The impact of genetic factors on response to glucocorticoids therapy in IBD

Abstract

Glucocorticosteroids (GCs) are used for many years as first-line drugs for the achievement of remission in exacerbations of inflammatory bowel disease (IBD). However, close to 20% of patients are resistant to GCs, and 40% of patients become dependent on GCs. The challenge of today's personalized medicine is the anticipation of the steroid therapy effects even before the initiation of treatment. As several studies show, individually variable response to GCs in population has a genetic background and may depend on gene variability encoding proteins involved in the function and metabolism of GCs. To those genes belong: NR3C1--responsible for the synthesis of GC receptor (GR); Hsp90, HSP70, STIP1, FKB5--genes of GR protein complex; ABCB1 and IPO13 coding glycoprotein p170; and importin 13--involved in GCs transport; IL1A, IL1B, IL2, IL4, IL8, IL10, TNF, and MIF--genes of the epithelial pro-inflammatory factors synthesis, which excessive activation causes steroid resistance as well as CYP3A4 and CYP3A5--encoding GCs biotransformation enzymes. This work systematizes and sums up the state of current knowledge in the field of pharmacogenetics as well as expectations for the future in the realm of individualized medicine in IBD patients treated with GC drugs.

Immunopathology alters Th17 cell glucocorticoid sensitivity

“…While glucocorticoids are effective to control exacerbations and induce remission of Crohn's disease in the majority of patients, approximately 20% of patients with Crohn's disease are resistant to glucocorticoids (Table ). Elevated Th17 cells and increased IL‐17A levels have been found in lesions of Crohn's disease .…”

NGS study of glucocorticoids response genes in inflammatory bowel disease patients

“…Variants in the remaining studied 7 genes that were studied (IL-1B, IL-2, IL-10, IL-4, JUN, CYP3A4, IPO13) did not meet these selection criteria and were not qualified for further analysis. Moreover, in the literature described in response to the GCS context, the loci in the NR3C1 (c.1184+646C>G and p.Asn767Asn), ABCB1 (c.2685+49T>C, p.Gly412Gly and p.Ile1145Ile) and TNF (c.-308G>A and c.-238G>A) genes were also included [11]. The highest average number of NGS reads (above 400×) was observed for variants p.Cys13Ser (rs61745470) and p.Met71Leu (rs8005905) of the HSPA4 and HSP90AA genes, respectively.…”

“…Although the reason for the differential response is multifactorial, including disease severity and complications, as well as environmental factors, it can be expected that the genetic component plays the most crucial role, which is estimated at up to 95% [9,10]. To date, most pharmacogenetic research on GCs has indicated the NR3C1 gene coding for the GCs receptor (GR) protein and the ABCB1 gene responsible for synthesis of the multidrug resistance protein 1a membrane GC efflux transporter whose overexpression results in decreased cytoplasmic GC concentration [11,12]. Fewer GC response studies also concern the participation of the FKBP5, TNF, and NLRP1 genes coding for co-chaperone 51 kDa FK506-binding protein (FKBP-51), tumor necrosis factor (TNF) and NACHT, LRR and PYD domain-containing protein 1, respectively [13][14][15][16].…”

“…Polymorphisms in genes involved in the nuclear transport factors (importin IPO13) or in the metabolism of these hormones, i.e. cytochromes P450 (CYP3A4, CYP3A5), have also been suggested as other possible candidates of GC response modulators [11]. On the one hand, science emphasizes the role of genetics in predicting GCs' clinical reactions and on the other hand, practice indicates the need of personalized medicine for improving the GC efficacy and safety rates [9,13].…”

Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies

“…A review has proposed different markers associated with steroid therapy outcomes in patients with IBD 21. The most-studied molecule is the multidrug-resistant (MDR1) gene code for a drug efflux pump P-glycoprotein-170 (permeability glycoprotein or Pgp), which is expressed on the apical surface of lymphocytes and intestinal epithelial cells.…”