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

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