CLINICAL STUDY Genetic variation in receptor protein tyrosine phosphatase s is associated with type 2 diabetes in Swedish Caucasians Ewa-Carin La ˚ngberg, Harvest F Gu, Sofia Nordman, Suad Efendic and Claes-Go ¨ran O ¨ stenson Department of Molecular Medicine and Surgery, Karolinska Institutet, Rolf Luft Center for Diabetes Research, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden (Correspondence should be addressed to E-C La ˚ngberg; Email: ewa-carin.langberg@ki.se) Abstract Objective: Previously, it has been demonstrated that receptor protein tyrosine phosphatase s (RPTPs) is involved in glucose homeostasis and insulin signaling in several animal models. The aim of this study was to evaluate whether polymorphisms in this gene influence the development of type 2 diabetes (T2D) in humans. Design: We investigated how genetic variations in the RPTPs gene influence susceptibility to impaired glucose tolerance (IGT) and T2D, in Swedish men and women. Methods: Genotyping of single nucleotide polymorphisms (SNPs) was performed by dynamic allele- specific hybridization in a total of 1057 Swedish Caucasians including 497 subjects with normal glucose tolerance (NGT), 262 subjects with IGT, and 298 patients with T2D. Results: SNPs rs1143699, rs4807015, and rs1978237 were found to be associated with T2D. SNP rs1143699 was associated with male T2D patients when compared with NGT controls (odds ratio; ORZ1.57; PZ0.029). SNP rs4807015 showed association with T2D patients when compared with NGT controls (ORZ1.32; PZ0.025). Finally, SNP rs1978237 was associated with T2D patients when compared with NGT controls (ORZ1.59; PZ0.002). Logistic regression analysis demonstrated that for SNP rs1143699 in men, C/C homozygosity conveys an increased risk of T2D (ORZ2.19; PZ0.035), while SNP rs4807015 was associated with an increased risk of T2D in both men and women (ORZ1.74; PZ0.029). SNP rs1978237 also demonstrated a risk of T2D in men and women (ORZ1.59; PZ0.026). Conclusions: This study provides evidence for association of SNPs in the RPTPs gene with T2D in Swedish Caucasians. SNPs rs1143699, rs4807015, and rs1978237 confer an increased risk of developing T2D. European Journal of Endocrinology 157 459–464 Introduction Type 2 diabetes (T2D) is a multifactorial disease that involves insulin resistance and impaired glucose- induced insulin release (1). In most patients, T2D results from alterations of several genes, where each of them has a partial and additive effect (2). T2D is also influenced by lifestyle, such as a high calorie intake and sedentary behavior leading to overweight (3) . Identification of genes influencing genetic variation in disease offers a better understanding of molecular mechanisms underlying T2D pathogenesis, which is a prerequisite for development of therapeutic methods (4). We have previously demonstrated that the receptor protein tyrosine phosphatase s (RPTPs) gene, also known as PTPs, is overexpressed by w60% in pancreatic islets and liver of spontaneously diabetic Goto–Kakizaki (GK) rats that have impaired insulin secretion. When islet RPTPs was inhibited by antisense, improved glucose-induced insulin secretion was seen in GK islets (5). In addition, RPTPs knockout (K/K) mice have shown decreased plasma glucose and insulin levels in the fasted state when compared with wild-type controls. The mice also had increased whole-body insulin sensitivity, suggesting that RPTPs affects insulin signaling in insulin-sensitive tissues (6). RPTPs has a function in the cellular receptor signaling, which is critical for signal transduction in both normal and pathophysiological conditions (7). It is a member of the leukocyte antigen-related (LAR) RPTP family, which has been suggested to act in key steps of neural development and also in diabetes and cancer (8). LAR, a protein closely related to RPTPs, has negative regulatory effects in the insulin signaling pathway when it is overexpressed (9). The RPTPs gene gives rise to several different distinct isoforms (10). PTPs are key regulators of the insulin receptor signal transduction pathway and the RPTPs gene has been shown to be highly expressed in insulin target tissues, such as liver, European Journal of Endocrinology (2007) 157 459–464 ISSN 0804-4643 q 2007 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0114 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 06/17/2020 08:05:58AM via Massachusetts Inst of Technology