Endocrine Abstracts

Objective: Glucocorticoids exert their effects through the glucocorticoid receptor (GR). The local, cell-type specific glucocorticoid effect is modulated by the 11β-hydroxysteroid dehydrogenase enzymes (HSD11B) responsible for the interconversion of cortisone and cortisol. Individual sensitivity against glucocorticoids and activity of the HSD11B enzymes are at least partly determined by genetic factors.

Aim: To test whether SNPs of GR and HSD11B1 genes (N363S-rs6195, BclI-rs41423247, A3669G-rs6198 of GR; and rs12086634, rs4844880 of HSD11B1) influence the glucocorticoid replacement dosage, and clinical/laboratory parameters in patients with Addison’s disease.

Patients and methods: 67 patients with primary adrenal insufficiency diagnosed and treated at the 2nd Department of Medicine, Semmelweis University were studied. Clinical, laboratory data, and the dosage of the hormone replacement therapy were collected. Peripheral blood DNA was isolated, and the GR gene SNPs were examined using allele-specific PCR (for BclI and N363S) or TaqMan assay on real-time PCR (for A3669G, rs12086634, and rs4844880). Genotype distribution was compared to those observed in the general Hungarian population using χ² or Fischer’ exact t-test. ANOVA followed by power analysis was used for association studies.

Results: The allele frequency of N363S polymorphism was higher in patients compared to the control group. Among GR gene SNPs only the Bcl1 polymorphism associated with BMI; the number of homozygous carriers was significantly higher than that of heterozygous carriers or non-carriers (P=0.007, power: 100%). The disease appeared significantly earlier in patients harboring A3669G SNP. The rs4844880 SNP associated with higher BMI and with higher bodyweight-adjusted glucocorticoid substitution dose, the disease developed in significantly later age in these patients. Annual decrease of bone mineral density, t-score and z-score at lumbal spine was significantly lower in carriers compared to non-carriers.

Conclusion: SNPs of GR and HSD11B1 genes may be important genetic factors in the pathogenesis and therapy-related morbidities in patients with primary adrenal insufficiency.

Disclosure: The authors acknowledge the financial support from Hungarian Scientific Research Fund (OTKA, PD100648 (A Patocs)) and Technology Innovation Fund, National Developmental Agency (KTIA-AIK-2012-12-1-0010).