BclI glucocorticoid receptor polymorphism is associated with greater body fatness: the Hoorn and CODAM studies.

Abstract

The BclI polymorphism in the glucocorticoid receptor (GR) gene is associated with enhanced glucocorticoid (GC) sensitivity. Our objective was to investigate the association of the BclI polymorphism with body fatness and insulin resistance. We conducted an observational cohort study, combining data from 2 cohort studies enriched with individuals with impaired glucose metabolism and/or diabetes mellitus type 2 (DM2). We examined 1228 participants (mean age 64.7 years, 45% women) from the Cohort Study on Diabetes and Atherosclerosis Maastricht (CODAM, n = 543) and the Hoorn Study (n = 685). Body mass index (BMI), waist and hip circumferences, and waist-to-hip ratio (WHR) were obtained; insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA2-IR). We identified 519 noncarriers (CC), 540 heterozygous (CG) carriers, and 169 homozygous (GG) carriers of the G-allele of the BclI polymorphism. Homozygous carriers had a higher BMI (28.9 vs 27.9 kg/m(2)) and waist (99.6 vs 97.2 cm) and hip (105.5 vs 103.2 cm) circumference compared with noncarriers, also after adjustment for age, sex, cohort, glucose tolerance, and lifestyle risk factors: β = 0.94 kg/m(2) (95% confidence interval, 0.24-1.63), β = 2.84 cm (0.95;4.73) and β = 2.38 cm (0.88-3.87), respectively. Similar results were obtained when comparing homozygous carriers with heterozygous carriers: β = 1.03 kg/m(2) (0.34-1.72), β = 2.20 cm (0.31-4.08) and β = 1.99 cm (0.51-3.48), respectively. There were no differences in WHR. Ln-HOMA2-IR was higher in GG carriers compared with CG carriers; 0.29 vs 0.17 [β = 0.09 (0.01-0.17)], but this effect was attenuated after adjustment for BMI [β = 0.04 (-0.04 to 0.11)]. Homozygous carriers of the BclI polymorphism of the GR gene have significantly greater total body fatness, contributing to higher HOMA2-IR, compared with heterozygous carriers and noncarriers.