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PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

Nature Genetics volume 34, pages 267–273 (2003)Cite this article

Abstract

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

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Figure 1: Schematic overview of GSEA.
Figure 2: OXPHOS gene expression is reduced in diabetic muscle.
Figure 3: OXPHOS-CR represents a coregulated subset of OXPHOS genes responsive to the transcriptional coactivator PGC-1α.
Figure 4: OXPHOS-CR predicts total-body aerobic capacity (VO2max).

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References

  1. Zimmet, P. Globalization, coca-colonization and the chronic disease epidemic: can the Doomsday scenario be averted? J. Intern. Med. 247, 301–310 (2000).

    Article  CAS  Google Scholar 

  2. Fajans, S.S., Bell, G.I. & Polonsky, K.S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N. Engl. J. Med. 345, 971–980 (2001).

    Article  CAS  Google Scholar 

  3. Golub, T.R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    Article  CAS  Google Scholar 

  4. Doniger, S.W. et al. MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data. Genome Biol. 4, R7 (2003).

    Article  Google Scholar 

  5. Draghici, S., Khatri, P., Martins, R.P., Ostermeier, G.C. & Krawetz, S.A. Global functional profiling of gene expression. Genomics 81, 98–104 (2003).

    Article  CAS  Google Scholar 

  6. Tusher, V.G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 98, 5116–5121 (2001).

    Article  CAS  Google Scholar 

  7. Sreekumar, R., Halvatsiotis, P., Schimke, J.C. & Nair, K.S. Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 51, 1913–1920 (2002).

    Article  CAS  Google Scholar 

  8. Yang, X., Pratley, R.E., Tokraks, S., Bogardus, C. & Permana, P.A. Microarray profiling of skeletal muscle tissues from equally obese, non-diabetic insulin-sensitive and insulin-resistant Pima Indians. Diabetologia 45, 1584–1593 (2002).

    Article  CAS  Google Scholar 

  9. Kropf, S. & Lauter, J. Multiple tests for different sets of variables using a data-driven ordering of hypotheses, with an application to gene expression data. Biometrical J. 44, 789–800 (2002).

    Article  Google Scholar 

  10. Storey, J.D. A direct approach to false discovery rates. J. R. Statist. Soc. B 64, 479–498 (2002).

    Article  Google Scholar 

  11. Liu, G. et al. NetAffx: Affymetrix probesets and annotations. Nucleic Acids Res. 31, 82–86 (2003).

    Article  CAS  Google Scholar 

  12. Su, A.I. et al. Large-scale analysis of the human and mouse transcriptomes. Proc. Natl. Acad. Sci. USA 99, 4465–4470 (2002).

    Article  CAS  Google Scholar 

  13. Bjorntorp, P., Schersten, T. & Fagerberg, S.E. Respiration and phosphorylation of mitochondria isolated from the skeletal muscle of diabetic and normal subjects. Diabetologia 3, 346–352 (1967).

    Article  CAS  Google Scholar 

  14. Simoneau, J.A., Colberg, S.R., Thaete, F.L. & Kelley, D.E. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J. 9, 273–278 (1995).

    Article  CAS  Google Scholar 

  15. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

    Article  CAS  Google Scholar 

  16. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  Google Scholar 

  17. Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow- twitch muscle fibres. Nature 418, 797–801 (2002).

    Article  CAS  Google Scholar 

  18. Scarpulla, R.C. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim. Biophys. Acta 1576, 1–14 (2002).

    Article  CAS  Google Scholar 

  19. Brown, G.C. Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem. J. 284, 1–13 (1992).

    Article  CAS  Google Scholar 

  20. Eriksson, K.F. & Lindgarde, F. Impaired glucose tolerance in a middle-aged male urban population: a new approach for identifying high-risk cases. Diabetologia 33, 526–531 (1990).

    Article  CAS  Google Scholar 

  21. Kelley, D.E., He, J., Menshikova, E.V. & Ritov, V.B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).

    Article  CAS  Google Scholar 

  22. van Dam, R.M. & Feskens, E.J. Coffee consumption and risk of type 2 diabetes mellitus. Lancet 360, 1477–1478 (2002).

    Article  Google Scholar 

  23. Ojuka, E.O., Jones, T.E., Han, D.H., Chen, M. & Holloszy, J.O. Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle. FASEB J. 17, 675–681 (2003).

    Article  CAS  Google Scholar 

  24. Florez, J.C., Hirschhorn, J.N. & Altshuler, D. The inherited basis of diabetes mellitus: general lessons for the genetic analysis of complex traits. Annu. Rev. Genomics Hum. Genet. (in the press).

  25. Ek, J. et al. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia 44, 2220–2226 (2001).

    Article  CAS  Google Scholar 

  26. Hara, K. et al. A genetic variation in the PGC-1 gene and insulin resistance. Diabetologia 45, 740–743 (2002).

    Article  CAS  Google Scholar 

  27. Lacquemant, C., Chikri, M., Boutin, P., Samson, C. & Froguel, P. No association between the G482S polymorphism of the proliferator-activated receptor-γ coactivator-1 (PGC-1) gene and Type II diabetes in French Caucasias. Diabetologia 45, 602–603; author reply 604 (2002).

    Article  CAS  Google Scholar 

  28. Groop, L. et al. Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 45, 1585–1593 (1996).

    Article  CAS  Google Scholar 

  29. Eriksson, K.F., Saltin, B. & Lindgarde, F. Increased skeletal muscle capillary density precedes diabetes development in men with impaired glucose tolerance. A 15-year follow-up. Diabetes 43, 805–808 (1994).

    Article  CAS  Google Scholar 

  30. Schalin-Jantti, C., Laurila, E., Lofman, M. & Groop, L.C. Determinants of insulin-stimulated skeletal muscle glycogen metabolism in man. Eur. J. Clin. Invest. 25, 693–698 (1995).

    Article  CAS  Google Scholar 

  31. Tamayo, P. et al. Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation. Proc. Natl. Acad. Sci. USA 96, 2907–2912 (1999).

    Article  CAS  Google Scholar 

  32. Eisen, M.B., Spellman, P.T., Brown, P.O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95, 14863–14868 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Ladd, M. Gaasenbeek and G. Ahlqvist for technical assistance; L. Gaffney for preparing illustrations; D. Stram and R. Heinrich for discussions; M. Patti and colleagues for sharing their manuscript before publication; B. Gewurz, E. Rosen, members of D.A. and E.S.L.'s labs for comments on the manuscript; and the individuals who volunteered for this study. V.K.M. is supported by a Howard Hughes Medical Institute physician postdoctoral fellowship. C.M.L. was supported by the Foundation for Strategic Research, the Royal Physiographic Society, the Sven Lundgrens Foundation and the Albert Pahlssons Foundation. T.R.G. is an Investigator of the Howard Hughes Medical Institute. J.N.H. is the recipient of a Career Development Award of the Burroughs Welcome Fund. D.A. is a Clinical Scholar in Translational Research of the Burroughs Welcome Fund and a Charles E. Culpeper Scholar of the Rockefeller Brothers Fund. This work was supported in part by grants from Affymetrix, Millennium Pharmaceuticals and Bristol-Myers Squibb to E.S.L. and from the Sigrid Juselius Foundation, the Juvenile Diabetes Foundation-Wallenberg Foundation, the Swedish Medical Research Council, the Novo-Nordisk Foundation and a European Community Genomics Integrated Force for Type 2 Diabetes grant to L.C.G.

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Author notes

  1. Vamsi K Mootha and Cecilia M Lindgren: These authors contributed equally to this work.

  2. David Altshuler and Leif C Groop: These two authors contributed equally to this work.

Authors and Affiliations

  1. Whitehead Institute/MIT Center for Genome Research, Cambridge, Massachusetts, USA

    Vamsi K Mootha, Cecilia M Lindgren, Aravind Subramanian, Smita Sihag, Joseph Lehar, Nicholas Houstis, Mark J Daly, Nick Patterson, Jill P Mesirov, Todd R Golub, Pablo Tamayo, Eric S Lander, Joel N Hirschhorn & David Altshuler

  2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Vamsi K Mootha & David Altshuler

  3. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Vamsi K Mootha

  4. Department of Endocrinology, Wallenberg Laboratory, University Hospital MAS, Lund University, Malmo, S-205 02, Sweden

    Cecilia M Lindgren, Karl-Fredrik Eriksson, Emma Carlsson, Martin Ridderstråle, Esa Laurila & Leif C Groop

  5. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Pere Puigserver, Todd R Golub & Bruce Spiegelman

  6. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Eric S Lander

  7. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Joel N Hirschhorn & David Altshuler

  8. Divisions of Pediatrics and Endocrinology, Children's Hospital, Boston, Massachusetts, USA

    Joel N Hirschhorn

  9. Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    David Altshuler

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  1. Vamsi K Mootha
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Correspondence to David Altshuler or Leif C Groop.

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Mootha, V., Lindgren, C., Eriksson, KF. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34, 267–273 (2003). https://doi.org/10.1038/ng1180

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