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The Common –866G/A Polymorphism in the Promoter Region of the UCP-2 Gene Is Associated with Reduced Risk of Type 2 Diabetes in Caucasians from Italy

Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza (A.B., O.L., A.C., R.D.P., V.T.), San Giovanni Rotondo, Italy; Unit of Genetics, Scientific Institute Casa Sollievo della Sofferenza (A.Q., M.C.), San Giovanni Rotondo, Italy; Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud (F.P.), S. Maria Imbaro, Italy; Casa Sollievo della Sofferenza-Mendel Institute (S.P., V.T.), Rome, Italy; and Department of Clinical Sciences, University La Sapienza (V.T.), Rome, Italy

Address all correspondence and requests for reprints to: Dr. Angela Bulotta, Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, Viale Padre Pio, 71013 San Giovanni Rotondo (FG), Italy. E-mail: a.bulotta{at}operapadrepio.it.

Uncoupling protein-2 (UCP2) regulates insulin secretion and may play an important role in linking obesity to type 2 diabetes (T2D). Previous studies of the role of the UCP2 promoter –866G/A single nucleotide polymorphisms (SNP) in T2D have given opposite results. We tested the distribution of the –866G/A SNP in 746 T2D patients and 327 healthy unrelated Caucasians from Italy. We also tested for an effect of the P12A variant of the peroxisomal proliferator-activated receptor-2 (PPAR2) gene on diabetes risk given by the UCP2 SNP. Compared with –866G/G carriers, a progressively reduced (P = 0.01) risk of T2D was observed in –866G/A and –866A/A subjects, with the latter showing an approximately 50% risk reduction [odd ratio (OR), 0.51; 95% confidence interval (CI), 0.3–0.8; P = 0.003]. Conversely, the –866G/G genotype was associated with increased risk (OR, 1.31; 95% CI, 1.01–1.71). Overall, the population risk attributable to the UCP2 –866G/G genotype was about 12%. After stratifying for the PPAR2 polymorphism, the increased risk conferred by the UCP2 G/G genotype was still evident among P12/P12 homozygous subjects (n = 801; OR, 1.38; 95% CI, 1.04–1.83), but seemed to disappear among the X12/A12 subjects (i.e. P12/A12 heterozygous or A12/A12 homozygous subjects; n = 137; OR, 0.87; 95% CI, 0.40–1.91). Whether this apparent difference is entirely due to the different number of carriers of the two PPAR2 genotypes is a likely possibility that deserves deeper investigation. In conclusion, in our population, the –866G/A SNP is associated with T2D. Additional studies in larger samples are needed to investigate the possibility of a concomitant effect of modifier genes such as PPAR2.

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