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. Diabetes 53: 1900 -1904, 2004 T he metabolic syndrome, a cluster of metabolic abnormalities that can include type 2 diabetes, hypertension, central obesity, and dyslipidemia, occurs at a high rate in the U.S., Europe, and Scandinavia (1-4). Insulin resistance is the focal component of the metabolic syndrome, and both genetic and environmental factors contribute to its development (4). Much progress has been made toward understanding the regulation of insulin action and the molecular defects that give rise to insulin resistance (5).INPPL1 is a negative regulator of insulin signaling, and Inppl1 inactivation in mice results in increased insulin sensitivity (6). INPPL1 is in human chromosome 11q13-14, which has suggested linkage to type 2 diabetes, hypertension, and insulin resistance (7-9). In the rat, Inppl1 is in an interval on chromosome 1 linked to glucose intolerance and adiposity in the spontaneously diabetic (type 2) GotoKakizaki rat (10,11) and to hypertension in the spontaneously hypertensive rat (12). We identified a missense variant in Inppl1 specific to both rat strains that increases inhibition of insulin signaling compared with wild-type Inppl1 (10). Furthermore, in type 2 diabetic patients, we found a 16-bp deletion of an adenylate/uridylate-rich element in the 3Ј untranslated region of INPPL1, which in vitro causes changes consistent with a role in insulin resistance (10). Seven of nine patients with this mutation were hypertensive, and five were obese.To investigate the role of genetic variation in INPPL1 in the metabolic syndrome, we first resequenced the gene (15.2 kb), including all exons and introns in a panel of 64 individuals. We describe a total of 49 variants ( Fig. 1; a table of single nucleotide polymorphisms [SNPs] is available in the online appendix at http:// diabetes.diabetesjournal.org and at http://www.well. ox.ac.uk/rat_mapping_resources/SHIP2). At first we genotyped all polymorphic markers, but in later stages we discarde...

Genetic architecture of quantitative traits in mice, flies, and humans

“…For example, evidence from QTL mapping and analyses of knockouts implicates Tnfsf4 in diet-induced atherosclerosis in mice (Wang et al 2005b); however, genetic association studies have not provided consistent evidence for its involvement in humans (Koch et al 2008). Similar difficulties are found for the involvement of type II SH2 domain-containing inositol 5-phosphatase in the metabolic syndrome (Kaisaki et al 2004;Marcano et al 2007) and regulators of G protein signaling in anxiety (Fullerton et al 2008).…”

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes

“…These are British families of European descent containing a T2D patient with one or more siblings. Incidence of hypertension in the DIF T2D patients was 38%, whereas 59% of the nondiabetic subjects had hypertension (30). Other phenotype details regarding impaired glycemic control, obesity, and lipid parameters are described in ref.…”

“…Other phenotype details regarding impaired glycemic control, obesity, and lipid parameters are described in ref. 30.…”

“…To test the relevance of BMAL1 polymorphisms to human hypertension and extend the study to the broad context of insulin resistance, which accounts for the spectrum of SHR pathophysiology (29) and the biological function of the gene (17,19), we carried out extensive sequence and SNP analyses in British families ascertained through a T2D proband (30). The National Center for Biotechnology Information dbSNP database, the International HapMap Project SNP database, and our original sequencing data in 96 individuals provided us with 19 SNPs for the initial phase of SNP genotyping.…”

Diabetes quantitative trait locus research: from physiology to genetics and back

“…The relevance of QTL findings in animal models to human disorders remains a topic of debate and continues to raise some scepticism. However, some reasons for optimism come from the recent demonstration that sequence variation in the gene encoding type II SH2 domain-containing inositol 5-phosphatase accounts for both a diabetes QTL in a polygenic rat model and susceptibility to major components of the metabolic syndrome in humans [9]. Given the high degree of synteny (preservation of gene content and gene mapping order) between rodent and human genomes [10], and extensive cDNA sequence similarities between species, identifying human chromosomal segments homologous to the A/J haplotype in the congenic strain derived by Kobayashi et al is straightforward, and can be used to prioritise genetic association and linkage studies in humans.…”