Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index.

Abstract

Sensitivity to glucocorticoids differs between individuals, partially due to genetic variation in the glucocorticoid receptor (GR) gene. We studied the sequence alteration of a previously described intronic BclI polymorphism of the GR gene, and investigated whether there was an association with sensitivity to glucocorticoids and anthropometric parameters in a group of healthy elderly individuals. In study group 1, two overnight dexamethasone suppression tests (DSTs) were performed: with 1 mg dexamethasone, and 2.5 years later with 0.25 mg dexamethasone. Anthropometric parameters were measured in a larger population (study group 2), as well as in a third study group, in which we also measured body composition by dual-energy X-ray absorbtiometry (DEXA) scans. Groups 1 and 2, respectively, 191 and 1963 male and female participants of the Rotterdam study, a population-based study in Dutch elderly. Study group 3: 370 elderly males (mean age 77.8 +/- 0.2 years) from Zoetermeer, the Netherlands. We identified the BclI restriction site polymorphism as a C/G substitution in intron 2, 646 nucleotides downstream from exon 2. After both 1 mg and 0.25 mg DST, heterozygous (CG) and homozygous G-allele carriers (GG) had lower cortisol levels than CC-carriers (P = 0.01 and P = 0.02, respectively). In study group 2, we found a lower body mass index (BMI; P = 0.006) and waist-hip ratio (WHR; P = 0.02) in G-allele carriers. In study group 3, again we found a lower BMI (P = 0.05) in G-allele carriers. No differences were found in fat mass. However, lean mass tended to be lower in G-allele carriers (P = 0.07). We characterized a BclI-RFLP (restriction fragment length polymorphism) of the GR gene as a C/G polymorphism in intron 2 of which the G-allele was associated with hypersensitivity to glucocorticoids. This resulted in a lower BMI in older individuals in general, while our study in elderly males suggests that the lower BMI is probably due to a greater loss of lean mass during the ageing process.