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
Angela Bulotta,
Ornella Ludovico,
Angelo Coco,
Rosa Di Paola,
Alessandro Quattrone,
Massimo Carella,
Fabio Pellegrini,
Sabrina Prudente and
Vincenzo Trischitta
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 andmay play an important role in linking obesity to type 2 diabetes(T2D). Previous studies of the role of the UCP2 promoter –866G/Asingle nucleotide polymorphisms (SNP) in T2D have given oppositeresults. We tested the distribution of the –866G/A SNPin 746 T2D patients and 327 healthy unrelated Caucasians fromItaly. We also tested for an effect of the P12A variant of theperoxisomal proliferator-activated receptor-2 (PPAR2) gene ondiabetes risk given by the UCP2 SNP. Compared with –866G/Gcarriers, a progressively reduced (P = 0.01) risk of T2D wasobserved in –866G/A and –866A/A subjects, with thelatter 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 associatedwith increased risk (OR, 1.31; 95% CI, 1.01–1.71). Overall,the population risk attributable to the UCP2 –866G/G genotypewas about 12%. After stratifying for the PPAR2 polymorphism,the increased risk conferred by the UCP2 G/G genotype was stillevident among P12/P12 homozygous subjects (n = 801; OR, 1.38;95% CI, 1.04–1.83), but seemed to disappear among theX12/A12 subjects (i.e. P12/A12 heterozygous or A12/A12 homozygoussubjects; n = 137; OR, 0.87; 95% CI, 0.40–1.91). Whetherthis apparent difference is entirely due to the different numberof carriers of the two PPAR2 genotypes is a likely possibilitythat deserves deeper investigation. In conclusion, in our population,the –866G/A SNP is associated with T2D. Additional studiesin larger samples are needed to investigate the possibilityof a concomitant effect of modifier genes such as PPAR2.
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