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Haplotype Structures and Large-Scale Association Testing of the 5' AMP-Activated Protein Kinase Genes PRKAA2, PRKAB1, and PRKAB2 With Type 2 Diabetes

¹ Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
³ Department of Genetics, Harvard Medical School, Boston, Massachusetts
⁴ Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
⁵ Department of Clinical Science, University Hospital MAS, Lund University, Malmö, Sweden
⁶ Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
⁷ University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
⁸ Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
⁹ Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
¹⁰ Department of Medicine, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Jose C. Florez, Diabetes Unit/Dept. of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114. E-mail: jcflorez{at}partners.org

Abbreviations: AMPK, AMP-activated protein kinase; GRR, genotype relative risk; ISI, insulin sensitivity index; LD, linkage disequilibrium; MAF, minor allele frequency; OGTT, oral glucose tolerance test; PPAR, peroxisome proliferator–activated receptor; SNP, single nucleotide polymorphism

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.

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