A common intron 2 polymorphism of the glucocorticoid receptor gene is associated with insulin resistance in men

Objective Clinical similarities between the metabolic syndrome and Cushing's syndrome have led to speculation of genetic association between them. The Bcl1 polymorphism in intron 2 of the glucocorticoid receptor (GR) gene has been associated with insulin resistance/hyperinsulinaemia. Our objective was to test the association of rs2918419, a T→C single nucleotide change in intron 2 downstream of the Bcl1 locus, with components of the metabolic syndrome and its interaction with the Bcl1 locus.

Design and methods We genotyped a subsample of 325 White subjects (116 men) in the Newcastle Heart Project (NHP), a population-based study in north-east England. Gender-specific statistical analysis by stepwise backward multiple regression was performed to test the association of allele status with adiposity, glucose and insulin responses to oral glucose tolerance test (OGTT), fasting lipids and blood pressure.

Results Minor allele frequency was 0·14 for rs2918419 and 0·39 for the Bcl1 polymorphism. rs2918419 was associated with higher fasting insulin concentration and insulin resistance in men but not in women. Contrary to earlier studies, the Bcl1 polymorphism on its own was not associated with insulin resistance/hyperinsulinaemia in either gender. Subjects carrying variant rs2918419 alleles also had variant alleles at the Bcl1 locus. In men, but not women, Bcl1 variant alleles on a background of rs2918419 wild-type alleles associated with lower fasting insulin compared to wild-type alleles at both loci or variant alleles at both loci.

Conclusions We report that rs2918419 was linked with hyperinsulinaemia and insulin resistance in men. Carrying Bcl1 variant alleles without rs2918419 was not associated with hyperinsulinaemia/insulin resistance. Previous reports of the association of Bcl1 polymorphism with obesity-related characteristics may reflect linkage disequilibrium with rs2918419.