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.

journal_name

Clin Chem

journal_title

Clinical chemistry

authors

Meshkani R,Taghikhani M,Al-Kateb H,Larijani B,Khatami S,Sidiropoulos GK,Hegele RA,Adeli K

doi

10.1373/clinchem.2007.088146

subject

Has Abstract

pub_date

2007-09-01 00:00:00

pages

1585-92

issue

9

eissn

0009-9147

issn

1530-8561

pii

clinchem.2007.088146

journal_volume

53

pub_type

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