The N363S polymorphism of the glucocorticoid receptor: Potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus

Considerable evidence suggests that diabetes mellitus and hypertension are influenced by genetic factors. Studies in humans have associated glucocorti coid receptor (GR) polymorphisms with high blood pressure, insulin sensitiv ity, body mass index, increased visceral fat, and variations in tissue-spec ific steroid sensitivity. The N363S polymorphism of the GR results in an as paragine to serine amino acid substitution in a modulatory region of the re ceptor. Phosphorylation of serine residues in this region has been shown to enhance transactivation of GR responsive genes. The aim of this study was to investigate the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European o rigin living in the northeast of the United King-dom. Blood samples from 13 5 males and 240 females were characterized for 363 allele status. The overa ll frequency of the 363S allele was 3.0%, 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. The data show a significa nt association of the 3639 allele with increased waist to hip ratio in male s but not females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, and glucose tolerance status. The results of this study suggest that this GR polymorphism may contribute to central obesity in men. Further studies are required to elucidate the pr operties of GR(363S) at a molecular level.