Glucocorticoid receptor polymorphisms rs6198 and rs41423247 and hydrocortisone dose in Addison's disease

Glucocorticoid receptor (GR) single nucleotide polymorphisms (SNP) may have an impact on clinical outcome parameters in patients with autoimmune Addison's disease (AAD). The GR-SNP rs6198 is associated with a relative GR-resistance to cortisol whereas the GR-SNP rs41423247 appears to increase sensitivity. Aim of this study was to determine the role of the GR-SNPs in German AAD patients in relation to daily Hydrocortisone (HC) -dose and Body mass index (BMI). AAD patients (n = 370, females (f)= 255, males (m)= 107) and healthy controls (HC; n = 372, f = 172, m = 200) were genotyped for rs6198 using real time PCR method and for rs41423247 by restriction fragment length polymorphism. Clinical parameters were collected by a questionnaire. Three groups were analyzed: HC dose < 20 mg low dose, 20 – 30 mg average dose, > 30 mg high dose; and BMI: < 18,5 underweight, 18,5 – 24,9 normal weight, 25 – 29.9 overweight, > 29.9 obesity. The case-control comparison showed no difference in both SNPs. However, in AAD patients with a low daily HC-dose the rs6198 homozygosity AA showed a trend to be more frequent than in HC while AG was found less frequently (p_genotype= 0.11). Beyond that the same AAD patients showed a trend to carry AA more frequently as well, compared to AAD patients with an average or high HCS-dose (p_genotype= 0.8). After subdividing AAD patients into males and females, male overweight AAD patients showed to be more frequently homozygous GG of rs41423247 HC (p_genotype= 0.03). The allele frequency G was carried more frequently in male overweight AAD patients than the allele C (p_allele= 0.006) compared to HC. Our data suggest that the GR-SNP rs6198 may influence the sensitivity to HC-treatment in male AAD patients to gain weight. These observations extend the concept of pharmacogenomic variation under glucocorticoid treatment and may lead to individualized treatment strategies in AAD.