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A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome
Author(s) -
Valassi Elena,
Aulinas Anna,
Glad Camilla AM,
Johannsson Gudmundur,
Ragnarsson Oskar,
Webb Susan M
Publication year - 2017
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.13414
Subject(s) - medicine , endocrinology , ketoconazole , interquartile range , snp , cushing syndrome , single nucleotide polymorphism , genotype , metyrapone , cushing's disease , adrenalectomy , gastroenterology , cyp17a1 , biology , gene , disease , genetics , antifungal , dermatology
Summary 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 ( SNP s) were analysed: rs6410 ( CYP 11B1 gene), rs1799998 and rs4546 ( CYP 11B2 gene), and rs6163 ( CYP 17A1 gene). The associations between SNP s 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 CYP 17A1 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.