Polymorphisms in Type II SH2 Domain–Containing Inositol 5-Phosphatase (INPPL1, SHIP2) Are Associated With Physiological Abnormalities of the Metabolic Syndrome

Polymorphisms in Type II SH2 Domain–Containing Inositol 5-Phosphatase ( INPPL1 , SHIP2) Are Associated With Physiological Abnormalities of the Metabolic Syndrome Pamela J. Kaisaki 1 , Marc Delépine 2 , Peng Y. Woon 1 , Liam Sebag-Montefiore 1 , Steven P. Wilder 1 , Stephan Menzel 1 , Nathalie Vionnet 2 , Evelyne Marion 3 , Jean-Pierre Riveline 4 , Guillaume Charpentier 4 , Stéphane Schurmans 3 , Jonathan C. Levy 5 , Mark Lathrop 2 , Martin Farrall 6 and Dominique Gauguier 1 1 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K 2 National Centre for Genotyping, Evry, France 3 Institut de Recherches en Biologie Humaine et Moléculaire, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium 4 Service d’Endocrinologie-Diabétologie, CH Sud Francilien, Corbeil-Essonnes, France 5 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K 6 Department of Cardiovascular Medicine, University of Oxford, Oxford, U.K Address correspondencereprint requests to Pamela J. Kaisaki, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford OX3 7BN, U.K. E-mail: pamela.kaisaki{at}well.ox.ac.uk Abstract Type II SH2 domain–containing inositol 5-phosphatase ( INPPL1, or SHIP2) plays an important role in the control of insulin sensitivity. INPPL1 mutations affecting gene function have been found in rat models of type 2 diabetes and hypertension and in type 2 diabetic patients. We investigated the influence of nucleotide variation in INPPL1 on components of the metabolic syndrome. Following comprehensive resequencing of the gene, we genotyped 12 informative polymorphisms in 1,304 individuals from 424 British type 2 diabetes families that were characterized for several metabolic phenotypes. We have found highly significant associations of single nucleotide polymorphisms (SNPs) and haplotypes of INPPL1 with hypertension as well as with other components of the metabolic syndrome. In a cohort of 905 French type 2 diabetic patients, we found evidence of association of INPPL1 SNPs with the presence of hypertension. We conclude that INPPL1 variants may impact susceptibility to disease and/or to subphenotypes involved in the metabolic syndrome in some diabetic patients. DIF, Diabetes in Families PDT, pedigree disequilibrium test SNP, single nucleotide polymorphism Footnotes Additional information for this article can be found in an online appendix at http://diab