GLUCOCORTICOID RECEPTOR POLYMORPHISM, SKIN VASOCONSTRICTION, AND OTHER METABOLIC INTERMEDIATE PHENOTYPES IN NORMAL HUMAN-SUBJECTS

Genetic variation of the glucocorticoid receptor (GR) locus is associa ted with differences in blood pressure. To define the intermediate phe notypes associated with this variation, we investigated the biochemica l and clinical significance of a BclI restriction fragment length poly morphism of the GR locus in 64 normal male volunteers. Blood samples w ere genotyped as either AA (homozygous large allele; n = 6), Aa (heter ozygous; n = 51), or aa (homozygous small allele, n = 7). Four primary glucocorticoid variables were measured including GR binding character istics and glucocorticoid-sensitive lysozyme release of leukocytes in, vitro and the blanching response of forearm skin to budesonide. A lar ge number of secondary variables (urinary and plasma steroid measureme nts,blood pressure and indices of body fat metabolism, and routine bio chemical and hematological measurements) were also considered. lit viv o sensitivity to budesonide was greater in AA than aa individuals (mea n +/- SE EC50 values: 13 +/- 5 and 42 +/- 10 ng; P < 0.01). In contras t, leukocytes of AA subjects tended to have lower affinity and reduced sensitivity for dexamethasone, although these effects were not statis tically significant. Based on urinary steroid measurements, 11 beta-hy droxysteroid dehydrogenase activity [ratio of tetrahydrocortisol (THF) to tetrahydrocortisone (THE) metabolites] was not affected by genotyp e. The relative activities of 5 alpha- and 5 beta-reductase activity ( allo-THF/THF + THE) appeared lower in AA than aa subjects (0.22 +/- 0. 04 cf: 0.33 +/- 0.06; P < 0.005) but were not judged to be significant ly different when corrected for multiple comparisons. Single and multi variate analyses were carried out to determine which variables influen ce GR binding characteristics and glucocorticoid responsiveness and to see whether cardiovascular risk factors (blood pressure and body fat) were influenced by glucocorticoid-dependent functions. Only 15-20% of the variations in the dissociation constant (K-d) and maximum binding capacity (B-max) were influenced by other variables; plasma cholester ol was the most important for affinity and plasma sodium concentration for binding capacity. Multivariate analysis showed that several facto rs including GR genotype and urinary cortisol account for 10% of the v ariation of in vivo responses to glucocorticoid hormones; plasma calci um concentration was the only variable that contributed to in vitro se nsitivity of leukocytes to dexamethasone. Glucocorticoid-dependent res ponses were of negligible importance in determining blood pressure or percentage body fat within the narrow physiological ranges of the pres ent study. We conclude that GR genotype affects steroid sensitivity in a tissue-specific manner because of altered GR function or possibly b ecause of linkage to a locus that controls hormone access to the recep tor by influencing steroid metabolism.