title: Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome.
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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, UK. pamela.kaisaki@well.ox.ac.uk
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: Marc
authors.initials: M
authors.lastname: Delépine
authors.forename: Peng Y
authors.initials: PY
authors.lastname: Woon
authors.forename: Liam
authors.initials: L
authors.lastname: Sebag-Montefiore
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilder
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vionnet
authors.forename: Evelyne
authors.initials: E
authors.lastname: Marion
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Riveline
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schurmans
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Levy
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
mesh_terms: D000368:Aged; D000818:Animals; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000503:physiopathology*; D008875:Middle Aged; D008969:Molecular Sequence Data; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases