Haplotype Structures and Large-Scale Association Testing of the 5′ AMP-Activated Protein Kinase Genes PRKAA2, PRKAB1, and PRKAB2 With Type 2 Diabetes
- Maria W. Sun12,
- Jennifer Y. Lee12,
- Paul I.W. de Bakker123,
- Noël P. Burtt2,
- Peter Almgren4,
- Lennart Råstam5,
- Tiinamaija Tuomi6,
- Daniel Gaudet7,
- Mark J. Daly28,
- Joel N. Hirschhorn239,
- David Altshuler123810,
- Leif Groop46 and
- Jose C. Florez12810
- 1Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- 2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- 3Department of Genetics, Harvard Medical School, Boston, Massachusetts
- 4Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
- 5Department of Clinical Science, University Hospital MAS, Lund University, Malmö, Sweden
- 6Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
- 7University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
- 8Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- 9Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
- 10Department 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
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.
- 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
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
M.W.S. is currently affiliated with the University of California-Davis School of Medicine, Sacramento, California. J.Y.L. is currently affiliated with the Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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- Accepted December 9, 2005.
- Received October 31, 2005.
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