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


METHODS
We conducted a birth cohort study that included 437 men and women born in Helsinki, Finland, during 1924-1933, whose birth measurements were recorded.


METHODS
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.
Rautanen
Anna
A
Department of Medical Genetics, University of Helsinki, FIN-00014 Helsinki, Finland.
Eriksson
Johan G
JG
Kere
Juha
J
Andersson
Sture
S
Osmond
Clive
C
Tienari
Pentti
P
Sairanen
Heikki
H
Barker
David J P
DJ
Phillips
David I W
DI
Forsén
Tom
T
Kajantie
Eero
E
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001724:Birth Weight / Q000502:physiology*; D001786:Blood Glucose / Q000032:analysis; D049628:Body Size / Q000502:physiology*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D018149:Glucose Intolerance / Q000453:epidemiology*; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D010912:Pituitary-Adrenal Function Tests; D010913:Pituitary-Adrenal System / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000502:physiology; D012463:Saliva / Q000737:chemistry
D001786:Blood Glucose; D011965:Receptors, Glucocorticoid; D006854:Hydrocortisone