Association Testing of the Protein Tyrosine Phosphatase 1B Gene (PTPN1) With Type 2 Diabetes in 7,883 People

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 6; pp. 1884 - 1891
• Main Authors: Florez, Jose C., Agapakis, Christina M., Burtt, Noël P., Sun, Maria, Almgren, Peter, Råstam, Lennart, Tuomi, Tiinamaija, Gaudet, Daniel, Hudson, Thomas J., Daly, Mark J., Ardlie, Kristin G., Hirschhorn, Joel N., Groop, Leif, Altshuler, David
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2005
• Subjects: Base Sequence; Biological and medical sciences; Case-Control Studies; Chromosome Mapping; Chromosomes; Clinical Medicine; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology and Diabetes; Endocrinopathies; Endokrinologi och diabetes; Genetic aspects; Genetic Predisposition to Disease; Genetic research; Genotype; Glucose; Haplotypes; Humans; Insulin resistance; Klinisk medicin; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Metabolism; Phenotype; Phosphatase; Polymorphism; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases - genetics; Proteins; Signal transduction; Type 2 diabetes; United States; Endocrinopathy; Type 2 diabetes; Association; Gene; Enzyme; Phosphoric monoester hydrolases; Hydrolases; Metabolic diseases; Esterases; Protein-tyrosine-phosphatase
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/diabetes.54.6.1884

Association Testing of the Protein Tyrosine Phosphatase 1B Gene ( PTPN1 ) With Type 2 Diabetes in 7,883 People Jose C. Florez 1 2 3 4 , Christina M. Agapakis 1 3 , Noël P. Burtt 3 , Maria Sun 1 3 , Peter Almgren 5 , Lennart Råstam 6 , Tiinamaija Tuomi 7 , Daniel Gaudet 8 , Thomas J. Hudson 9 , Mark J. Daly 3 , Kristin G. Ardlie 10 , Joel N. Hirschhorn 3 11 12 , Leif Groop 5 and David Altshuler 1 2 3 4 11 1 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Medicine (Diabetes Unit), Massachusetts General Hospital, Boston, Massachusetts 3 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 4 Department of Medicine, Harvard Medical School, Boston, Massachusetts 5 Department of Clinical Sciences—Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden 6 Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden 7 Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland 8 University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada 9 McGill University and Genome Quebec Innovation Centre, Montreal, Canada 10 Genomics Collaborative Division, SeraCare LifeSciences, Cambridge, Massachusetts 11 Department of Genetics, Harvard Medical School, Boston, Massachusetts 12 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts Address correspondence and reprint requests to Leif Groop, Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden. E-mail: leif.groop{at}med.lu.se . Or David Altshuler, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114. E-mail: altshuler{at}molbio.mgh.harvard.edu Abstract Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, inactivates the insulin signal transduction cascade by dephosphorylating phosphotyrosine residues in insulin signaling molecules. Due to its chromosomal location under a chromosome 20 linkage peak and the metabolic effects of its absence in knockout mice, it is a candidate gene for type 2 diabetes. Recent studies have associated common sequence variants in PTPN1 with type 2 diabetes and diabetes-related phenotypes. We sought to replicate the association of common single nucleotide polymorphisms (SNPs) and haplotypes in PTPN1 with type 2 diabetes, fasting plasma glucose, and insulin sensitivity in a large collection of subjects. We assessed linkage disequilibrium, selected tag SNPs, and typed these markers in 3,347 cases of type 2 diabetes and 3,347 control subjects as well as 1,189 siblings discordant for type 2 diabetes. Despite power estimated at >95% to replicate the previously reported associations, no statistically significant evidence of association was observed between PTPN1 SNPs or common haplotypes with type 2 diabetes or with diabetic phenotypes. CEPH, Centre d’Etude du Polymorphisme Humain GCI, Genomics Collaborative, Inc ISI, insulin sensitivity index LD, linkage disequilibrium OGTT, oral glucose tolerance test PTP, protein tyrosine phosphatase SNP, single nucleotide polymorphism UTR, untranslated region Footnotes L.G. and D.A. jointly supervised this work. L.G. has received consulting fees from and served on advisory panels for Aventis-Sanofi, Bristol-Myers Squibb, Kowa, and Roche. D.A. has received consulting fees from and served on an advisory panel for GCI. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . 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. Accepted March 7, 2005. Received January 24, 2005. DIABETES