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

  1. Pamela J. Kaisaki1,
  2. Marc Delépine2,
  3. Peng Y. Woon1,
  4. Liam Sebag-Montefiore1,
  5. Steven P. Wilder1,
  6. Stephan Menzel1,
  7. Nathalie Vionnet2,
  8. Evelyne Marion3,
  9. Jean-Pierre Riveline4,
  10. Guillaume Charpentier4,
  11. Stéphane Schurmans3,
  12. Jonathan C. Levy5,
  13. Mark Lathrop2,
  14. Martin Farrall6 and
  15. Dominique Gauguier1
  1. 1The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
  2. 2National Centre for Genotyping, Evry, France
  3. 3Institut de Recherches en Biologie Humaine et Moléculaire, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium
  4. 4Service d’Endocrinologie-Diabétologie, CH Sud Francilien, Corbeil-Essonnes, France
  5. 5Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
  6. 6Department of Cardiovascular Medicine, University of Oxford, Oxford, U.K
  1. 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.

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  1. doi: 10.2337/diabetes.53.7.1900 Diabetes July 2004 vol. 53 no. 7 1900-1904
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