title: Haplotype structures and large-scale association testing of the 5' AMP-activated protein kinase genes PRKAA2, PRKAB1, and PRKAB2 [corrected] with type 2 diabetes.
abstract: AMP-activated protein kinase (AMPK) is a key molecular regulator of cellular metabolism, and its activity is induced by both metformin and thiazolidinedione antidiabetic medications. It has therefore been proposed both as a putative agent in the pathophysiology of type 2 diabetes and as a valid target for therapeutic intervention. Thus, the genes that encode the various AMPK subunits are intriguing candidates for the inherited basis of type 2 diabetes. We therefore set out to test for the association of common variants in the genes that encode three selected AMPK subunits with type 2 diabetes and related phenotypes. Of the seven genes that encode AMPK isoforms, we initially chose PRKAA2, PRKAB1, and PRKAB2 because of their higher prior probability of association with type 2 diabetes, based on previous reports of genetic linkage, functional molecular studies, expression patterns, and pharmacological evidence. We determined their haplotype structure, selected a subset of tag single nucleotide polymorphisms that comprehensively capture the extent of common genetic variation in these genes, and genotyped them in family-based and case/control samples comprising 4,206 individuals. Analysis of single-marker and multi-marker tests revealed no association with type 2 diabetes, fasting plasma glucose, or insulin sensitivity. Several nominal associations of variants in PRKAA2 and PRKAB1 with BMI appear to be consistent with statistical noise.
authors.affiliation: Dept. of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Maria W
authors.initials: MW
authors.lastname: Sun
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Noël P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Lennart
authors.initials: L
authors.lastname: Råstam
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D055372:AMP-Activated Protein Kinases; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D007527:Isoenzymes; D009097:Multienzyme Complexes; C526181:PRKAA2 protein, human; C526182:PRKAB1 protein, human; C526183:PRKAB2 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases