Association of Protein Tyrosine Phosphatase 1B Gene Polymorphisms With Measures of Glucose Homeostasis in Hispanic Americans

Abstract

P rotein phosphorylation at tyrosine is a key regulatory event that modulates intracellular signaling pathways involved in signal transduction. Protein tyrosine phosphatase (PTP)-1B is a ubiquitously expressed protein (1) that catalyzes the dephosphorylation of proteins at tyrosyl residues. PTP-1B has been implicated (2-4) in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment of the insulin receptor. In mouse models, disruption of the PTPN1 gene resulted in increased insulin sensitivity and resistance to diet-induced obesity (5,6). Further evidence for the role of PTP-1B in insulin sensitivity is seen in knockout mice, in which there was increased phosphorylation of the insulin receptor in liver and muscle tissue (5,6). These observations suggest that PTP-1B plays a role in modulating signal transduction, and defects in PTP-1B expression could lead to insulin resistance.The 10 exons of PTPN1 span Ͼ74 kb of chromosome 20q13.13, with the first intron containing Ͼ50 kb of the sequence. Several investigators (7-9) have searched PTPN1 for DNA sequence variants, e.g., single nucleotide polymorphisms (SNPs). Variation within the coding region of PTPN1 is relatively uncommon. Echwald et al. (7) identified a P387L variant that was found in 2.6% of type 2 diabetic individuals and 1% of healthy control subjects, which showed evidence of impaired in vitro serine phosphorylation of the PTP-1B peptide. Mok et al. (8) identified a 981C3 T polymorphism (5% minor allele frequency) that corresponded to a silent mutation in the PTP-1B protein

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

“…The function of PTP1B and PTPN2 in these pathways has been a focus for type 2 diabetes (T2D) which is associated with the PTPN1 gene [79][80][81]. Although the PTPN2 gene is not associated with susceptibility to T2D, altered PTPN2 expression can impact hepatic gluconeogenesis.…”

Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians

“…In a study of white subjects, Bento et al observed associations between several non-coding singlenucleotide polymorphisms (SNPs) positioned across PTPN1 and type 2 diabetes [2], whereas, in a study of Hispanic American subjects, Palmer et al observed associations between several of the same SNPs and insulin sensitivity and/or fasting glucose levels [3]. Subsequent replication studies of these initial reports have provided weaker or negative results for associations with type 2 diabetes or related phenotypes [4][5][6].…”

“…None of the 26 polymorphic SNPs was associated with either type 2 diabetes or BMI (Table 1). Although the sample size of the 1,037 subjects is comparable or larger than the Bento et al [2] and Palmer et al [3] studies, it may nonetheless have low statistical power to detect variants with modest effects. The power to detect an association depends on the number of case and control subjects, the prevalence of disease and the effect of the associated alleles (e.g.…”

“…Genotyping of SNPs Thirty-one previously analysed SNPs near or within PTPN1 [2][3][4]6] were genotyped by SNPlex (Applied Biosystems, Foster City, CA, USA) following the manufacture's protocol or by allelic discrimination PCR (Assays-by-Design Service; Applied Biosystems). Genotyping of the SNPs included 100 blind duplicate samples.…”

Genetics of Diabetes and Its Complications

“…Common variants in peroxisome proliferator-activated receptor-␥ (13) and KCNJ11 (14) may predispose to type 2 diabetes with relatively low odds ratios (approximately 1.2). Variants that affect insulin signaling through IRS-1 (15,16) and glucose homeostasis PTPN1 (17,18) seem to be less common in frequency, suggesting that combinations of rare and common variants contribute to risk for type 2 diabetes in different pathways in different populations.…”