No Evidence for Involvement of the Promoter Polymorphism - 866 G/A of the UCP2 Gene in Childhood-Onset Obesity in Humans

Abstract

Recently, an association between obesity and the G-allele of the - 866 G/A polymorphism in the promoter region of uncoupling protein-2 gene (UCP2) was reported. Both allele frequencies and genotype distributions for this polymorphism differed between obese individuals and never-obese controls.

We attempted to confirm this finding. Genotyping was performed by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis (PCR-RFLP).

We analysed transmission disequilibrium of the (wild type) G-allele for 200 extremely obese children and adolescents from 93 concordant sib pair families using the pedigree disequilibrium test. Additionally, using a one-sided asymptotic Pearson's χ²-test, we tested whether the G-allele occurs more frequently in 277 extremely obese children and adolescents (including the 93 index patients of the concordant sib pairs) than in 188 never-obese controls. The one-sided asymptotic Cochran Armitage trend test was used to determine differences in genotype frequencies between extremely obese and healthy underweight individuals.

The PDT analysis revealed no evidence for transmission disequilibrium in obesity. Allele and genotype frequencies did not differ between the extremely obese and never-obese subjects. In conclusion, we cannot confirm the results of [Esterbauer et al. (2001]) in our young sample.

Early-onset obesity - Percentiles

References

• 1 Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning B S, Miroux B, Couplan E, Alves-Guerra M C, Goubern M, Surwit R, Bouillaud F, Richard D, Collins S, Ricquier D. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production.  Nat Genet. 2000;  26 435-439
• 2 Boss O, Muzzin P, Giacobino J P. The uncoupling proteins, a review.  Eur J Endocrinol. 1998;  139 1-9
• 3 Boss O, Hagen T, Lowell B B. Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Review.  Diabetes. 2000;  49 143-156
• 4 Cassell P G, Neverova M, Janmohamed S, Uwakwe N, Qureshi A, McCarthy M I, Saker P J, Albon L, Kopelman P, Noonan K, Easlick J, Ramachandran A, Snehalatha C, Pecqueur C, Ricquier D, Warden C, Hitman G A. An uncoupling protein 2 gene variant is associated with a raised body mass index but not Type II diabetes.  Diabetologia. 1999;  42 688-692
• 5 Comuzzie A G, Almasy L, Cole S A, Boss O, Giacobino J P, Muzzin P, Stern M P, MacCluer J W, Blangero J, Hixson J E. Linkage exclusion analysis of the chromosome 11 region containing UCP2 and UCP3 with obesity-related phenotypes in Mexican Americans.  Int J Obes Relat Metab Disord. 2000;  24 1065-1068
• 6 Dalgaard L T, Pedersen O. Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes.  Diabetologia. 2001;  44 946-965
• 7 Dulloo A G, Samec S. Uncoupling proteins: Do they have a role in body weight regulation?.  News Physiol Sci. 2000;  15 313-318
• 8 Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg A D, Patsch J R, Krempler F, Patsch W. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans.  Nat Genet. 2001;  28 178-183
• 9 Evans D, Minouchehr S, Hagemann G, Mann W A, Wendt D, Wolf A, Beisiegel U. Frequency of and interaction between polymorphisms in the beta3-adrenergic receptor and in uncoupling proteins 1 and 2 and obesity in Germans.  Int J Obes Relat Metab Disord. 2000;  24 1239-1245
• 10 Hebebrand J, Himmelmann G W, Heseker H, Schäfer H, Remschmidt H. Use of percentiles for the body mass index in anorexia nervosa: Diagnostic, epidemiological, and therapeutic considerations.  Int J Eat Dis. 1996;  19 359-369
• 11 Hinney A, Lentes K U, Rosenkranz K, Barth N, Roth H, Ziegler A, Hennighausen K, Coners H, Wurmser H, Jacob K, Romer G, Winnikes U, Mayer H, Herzog W, Lehmkuhl G, Poustka F, Schmidt M H, Blum W F, Pirke K M, Schafer H, Grzeschik K H, Remschmidt H, Hebebrand J. Beta 3-adrenergic-receptor allele distributions in children, adolescents and young adults with obesity, underweight or anorexia nervosa.  Int J Obes Relat Metab Disord. 1997;  21 224-230
• 12 Klannemark M, Orho M, Groop L. No relationship between identified variants in the uncoupling protein 2 gene and energy expenditure.  Eur J Endocrinol. 1998;  139 217-223
• 13 Martin E R, Monks S A, Warren L L, Kaplan N L. A test for linkage and association in general pedigrees: the pedigree disequilibrium test.  Am J Hum Genet. 2000;  67 146-154
• 14 Millet L, Vidal H, Andreelli F, Larrouy D, Riou J P, Ricquier D, Laville M, Langin D. Increased uncoupling protein-2 and - 3 mRNA expression during fasting in obese and lean humans.  J Clin Invest. 1997;  100 2665-2670
• 15 Oberkofler H, Liu Y M, Esterbauer H, Hell E, Krempler F, Patsch W. Uncoupling protein-2 gene: reduced mRNA expression in intraperitoneal adipose tissue of obese humans.  Diabetologia. 1998;  41 940-946
• 16 Otabe S, Clement K, Rich N, Warden C, Pecqueur C, Neverova M, Raimbault S, Guy-Grand B, Basdevant A, Ricquier D, Froguel P, Vasseur F. Mutation screening of the human UCP 2 gene in normoglycemic and NIDDM morbidly obese patients: lack of association between new UCP 2 polymorphisms and obesity in French Caucasians.  Diabetes. 1998;  47 840-842
• 17 Saar K, Geller F, Ruschendorf F, Reis A, Friedel S, Schäuble N, Nurnberg P, Siegfried W, Goldschmidt H P, Schafer H, Ziegler A, Remschmidt H, Hinney A, Hebebrand J. Genome scan for childhood and adolescent obesity in German families.  Pediatrics. 2003;  111 321-327
• 18 Schonfeld-Warden N A, Warden C H. Physiological effects of variants in human uncoupling proteins: UCP2 influences body-mass index.  Biochem Soc Trans. 2001;  29 777-784
• 19 Serdula M K, Ivery D, Coates R J, Freedman D S, Williamson D F, Byers T. Do obese children become obese adults? A review of the literature.  Prev Med. 1993;  22 167-177
• 20 Tu N, Chen H, Winnikes U, Reinert I, Marmann G, Pirke K M, Lentes K U. Structural organization and mutational analysis of the human uncoupling protein-2 (hUCP2) gene.  Life Sci. 1999;  64 PL41-50
• 21 Walder K, Norman R A, Hanson R L, Schrauwen P, Neverova M, Jenkinson C P, Easlick J, Warden C H, Pecqueur C, Raimbault S, Ricquier D, Silver M H, Shuldiner A R, Solanes G, Lowell B B, Chung W K, Leibel R L, Pratley R, Ravussin E. Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians.  Hum Mol Genet. 1998;  7 1431-1435
• 22 Wittchen H U, Lachner G, Wunderlich U, Pfister H. Test-retest reliability of the computerized DSM-IV version of the Munich-Composite International Diagnostic Interview (M-CIDI).  Soc Psychiatry Psychiatr Epidemiol. 1998;  33 568-578
• 23 Yanovski J A, Diament A L, Sovik K N, Nguyen T T, Li H, Sebring N G, Warden C H. Associations between uncoupling protein 2, body composition, and resting energy expenditure in lean and obese African American, white, and Asian children.  Am J Clin Nutr. 2000;  71 1405-1420