A Common Genetic Variant in the 17alpha-Hydroxylase Gene Influences the Therapeutic Response to Steroidogenesis Inhibitors in Patients with Cushing's Syndrome

Presentation Number: OR02-6
Date of Presentation: April 4th, 2017

Elena Valassi*1, Anna Aulinas2, Camilla AM Glad3, Gudmundur Johannsson3, Oskar Ragnarsson3 and Susan M. Webb1
1Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 2Endocrinology/Medicine Departments, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 3Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and The Department of Endocrinology-Diabetes-Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden


Steroidogenesis inhibitors, such as ketoconazole (KTZ) and metyrapone (MTP), are used to lower circulating cortisol levels prior to surgery in patients with Cushing’s syndrome (CS). Nonetheless, normalization of cortisol concentrations is only reached in around half of patients treated with steroidogenesis inhibitors, possibly explained by inter-individual differences of common genetic variants in the genes affecting steroid synthesis. The aim of our study was to examine the influence of polymorphisms in genes involved in the adrenal steroid biosynthesis on the biochemical response to preoperative therapy with KTZ and/or MTP in previously untreated patients with CS. Fifty-four patients with CS [46 women; mean age 39.7±12.7 years, 83% with CD and 17% with an adrenal adenoma], treated with steroidogenesis inhibitors prior to surgery were evaluated. Thirty-seven percent of them were treated with MTP, 20% with KTZ, and 42% with a combination of both medications. All the CD patients subsequently underwent transsphenoidal surgery (TSS). Four single-nucleotide polymorphisms (SNPs) in three genes were analyzed using TaqMan SNP genotyping; rs6410 in the CYP11B1, rs4546 and rs1799998 in the CYP11B2, and rs6163 in the CYP17A1 genes. Genotyping success rate ranged between 95.2% and 98.4% and all SNPs conformed to the Hardy-Weinberg Equilibrium (Chi-square p>0.05). Control of hypercortisolism, as defined by normalization of urinary free cortisol (UFC; normal range, 50-280 nmol/24h), was achieved in 50% of patients after a median (interquartile range, IQR) duration of preoperative treatment with steroidogenesis inhibitors of 5 (5.3) months. The rs6163 SNP in the CYP17A1 gene was associated with pharmacological control of hypercortisolism. In particular, patients with the CC genotype were more likely to be controlled by medications as compared with AC/AA [OR 0.25 (95%CI, 0.075-0.88); p=0.031]. Thirteen of 18 patients (72%) who carried the CC genotype were controlled vs. 14/35 (40%) of those with the AC/AA genotypes (p=0.042). The remission rate in CD patients after TSS was 77%. The rs6163 SNP was inversely associated with postsurgical levels of UFC (β=-0.47, p=0.003) in CD patients, which remained significant after adjusting for preoperative UFC concentrations (p=0.042). Patients with the CC genotype had lower postoperative UFC concentrations than those with the AC/AA genotypes (39±21 vs. 430±590 nmol/24h, respectively; p=0.02). In conclusion, a polymorphism in the CYP17A1 gene was associated with the treatment response, as assessed by UFC, to steroidogenesis inhibitors in CS patients. In addition, the same genetic variant was a negative predictor of postoperative UFC levels in CD patients. Our data suggest that genetically based differences in the enzymes involved in the steroid biosynthesis may account for inter-individual variations in the response to steroidogenesis inhibitors.



Disclosure: GJ: Consultant, Viropharma, Consultant, Shire, Consultant, Astra Zeneca, Speaker, Ipsen, Speaker, Pfizer, Inc., Speaker, Merck Serono, Speaker, Novo Nordisk, Speaker, Novartis Pharmaceuticals, Speaker, Otsuka. Nothing to Disclose: EV, AA, CAG, OR, SMW