Nature Genetics
34, 267 - 273 (2003)
Published online: 15 June 2003; | doi:10.1038/ng1180
PGC-1 -responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesVamsi K Mootha1, 2, 3, 10, Cecilia M Lindgren1, 4, 10, Karl-Fredrik Eriksson4, Aravind Subramanian1, Smita Sihag1, Joseph Lehar1, Pere Puigserver5, Emma Carlsson4, Martin Ridderstråle4, Esa Laurila4, Nicholas Houstis1, Mark J Daly1, Nick Patterson1, Jill P Mesirov1, Todd R Golub1, 5, Pablo Tamayo1, Bruce Spiegelman5, Eric S Lander1, 6, Joel N Hirschhorn1, 7, 8, David Altshuler1, 2, 7, 9, 11
& Leif C Groop4, 111
Whitehead Institute/MIT Center for Genome Research, Cambridge, Massachusetts, USA. 2
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 4
Department of Endocrinology, Wallenberg Laboratory, University Hospital MAS, Lund University, S-205 02 Malmo, Sweden. 5
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 6
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 7
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. 8
Divisions of Pediatrics and Endocrinology, Children's Hospital, Boston, Massachusetts, USA. 9
Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. 10
These authors contributed equally to this work. 11
These two authors contributed equally to this work.
Correspondence should be addressed to David Altshuler altshuler@molbio.mgh.harvard.edu or Leif C Groop leif.groop@endo.mas.lu.seDNA 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-1 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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at the crossroads of type 2 diabetes
