Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia.

Glucocorticoids (GC) replacement are the mainstay treatment for 21-hydroxylase deficiency (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH), in its classical form. There are novel insights into the genetic basis of the GC action diversity that point to an important role for GC receptor (GR) gene polymorphisms, suggesting a possible modulation in occurrence of metabolic disorders, what may be relevant to clinical management of 21-OHD. The aim of this study was to investigate whether the five GR gene polymorphisms Tth111I, ER22, 23EK, BclI, 9ß (rs10052957, rs6189, rs6190, rs41423247, rs6198) and their combination into haplotypes are associated to different GC response in a cohort of classic 21-OHD subjects. GR genotype-phenotype associations were explored after a dexamethasone suppression test using very low-doses (VLD-DST), 20 and 40 µg/m². The final sample (n = 28) was selected based on the 102 individuals' previous genotypes classification, according to literature data of GC sensitivity or resistance. Thus, only patients with GC increased resistance (n = 18) or increased sensitivity (n = 10) profiles were selected. Out of 28 subjects aged 12 (2-34) years enrolled in this study, 75% were females, 75% presented the salt-wasting form (SW) and 25% the simple virilizing form (SV). Subjects who carried Tth111I and 9ß, associated or not to the ER22/23EK variants, showed an impaired DST response. Results did not differ significantly according to gender or body mass index. SV subjects with GC hypersensitivity-genotypes showed decreased average cortisol levels compared to those with GC resistance-genotypes (p = 0.0023). The Tth111I + 9ß/ Wild or Tth111I + ER22/23EK + 9ß/ Wild genotypes were associated to GC resistance in this population. This finding may be relevant given the challenges posed by therapeutic management with GC in CAH.

Glucocorticoid receptor Gene (NR3C1) Polymorphisms and Haplotypes in patients with congenital adrenal hyperplasia.

BACKGROUND: Lifelong glucocorticoid (GC) replacement is the mainstay treatment of congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency (21-OHD). Challenges posed by therapeutic management of these patients are well known, but novel insights into the variability in clinical response to GC highlight a role for single nucleotide polymorphisms (SNPs) of the glucocorticoid receptor gene (NR3C1). AIM: To assess whether six commonly studied NR3C1 SNPs, which were previously associated with modified response to GC, are associated with CAH. We further assessed the linkage disequilibrium (LD) among these NR3C1 SNPs and their combination into haplotypes. METHODS: Genotypes were determined by Taqman allele discrimination assays for Tth111I (rs10052957), ER22 (rs6189), 23 EK (rs6190), N363S (rs56149945), BclI (rs41423247) and 9ß (rs6198) in a Brazilian cohort of 102 unrelated 21-OHD patients and 163 unrelated healthy subjects (controls). Haplotypes were estimated using Haplo.stats, and LD among SNPs using Haploview. RESULTS: Heterozygous subjects for Tth111I were more frequent in 21-OHD patients (P = 0.004), while heterozygous for BclI were more frequent in controls (P = 0.049). We found a strong LD among the six NR3C1 SNPs, and four out of six common haplotypes contained the Tth111I-variant. Although we found no significant differences in overall haplotype analysis, the BclI-haplotype was less frequent among 21-OHD patients (P = 0.0180). CONCLUSIONS: BclI-haplotype was less common and heterozygous for Tth111I were more frequent in 21-OHD patients, while heterozygous for BclI were more frequent in controls. Our novel findings may contribute to further clinical studies on the prognostic value of NR3C1 haplotypes towards individualized treatment for 21-OHD patients.