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Associations of Body Size at Birth with Late-Life Cortisol Concentrations and Glucose Tolerance Are Modified by Haplotypes of the Glucocorticoid Receptor Gene

Departments of Medical Genetics (A.R., J.K.) and Neurology (P.T.), Biomedicum Helsinki, Finnish Genome Center (A.R.), and Department of Public Health (J.G.E.), University of Helsinki, FIN-00014 Helsinki, Finland; Department of Epidemiology and Health Promotion (A.R., J.G.E., T.F., E.K.), National Public Health Institute, FIN-00300 Helsinki, Finland; Department of Biosciences and Nutrition and Clinical Research Center (J.K.), Karolinska Institutet, SE-14157 Huddinge, Sweden; Hospital for Children and Adolescents (S.A., H.S., E.K.), Helsinki University Central Hospital, FIN-00029 HUS Helsinki, Finland; and Medical Research Council Epidemiology Resource Centre (C.O.) and Developmental Origins of Health and Disease Centre (D.J.P.B., D.I.W.P.), University of Southampton, Southampton SO16 6YD, United Kingdom

Address all correspondence and requests for reprints to: Eero Kajantie, M.D., Ph.D., Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail: eero.kajantie{at}helsinki.fi.

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.

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