Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases.
BACKGROUND
Glucocorticoids (GCs) are used in moderate-to-severe inflammatory bowel diseases (IBD) but their effect is often unpredictable.


OBJECTIVE
To determine the influence of 4 polymorphisms in the GC receptor [nuclear receptor subfamily 3, group C, member 1 (NR3C1)], interleukin-1β (IL-1β), and NACHT leucine-rich-repeat protein 1 (NALP1) genes, on the clinical response to steroids in pediatric patients with IBD.


METHODS
One hundred fifty-four young IBD patients treated with GCs for at least 30 days and with a minimum follow-up of 1 year were genotyped. The polymorphisms considered are the BclI in the NR3C1 gene, C-511T in IL-1β gene, and Leu155His and rs2670660/C in NALP1 gene. Patients were grouped as responder, dependant, and resistant to GCs. The relation between GC response and the genetic polymorphisms considered was examined using univariate, multivariate, and Classification and Regression Tree (CART) analysis.


RESULTS
Univariate analysis showed that BclI polymorphism was more frequent in responders compared with dependant patients (P=0.03) and with the combined dependant and resistant groups (P=0.02). Moreover, the NALP1 Leu155His polymorphism was less frequent in the GC responsive group compared with resistant (P=0.0059) and nonresponder (P=0.02) groups. Multivariate analysis comparing responders and nonresponders confirmed an association between BclI mutated genotype and steroid response (P=0.030), and between NALP1 Leu155His mutant variant and nonresponders (P=0.033). An association between steroid response and male sex was also observed (P=0.034). In addition, Leu155His mutated genotype was associated with steroid resistance (P=0.034). Two CART analyses supported these findings by showing that BclI and Leu155His polymorphisms had the greatest effect on steroid response (permutation P value=0.046). The second CART analysis also identified age of disease onset and male sex as important variables affecting response.


CONCLUSIONS
These results confirm that genetic and demographic factors may affect the response to GCs in young patients with IBD and strengthen the importance of studying high-order interactions for predicting response.
De Iudicibus
Sara
S
Department of Life Sciences, University of Trieste, Trieste, Italy.
Stocco
Gabriele
G
Martelossi
Stefano
S
Londero
Margherita
M
Ebner
Egle
E
Pontillo
Alessandra
A
Lionetti
Paolo
P
Barabino
Arrigo
A
Bartoli
Fiora
F
Ventura
Alessandro
A
Decorti
Giuliana
G
D000293:Adolescent; D002648:Child; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012044:Regression Analysis; D012189:Retrospective Studies; D012737:Sex Factors; D016896:Treatment Outcome
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid