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- Title
A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome.
- Authors
Valassi, Elena; Aulinas, Anna; Glad, Camilla AM; Johannsson, Gudmundur; Ragnarsson, Oskar; Webb, Susan M
- Abstract
Context Steroidogenesis inhibitors, such as ketoconazole ( KTZ) and metyrapone ( MTP), are used to lower hypercortisolism in patients with Cushing's syndrome ( CS). Cortisol normalization is not reached in all patients taking these medications. Objective To test the hypothesis that variants in genes affecting steroidogenesis contribute to different responses to KTZ and/or MTP in patients with CS. Patients and methods Fifty-four CS patients (46 women; mean [± SD] age, 39.7±12.7; 83% with Cushing's disease [ CD] and 17% with an adrenal adenoma) preoperatively treated with KTZ (20%), MTP (37%) or a combination of both (43%). Thirty-nine of these (72%) were described in a previous study investigating the outcome of preoperative treatment with KTZ or MTP in CS patients. Following single-nucleotide polymorphisms ( SNPs) were analysed: rs6410 ( CYP11B1 gene), rs1799998 and rs4546 ( CYP11B2 gene), and rs6163 ( CYP17A1 gene). The associations between SNPs and cortisol levels at the end of medical treatment were evaluated. Results Normalization of urinary free cortisol ( UFC) was achieved in 50% of patients after 5 months of treatment. Patients carrying the CC genotype of SNP rs6163 were more likely to be controlled than AC/ AA ( OR 0.25 [95% CI, 0.075-0.88]; P=.031). When only patients reaching eucortisolism after medical treatment were analysed, median interquartile range ( IQR) duration of treatment was shorter in patients carrying the CC genotype of SNP rs6163 as compared to AA/ AC carriers (4 [4.57] months vs 5.2 [6.1] months; P=.026). Conclusions A polymorphism in the CYP17A1 gene was associated with the response to steroidogenesis inhibitors in CS. Genetic differences in the steroidogenic enzymes might account for inter-individual variations in the responsiveness to adrenal-blocking agents.
- Subjects
KETOCONAZOLE; ANTIFUNGAL agents; PIPERAZINE; METOPIRONE; CUSHING'S syndrome
- Publication
Clinical Endocrinology, 2017, Vol 87, Issue 5, p433
- ISSN
0300-0664
- Publication type
Article
- DOI
10.1111/cen.13414