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

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

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.

Abbreviations: 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

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