MON-179 Association Between Long-Term Prednisolone Induced Adrenal Insufficiency and Polymorphisms in the Glucocorticoid Receptor Gene

Abstract

OBJECTIVE: Several biomarkers for glucocorticoid (GC) sensitivity have been proposed relevant for the inter-individual variation seen in treatment response and side effects to GC treatment. Four single nucleotide polymorphisms (SNPs) of the GC receptor (GR) gene have been associated with increased (Bcl1 and N363S) or decreased (9β and ER23/23EK) GC sensitivity. We investigated the influence of these proposed biomarkers for GC sensitivity on GC-induced adrenal insufficiency.SUBJECTS AND METHODS: We included 239 patients receiving long-term prednisolone treatment for rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) / giant cell arteritis (GCA), or after renal transplantation (RTx). Four GR gene SNPs (Bcl1 rs41423247; 9β rs6198; N363S rs56149945; ER22/23EK rs6189 + rs6190) were sequenced by Sanger sequencing. Adrenal function was evaluated by a 250 µg corticotropin stimulation test. To compare allele frequencies with background population, two control groups were generated from two regional whole-genome databases. We downscaled each genome dataset to 239 individuals/group to balance statistical analysis.RESULTS: In total 239 patients were genotyped and 178 of these (RA n=103, PMR/GCA n=47, RTx n=28) treated with a median current dose of 5 mg prednisolone/day (interquartile range 5-7 mg) and a median treatment duration of 48 months (interquartile range 22-111 months) completed the corticotropin test. Seventy-three (41%, CI95%: 34-48%) patients had an insufficient response to the corticotropin test. Neither the risk of adrenal insufficiency, unstimulated nor stimulated P-cortisol levels were directly associated with any of the GR SNPs. However, for both insensitive SNPs 9β and ER23/23EK the effect of current prednisolone dose on stimulated P-cortisol was smaller (higher dose did not suppress the cortisol level as much) in carriers vs. non-carriers (p=0.035 and p=0.0075). The same sensitivity-associated tendency was seen for the N363S, but not the Bcl1 SNP. The Bcl1 SNP occurred more frequently in our cohort compared with control groups (63% vs. 40%, p<0.0001). The same trend was seen for the other sensitive but less frequent SNP N363S. The 9β SNP also occurred more frequently in our cohort (18% vs. 13%, p=0.029), but depending on regional sub cohorts in one control group.CONCLUSION: The GR SNPs did not directly associate to the risk of adrenal insufficiency, unstimulated nor stimulated cortisol levels, respectively. However, the effect of prednisolone dose on stimulated cortisol depended on the GR SNPs: Cortisol was less suppressed with higher current prednisolone dose in patients carrying the insensitive SNPs. The substantially higher frequency of the Bcl1 SNP is remarkable even with modest n=239. It questions whether there is an association between carrying the sensitive GR SNPs and inability to taper GC treatment ending up in this cohort of long-term treated patients.