title: Polymorphisms within the protein tyrosine phosphatase 1B (PTPN1) gene promoter: functional characterization and association with type 2 diabetes and related metabolic traits.
abstract: BACKGROUND
  Protein tyrosine phosphatase 1B (PTPN1) dephosphorylates insulin receptors and attenuates insulin signaling. Polymorphisms in the coding sequence of PTPN1 have been variably associated with type 2 diabetes (T2D). We hypothesized that variations within the PTPN1 promoter might contribute to the development of T2D and related metabolic traits.
  
  
  METHODS
  We screened 2.0 kb of PTPN1 promoter in 174 T2D patients and 412 controls using PCR and denaturing HPLC. Association analysis was performed between diabetes and related traits and single-nucleotide polymorphism genotypes. We functionally tested 2 variants (-1023C>A and -51delA) by measuring their influence on luciferase activity in HepG2 cells and performing the electrophoretic mobility shift assay (EMSA).
  
  
  RESULTS
  One common (-1023C>A) and 6 rare (-51delA, -451A>G, -467T>C, -1045G>A, -1286-3bp-del, and -1291-9bp-del) variants were identified in the PTPN1 promoter. The -1023(C) allele had significant association with T2D that disappeared after we adjusted for established diabetes risk factors. The alleles of -1023C>A and -51delA variants did not show significant effects on the biochemical markers after adjustment for established diabetes risk factors in the nondiabetic and diabetic groups separately. The -51delA variant decreased luciferase gene expression in HepG2 cells by 2-fold. EMSA revealed a weaker binding of -51delA to specific protein family proteins compared with the A allele. The -1023C>A variant had no influence in either experiment.
  
  
  CONCLUSIONS
  The PTPN1 promoter variants -1023C>A and -51delA (which appears to be functional) were not associated with T2D or related traits in this study but must be investigated in a larger population to reveal any potential metabolic association.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Meshkani
authors.forename: Mohammad
authors.initials: M
authors.lastname: Taghikhani
authors.forename: Hussam
authors.initials: H
authors.lastname: Al-Kateb
authors.forename: Bagher
authors.initials: B
authors.lastname: Larijani
authors.forename: Shohreh
authors.initials: S
authors.lastname: Khatami
authors.forename: Gus Konstantinos
authors.initials: GK
authors.lastname: Sidiropoulos
authors.forename: Robert Alexander
authors.initials: RA
authors.lastname: Hegele
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: D000328:Adult; D000368:Aged; D001665:Binding Sites; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005838:Genotype; D018149:Glucose Intolerance / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; D008156:Luciferases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases