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SAT-346 POR Rs2286822 Polymorphism Is Associated with Clinical Features in Patients with Congenital Adrenal Hyperplasia Due to 21 Hydroxylase Deficiency

ABSTRACT: Abstract Patients with congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency present a strong genotype-phenotype correlation but variability in clinical features among patients carrying similar CYP21A2 mutations suggests that polygenic traits contribute to the phenotype. Aim of the present study is to evaluate whether polymorphisms in P450 oxoreductase (POR), a microsomal cofactor to 21 hydroxylase, contribute to the phenotype of patients with CYP21A2 mutations. Methods: Leukocyte DNA from 97 patients with CAH (49 classic, 48 non classic) due to CYP21A2 mutations and 43 control subjects were sequenced for POR, gene variants identified and their association with clinical features 21-hydroxylase deficiency assessed. Results: Several intronic and exonic variants in POR were identified, all in Hardy-Weinberg equilibrium in controls. Interestingly, patients with classic CAH carrying the rs2286822 polymorphism (CT/TT vs CC in intron 11) presented more severe Prader stage (81 vs 67%, p<0.05), higher prevalence of salt wasting (19 vs 0%, p<0.05), higher plasma ACTH levels (437 ± 85.3 vs 140 ± 18.1 pg/ml, p<0.05) at birth and both males and females were started earlier on steroid therapy (12 vs 23 days after birth, p<0.05) compared to wildtype. Conclusions: Our study shows that the POR rs2286822 polymorphism is associated with a more severe clinical presentation in patients with classic CAH due to 21 hydroxylase mutations. Of note, in vitro studies have shown that this polymorphism impacts POR activity in liver (1). Altogether, this evidence suggests that POR polymorphisms may contribute to clinical features in classic CAH. References (1) Zhang et al. Drug Metab Disp 44:1193-1200, 2016

SUBMITTER: Pecori Giraldi F

PROVIDER: S-EPMC6551646 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking.The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH.We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort.CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups.In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

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SAT-346 POR Rs2286822 Polymorphism Is Associated with Clinical Features in Patients with Congenital Adrenal Hyperplasia Due to 21 Hydroxylase Deficiency

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