Background: Cortisol availability to target tissues represents a complex interplay of synthesis, secretion, metabolism and excretion. A number of these processes are regulated by enzymes that are encoded by genes that are key candidates in determining the metabolic and cardiovascular phenotype in man. Measurement of a range of corticosteroid metabolites allows the activity of these enzymes to be inferred. We have studied the pattern of cortisol metabolite excretion in a large collection of nuclear families in order to examine the heritability of enzyme activity.
Methods: 573 individuals from 105 extended families ascertained through a hypertensive proband were studied. Excretion of corticosteroid metabolites [tetrahydrocortisol (THF), allo-THF, tetrahydrocortisone in 24-hour urine collections was measured by GCMS. Heritability of steroid phenotypes was determined by the MERLIN programme.
Results: There were significant differences in the heritability of different steroid phenotypes. Heritability for THE was 30.5%, for THF 36.5%, for allo-THF 42.2%, and for the ratio (THF + allo-THF)/THE 55.1
Discussion: The levels of the principal urinary metabolites of cortisol were found to be heritable, with the ratio of allo-THF+THF/THE, which acts as a marker of 11betaHSD1 activity, showing the strongest effect. This suggests that the variation on this activity is genetically determined. The enzyme regenerates cortisol from cortisone in a number of key target tissues, including adipose and liver and may be important in the pathogenesis of obesity and metabolic disease. These data suggest that genetic variation can influence this phenotype in a normal population.
24 - 26 Mar 2003
British Endocrine Societies