title: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.
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-1alpha 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.
authors.affiliation: Whitehead Institute/MIT Center for Genome Research, Cambridge, Massachusetts, USA.
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Karl-Fredrik
authors.initials: KF
authors.lastname: Eriksson
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.forename: Smita
authors.initials: S
authors.lastname: Sihag
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehar
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.forename: Emma
authors.initials: E
authors.lastname: Carlsson
authors.forename: Martin
authors.initials: M
authors.lastname: Ridderstråle
authors.forename: Esa
authors.initials: E
authors.lastname: Laurila
authors.forename: Nicholas
authors.initials: N
authors.lastname: Houstis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Bruce
authors.initials: B
authors.lastname: Spiegelman
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Leif C
authors.initials: LC
authors.lastname: Groop
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000502:physiology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects*; D032446:Myoblasts / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000494:pharmacology*
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D005947:Glucose