene with a cytosine to guanine substitution results in an exchange of proline (Pro) with alanine (Ala) in exon B (codon 12) of this gene. This polymorphism has been associated with high insulin sensitivity and low body weight, but no data have been published to date about its effect on early atherosclerosis. We investigated the relationship of the Pro12Ala polymorphism to early atherosclerosis, measured by the intima-media thickness (IMT). A total of 622 subjects were included, aged 40–70 yr, who were participants of the RIAD (Risk factors in Impaired glucose tolerance for Atherosclerosis and Diabetes) study and were at risk of developing type 2 diabetes. Altogether, 449 of the subjects had the common genotype (Pro12Pro), 162 had the Pro12Ala genotype, and 11 the Ala12Ala genotype. IMT was significantly decreased in subjects with the Ala12Ala genotype compared with subjects with the other two genotypes. Body mass index, free fatty acid levels, and leukocyte count were lower in subjects with the Ala12Ala genotype compared with subjects with the Pro12Pro or Pro12Ala genotypes. In multivariate analysis, the Ala12Ala genotype was a significant independent determinant of IMT. Furthermore, we demonstrated specific expression of the PPAR{gamma}2 gene in human atherosclerotic lesions as well as in cultured primary macrophages and foam cells. In conclusion, our data suggest that the Ala12Ala genotype of the PPAR{gamma}2 gene may protect from early atherosclerosis in subjects at risk for diabetes.




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