Avaliação da sensibilidade ao glicocorticoide em pacientes com Hiperplasia Adrenal Congênita

Abstract

Substitutive glucocorticoid (GC) long-term replacement serves as mainstay treatment of Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (D-21OH) in its classical form. There is great variability in the GC response and part of this variation could be explained by glucocorticoid receptor (GR) gene polymorphisms. The most studied GR gene polymorphisms (Tth111I, ER22, 23EK, N363S, BclI and 9β) are inherited in haplotypes and could lead to a GC response spectrum. Thereby, we studied the frequency of the GR polymorphisms (rs10052957, rs6189, rs6190, rs56149945, rs41423247, rs6198), with a case-control approach and subsequently explored genotype-phenotype correlations. The population of interest was composed of 102 subjects with 21OHD-classical form, recruited in 2016, at Hospital das Clínicas (HC-UFMG) endocrinology care centre; and 163 healthy controls. Strong linkage disequilibrium was seen between all polymorphisms. Heterozygous-Tth111I occurred more commonly amongst cases (p=0.004), while heterozygous-BclI was more common amongst controls (p=0.078). There were no statistical differences in overall haplotype frequencies, except for haplotype 4 (BclI), which occurred less commonly amongst cases (p=0.01795). Six main haplotypes were determined: Wild (55.3%); Tth111I + BclI (13.2%); Tth111I + 9β (12.3%); BclI (11.3%); Tth111I (3.4%); Tth111I + ER22/23EK + 9β (2.5%); it should be noted that four of them presented the Tth111I-variant. A subsample of cases was submitted to the very-low dose dexamethasone suppression test: 9 children, 9 adolescents, 10 adults, with a median age of 12 (2-34) years; 21 (75%) females, 7 (25%) males; 21 (75%) with the salt-wasting form (SW) and 7 (25%) with the simple virilizing form (SV). Carries of the Tth111I and 9β-variants, whether or not associated with the ER22/23EK- variants, showed less cortisol suppression, compared to BclI-carriers (p=0.098). Salt-wasting subjects had less cortisol suppression, compared to simple-virilizing (p<0.001). SV subjects with GC hypersensitivity-genotypes showed decreased average cortisol levels compared to those with GC resistance-genotypes (p=0.0023). Children younger than 10 years presented more cortisol suppression compared to adolescents and adults (p=0.035). The pharmacogenomic profile might help to predict the GC response and contribute to the discussion of a more individualized therapy, resulting in better long-term clinical outcomes.