Abstract for presentation at 11th International Congress of Human Genetics

Haplotypes of the glucocorticoid receptor gene are associated with gene expression levels and modify the association between body size at birth and cortisol concentrations in adult life

  • Anna Rautanen, University of Helsinki, Department of Medical Genetics; Finnish Genome Center, Helsinki, Finland
  • Prof Johan Eriksson, National Public Health Institute, Department of Epidemiology; University of Helsinki, Department of Public Health, Finland
  • Prof Juha Kere, Department of Biosciences at Novum and Clinical Research Centre, Karolinska Institutet, Huddinge, Sweden
  • Sture Andersson, Hospital of Children and Adolescents, Helsinki University Central Hospital, Finland
  • Prof David Barker, Developmental Origins of Health and Disease Centre, University of Southapmton, United Kingdom
  • Dr Clive Osmond, Developmental Origins of Health and Disease Centre, University of Southapmton, United Kingdom
  • Dr David Phillips, Developmental Origins of Health and Disease Centre, University of Southapmton, United Kingdom
  • Dr Eero Kajantie, National Public Health Institute, Department of Epidemiology, Finland

    • Background: Small size at birth is associated with common adult diseases such as type 2 diabetes and coronary heart disease. Programming of the regulation and function of glucocorticoids by conditions during early life has been suggested to play a key role in explaining this link.
    Aim: We assessed whether variation in the Glucocorticoid receptor gene (GR) mediates or modifies the association of small body size at birth with adult hypothalamic-pituitary-adrenal axis (HPAA) function.
    Methods/Results: Study subjects (163 men and 274 women) were selected from the Helsinki Birth Cohort of 7086 individuals born in Helsinki, Finland, between 1924-1933, whose birth measurements as well as extensive current metabolic phenotypes were recorded. We genotyped haplotype tagging single nucleotide polymorphisms (SNPs) of the GR locus, and constructed the haplotypes with a SNPHAP software. The type 2 haplotype, apparently the most diverged from the others, was associated with lower birth weight (P=0.02) and length (P=0.01). The association of short length at birth with increased fasting serum total cortisol (P=0.02) and free cortisol index (P=0.02) was confined to carriers of type 2 haplotype (p for interaction haplotype*length at birth=0.06 for total and 0.01 for free cortisol index). Since there are no amino acid changing SNPs in the type 2 haplotype, we assessed whether there was haplotype 2 specific variation in transcription level by sequencing individuals with heterozygous silent SNP tagging the haplotype 2 and comparing the allele peak height ratios between mRNA and genomic DNA samples.
    Conclusions: The transcription level of haplotype 2 was shown to be 93.7% of that of the other haplotypes (P=3x10-4). Our data suggest that the GR locus may contribute to the association of small birth size and HPAA function by a mechanism affecting regulation of GR expression.

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