Endocrine Abstracts

Introduction: Polymorphisms of the glucocorticoid (NR3C1) and mineralocorticoid receptor (NR3C2) have been linked to the regulation of HPA-axis and to glucocorticoid sensitivity. We investigated whether NR3C1 and NR3C2 polymorphisms correlate with the occurence of adrenal crises (AC) in patients with primary adrenal insufficiency (PAI).

Material and methods: We investigated 100 patients with PAI (70% women, mean age 51±15 years). DNA was extracted from whole-blood and NR3C1 and NR3C2 polymorphisms were genotyped by PCR and MALDI-TOFF mass spectrometry. Results were correlated with history of AC (number of events since first diagnosis and number of events per patient years), replacement therapy, HbA1c and 24-h blood pressure profile.

Results: Three NR3C1 polymorphisms (rs6198, rs17100289, rs4912911) and one NR3C2 (rs5522) polymorphism were significantly associated with a higher prevalence of AC. For NR3C1 rs6198, AC occured more often in C allele carriers (66% CC/CT vs 44% TT, P=0.04, OR 2.5 95% CI 1.0-6.0). For NR3C1 rs17100289, patients with AA genotype experienced more frequent AC (61% AA vs 40% TT/TA, P=003, OR 2.4 95% CI 1.0-5.5) and exhibited lower HbA1c levels (5.3 (4.8-8.2) AA vs 5.7 (4.6-8.1) TT/TA, P=0.03) and higher degrees of noctural blood pressure dipping (-14% (-26, -5) AA vs -8% (-19, 7) TT/TA, P=0.02). For NR3C1 rs4912911, AC occured more often within AA genotype (61% AA vs 38% GA/GG, P=0.021, OR 2.6 95% CI 1.1-5.8). For NR3C2 rs5522, AC occured more often in C allele carriers (74% TC/CC vs 44% TT, P=0.02, OR 3.5 95%CI 1.2-10.6).

Conclusion: We identified several NR3C1 and NR3C2 polymorphisms that are associated with a higher incidence of AC. The identified NR3C1 polymorphisms have been shown to decrease glucocorticoid sensitivity, whereas NR3C2 rs5522 seems to interfere with the glucocorticoid stress response. Our preliminary data suggests that inter-individual differences in glucocorticoid sensitivity may contribute to increased susceptibility to AC.