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

J Clin Endocrinol Metab. 2006 Nov;91(11):4544-51. doi: 10.1210/jc.2006-1065. Epub 2006 Aug 8.


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-pituitary-adrenal 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Birth Weight / physiology*
  • Blood Glucose / analysis
  • Body Size / physiology*
  • Cohort Studies
  • DNA Mutational Analysis
  • Female
  • Gene Frequency
  • Glucose Intolerance / epidemiology*
  • Glucose Tolerance Test
  • Haplotypes*
  • Humans
  • Hydrocortisone / analysis*
  • Hypothalamo-Hypophyseal System / physiology
  • Male
  • Molecular Sequence Data
  • Pituitary-Adrenal Function Tests
  • Pituitary-Adrenal System / physiology
  • Receptors, Glucocorticoid / genetics*
  • Receptors, Glucocorticoid / physiology
  • Saliva / chemistry


  • Blood Glucose
  • Receptors, Glucocorticoid
  • Hydrocortisone