Haplotype structures and large-scale association testing of the 5' AMP-activated protein kinase genes PRKAA2, PRKAB1, and PRKAB2 [corrected] with type 2 diabetes.
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.
Sun
Maria W
MW
Dept. of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Lee
Jennifer Y
JY
de Bakker
Paul I W
PI
Burtt
Noël P
NP
Almgren
Peter
P
Råstam
Lennart
L
Tuomi
Tiinamaija
T
Gaudet
Daniel
D
Daly
Mark J
MJ
Hirschhorn
Joel N
JN
Altshuler
David
D
Groop
Leif
L
Florez
Jose C
JC
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*
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