Associations of body size at birth with late-life cortisol concentrations and glucose tolerance are modified by haplotypes of the glucocorticoid receptor gene

Context: Small body size at birth is associated with cardiovascular disease and type 2 diabetes in adult life. This link may be in part mediated by early-life programming of the hypothalamic-pituitaryadrenal axis (HPAA) function. Objective: Our objective was to assess whether haplotypes of the glucocorticoid receptor (GR) gene modify this link. Design and Participants: We conducted a birth cohort study that included 437 men and women born in Helsinki, Finland, during 1924 1933, whose birth measurements were recorded. Main Outcome Measures: We studied how the oral glucose tolerance test and fasting plasma total and free cortisol concentrations and, in a subset of 162 women, a more detailed HPAA evaluation, are predicted by body size at birth and haplotypes of the GR locus. We also measured the haplotype-specific relative mRNA expression level for the haplotype of interest. Results: One of the haplotypes was associated with lower birth weight and length and higher fasting plasma and mean 24-h salivary cortisol. Moreover, this haplotype modified the association of length at birth with adult phenotypes; in carriers, short length at birth was associated with increased fasting plasma cortisol, cortisol/corticosteroid-binding globulin ratio, impaired glucose tolerance or diabetes [1 cm decrease corresponded to 1.36-fold odds ratio; 95% confidence interval (CI), 1.09-1.70; P = 0.007], and higher 120-min glucose (5.8%; 95% CI, 2.5-9.1%; P = 0.0007), but no association was seen in noncarriers (P for interaction was 0.06, 0.01, 0.02, and 0.01, respectively). The mRNA expression level of this haplotype was 93.7% (95% CI, 90.5 - 96.8%; P = 2.2 x 10(-4)) of the expression level of the other haplotypes. Conclusions: A common GR haplotype may contribute to and modify the association of short length at birth with adult glucose tolerance and HPAA function by a mechanism that affects regulation of GR expression.