Protein Tyrosine Phosphatase-1B Gene PTPN1

Selection of Tagging Single Nucleotide Polymorphisms and Association With Body Fat, Insulin Sensitivity, and the Metabolic Syndrome in a Normal Female Population

  1. Sandra D. O’Dell1
  1. 1Department of Clinical Developmental Sciences, St. George’s, University of London, London, U.K
  2. 2Georgia Prevention Institute, Department of Pediatrics, Medical College of Georgia, Augusta, Georgia
  3. 3Twin Research and Genetic Epidemiology Unit, St. Thomas’ Hospital, London, U.K
  1. Address correspondence and reprint requests to Dr. Sandra D. O’Dell, Nutrition Food and Health Centre, King’s College London, Franklin-Wilkins Building, 150 Stamford St., London SE19H, U.K. E-mail: sandra.o'dell{at}kcl.ac.uk

Abstract

Protein tyrosine phosphatase-1B negatively regulates leptin and insulin signaling, potentially contributing to hormonal resistance. We selected six tagging single nucleotide polymorphisms (SNPs) representing 18 common variants in the protein tyrosine phosphatase-1B gene (PTPN1) and tested their effect on serum leptin, body fat, and measures of insulin sensitivity and the metabolic syndrome in a large sample of normal female Caucasian twins (n = 2,777; mean age, 47.4 ± 12.5 years) from the St. Thomas’ U.K. Adult Twin Registry. SNP rs718049 was significantly associated with waist circumference (P = 0.008) and central fat (P = 0.035) and also with Avignon’s insulin sensitivity index (SiM) (P = 0.007), fasting insulin (P = 0.004), fasting glucose (P = 0.022), triglyceride (P = 0.023), and systolic blood pressure (P = 0.046). SNPs rs2282146 and rs1885177 were associated with SiM (P = 0.049 and P = 0.013, respectively), and 1484insG was associated with triglyceride (P = 0.029). A risk haplotype (7.3%) was associated with lower SiM (P = 0.036) and a protective haplotype (5.2%) with higher SiM (P = 0.057), with mean values in homozygotes differing by >1 SD (P = 0.003). The protective haplotype also showed lower triglyceride (P = 0.045) and lower systolic blood pressure (P = 0.006). Fine mapping analyses predicted significant associations with SiM and fasting insulin for several ungenotyped SNPs. PTPN1 variants appear to contribute to central fat and metabolic syndrome traits, secondary to their effect on insulin sensitivity.

  • Received May 26, 2005.
  • Accepted July 27, 2005.
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