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The Codon 17 Polymorphism of the CTLA4 Gene in Type 2 Diabetes Mellitus¹

Medical Department I, Centre of Internal Medicine, Klinikum of the Johann Wolfgang Goethe-University, 60590 Frankfurt/Main, Germany

Address correspondence and requests for reprints to: Prof. Dr. med. Klaus Badenhoop, Medizinische Klinik I, Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E-mail: badenhoop{at}em.uni-frankfurt.de

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BbvI. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 ± 0.8 vs. 49.5 ± 0.8 yr, mean ± SEM), lower body mass index (21.4 ± 0.5 vs. 24.4 ± 0.5 kg/m², P = 0.042), and basal C-peptide level (0.33 ± 0.07 vs. 0.53 ± 0.07nmol/L), as well as earlier start of insulin treatment (5.8 ± 1.2 vs. 8.7 ± 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ß-cell failure and the lower rate of microvascular complications in AA carriers.

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