Association Studies of BMI and Type 2 Diabetes in the Neuropeptide Y Pathway
A Possible Role for NPY2R as a Candidate Gene for Type 2 Diabetes in Men
- Catarina D. Campbell12,
- Helen N. Lyon12,
- James Nemesh13,
- Jared A. Drake13,
- Tiinamaija Tuomi45,
- Daniel Gaudet6,
- Xiaofeng Zhu7,
- Richard S. Cooper7,
- Kristin G. Ardlie8,
- Leif C. Groop49 and
- Joel N. Hirschhorn123
- 1Program in Genomics and Division of Endocrinology, Children's Hospital, Boston, Massachusetts
- 2Department of Genetics, Harvard Medical School, Boston, Massachusetts
- 3Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
- 4Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
- 5Folkhalsan Genetic Institute, Folkhalsan Research Center, and the Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
- 6University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
- 7Department of Preventive Medicine and Epidemiology, Loyola University Medical Center, Maywood, Illinois
- 8Genomics Collaborative/Seracare LifeSciences, Cambridge, Massachusetts
- 9Department of Clinical Sciences, Diabetes, and Endocrinology, University Hospital, Lund University, Malmö, Sweden
- Address correspondence and reprint requests to Joel N. Hirschhorn, Enders 561, Children's Hospital, 300 Longwood Avenue, Boston, MA 021115. E-mail: joelh{at}broad.mit.edu
Abstract
The neuropeptide Y (NPY) family of peptides and receptors regulate food intake. Inherited variation in this pathway could influence susceptibility to obesity and its complications, including type 2 diabetes. We genotyped a set of 71 single nucleotide polymorphisms (SNPs) that capture the most common variation in NPY, PPY, PYY, NPY1R, NPY2R, and NPY5R in 2,800 individuals of recent European ancestry drawn from the near extremes of BMI distribution. Five SNPs located upstream of NPY2R were nominally associated with BMI in men (P values = 0.001–0.009, odds ratios [ORs] 1.27–1.34). No association with BMI was observed in women, and no consistent associations were observed for other genes in this pathway. We attempted to replicate the association with BMI in 2,500 men and tested these SNPs for association with type 2 diabetes in 8,000 samples. We observed association with BMI in men in only one replication sample and saw no association in the combined replication samples (P = 0.154, OR = 1.09). Finally, a 9% haplotype was associated with type 2 diabetes in men (P = 1.73 × 10−4, OR = 1.36) and not in women. Variation in this pathway likely does not have a major influence on BMI, although small effects cannot be ruled out; NPY2R should be considered a candidate gene for type 2 diabetes in men.
- CEPH, Centre d'Etude du Polymorphisme Humain
- FHS, Framingham Heart Study
- NHLBI, National Heart, Lung, and Blood Institute
- NPY, neuropeptide Y
- PYY, polypeptide YY
- SNP, single nucleotide polymorphism
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 26 February 2007. DOI: 10.2337/db06-1051.
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Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1051.
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K.G.A. is currently affiliated with the Biological Samples Platform, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
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J.N.H has received samples from Genomics Collaborative/Seracare LifeSciences as part of a collaboration, and L.C.G. has been a consultant for and served on the advisory boards of Sanofi-Aventis, Bristol-Myers Squibb, and GlaxoSmithKline.
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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.
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- Accepted February 13, 2007.
- Received July 27, 2006.
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