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A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans

Nature Genetics volume 28, pages 178–183 (2001)Cite this article

Abstract

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue1,2. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis1,3 and is therefore a candidate gene for obesity4,5,6. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (∼63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.

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Figure 1: A UCP2 promoter polymorphism is associated with allele-specific mRNA expression.
Figure 2: Polymorphic sites in the 5′ region of the UCP2 gene, their pairwise linkage disequilibria (D'), their effects on promoter activity and identification of transcription factors potentially interacting with sequences adjacent to the –866 polymorphic site.

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References

  1. Fleury, C. et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet. 15, 269–272 (1997).

    Article  CAS  Google Scholar 

  2. Gimeno, R.E. et al. Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis. Diabetes 46, 900–906 (1997).

    Article  CAS  Google Scholar 

  3. Jaburek, M. et al. Transport function and regulation of mitochondrial uncoupling proteins 2 and 3. J. Biol. Chem. 274, 26003–26007 (1999).

    Article  CAS  Google Scholar 

  4. Bouchard, C., Perusse, L., Chagnon, Y.C., Warden, C. & Ricquier, D. Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans. Hum. Mol. Genet. 6, 1887–1889 (1997).

    Article  CAS  Google Scholar 

  5. Ricquier, D. & Bouillaud, F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem. J. 345, 161–179 (2000).

    Article  CAS  Google Scholar 

  6. Boss, O., Hagen, T. & Lowell, B.B. Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49, 143–156 (2000).

    Article  CAS  Google Scholar 

  7. Oberkofler, H. et al. Uncoupling protein-2 gene: reduced mRNA expression in intraperitoneal adipose tissue of obese humans. Diabetologia 41, 940–946 (1998).

    Article  CAS  Google Scholar 

  8. Walder, K. et al. Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians. Hum. Mol. Genet. 7, 1431–1435 (1998).

    Article  CAS  Google Scholar 

  9. Dalgaard, L.T., Sorensen, T.I., Andersen, T., Hansen, T. & Pedersen, O. An untranslated insertion variant in the uncoupling protein 2 gene is not related to body mass index and changes in body weight during a 26-year follow-up in Danish Caucasian men. Diabetologia 42, 1413–1416 (1999).

    Article  CAS  Google Scholar 

  10. Pecqueur, C. et al. Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J. Biol. Chem. 276, 8705–8712 (2001).

    Article  CAS  Google Scholar 

  11. Vaulont, S., Vasseur-Cognet, M. & Kahn, A. Glucose regulation of gene transcription. J. Biol. Chem. 275, 31555–31558 (2000).

    Article  CAS  Google Scholar 

  12. Rosenbaum, M., Leibel, R.L. & Hirsch, J. Obesity. N. Engl. J. Med. 337, 396–407 (1997).

    Article  CAS  Google Scholar 

  13. Ravussin, E. et al. Reduced rate of energy expenditure as a risk factor for body-weight gain. N. Engl. J. Med. 318, 467–472 (1988).

    Article  CAS  Google Scholar 

  14. Li, B. et al. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nature Med. 6, 1115–1120 (2000).

    Article  CAS  Google Scholar 

  15. Kopecky, J., Clarke, G., Enerback, S., Spiegelman, B. & Kozak, L.P. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J. Clin. Invest. 96, 2914–2923 (1995).

    Article  CAS  Google Scholar 

  16. Kozak, L.P. Uncoupling diet and diabetes. Nature Med. 6, 1092–1093 (2000).

    Article  CAS  Google Scholar 

  17. Otabe, S. et al. A genetic variation in the 5′ flanking region of the UCP3 gene is associated with body mass index in humans in interaction with physical activity. Diabetologia 43, 245–249 (2000).

    Article  CAS  Google Scholar 

  18. Cassell, P.G. et al. Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin. Diabetologia 43, 1558–1564 (2000).

    Article  CAS  Google Scholar 

  19. Schrauwen, P., Xia, J., Walder, K., Snitker, S. & Ravussin, E. A novel polymorphism in the proximal UCP3 promoter region: effect on skeletal muscle UCP3 mRNA expression and obesity in male non-diabetic Pima Indians. Int. J. Obes. Relat. Metab. Disord. 23, 1242–1245 (1999).

    Article  CAS  Google Scholar 

  20. Argyropoulos, G. et al. Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. J. Clin. Invest. 102, 1345–1351 (1998).

    Article  CAS  Google Scholar 

  21. Kiefer, I., Kunze, U., Mitsche, N. & Kunze, M. Obesity in Austria: epidemiologic and social medicine aspects. Acta Med. Austriaca. 25, 126–128 (1998).

    CAS  PubMed  Google Scholar 

  22. Esterbauer, H. et al. Uncoupling protein-3 gene expression: reduced skeletal muscle mRNA in obese humans during pronounced weight loss. Diabetologia 42, 302–309 (1999).

    Article  CAS  Google Scholar 

  23. Esterbauer, H., Oberkofler, H., Krempler, F., Strosberg, A.D. & Patsch, W. The uncoupling protein-3 gene is transcribed from tissue-specific promoters in humans but not in rodents. J. Biol. Chem. 275, 36394–36399 (2000).

    Article  CAS  Google Scholar 

  24. Zilberfarb, V. et al. Human immortalized brown adipocytes express functional beta3-adrenoceptor coupled to lipolysis. J. Cell Sci. 110, 801–807 (1997).

    CAS  PubMed  Google Scholar 

  25. Chiano, M.N. & Clayton, D.G. Fine genetic mapping using haplotype analysis and the missing data problem. Ann. Hum. Genet. 62, 55–60 (1998).

    Article  CAS  Google Scholar 

  26. Mander, A.P. & Clayton, D.G. Haplotype frequency estimation using an EM algorithm and log-linear modelling. Stata Tech. Bull. 55, 10–12 (2000).

    Google Scholar 

  27. Terwilliger, J.D. & Ott, J. Handbook of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1994).

    Google Scholar 

  28. Robins, J., Greenland, S. & Breslow, N.E. A general estimator for the variance of the Mantel-Haenszel odds ratio. Am. J. Epidemiol. 124, 719–723 (1986).

    Article  CAS  Google Scholar 

  29. Bradburn, M.J., Deeks, J.J. & Altman D.G. Metan – an alternative meta-analysis command. Stata Tech. Bull. 44, 4–15 (1998).

    Google Scholar 

  30. Heinemeyer, T. et al. Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms. Nucl. Acids Res. 27, 318–322 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The advice and assistance of P.-K. Pfeiffer in statistical analyses and the technical assistance of D. Pichler is acknowledged. This study was funded by the Austrian Federal Ministry of Science and Transport (GZ 70.063/1-Pr/4/2000) and by a grant from the Medizinische Forschungsgesellschaft Salzburg and the Stiftung Propter Homines, Vaduz, Liechtenstein.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Landeskliniken Salzburg, Austria

    Harald Esterbauer, Clemens Schneitler, Hannes Oberkofler & Wolfgang Patsch

  2. Department of Internal Medicine, University of Innsbruck, Austria

    Christoph Ebenbichler & Josef R. Patsch

  3. Department of Internal Medicine, Landeskliniken Salzburg, Austria

    Bernhard Paulweber & Friedrich Sandhofer

  4. Department of Neurology, Landeskliniken Salzburg, Austria

    Gunther Ladurner

  5. Department of Surgery, Krankenhaus Hallein, Austria

    Emanuel Hell

  6. Institute Cochin de Genetique Moleculaire, Paris, France

    A. Donny Strosberg

  7. Department of Internal Medicine, Krankenhaus Hallein, Austria

    Franz Krempler

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  1. Harald Esterbauer
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Correspondence to Wolfgang Patsch.

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Esterbauer, H., Schneitler, C., Oberkofler, H. et al. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet 28, 178–183 (2001). https://doi.org/10.1038/88911

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