Genetic Predictors of Glucocorticoid Response in Pediatric Patients With Inflammatory Bowel Diseases

Iudicibus, Sara De; Stocco, Gabriele; Martelossi, Stefano; Londero, Margherita; Ebner, E; Pontillo, Alessandra; Lionetti, Paolo; Barabino, A.; Bartoli, Francesca; Ventura, Alessandro; Decorti, Giuliana

doi:10.1097/mcg.0b013e3181e8ae93

Cited by 56 publications

(58 citation statements)

References 49 publications

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“…A signifi cantly higher frequency of the Bcl I-mutated genotype was observed in the GC-responsive patients than in the GC-dependent group [ 74 ]. These results have been subsequently confi rmed in a larger cohort of young patients with IBD [ 88 ] (Table 1 ).…”

Section: Gr Gene Polymorphismssupporting

confidence: 49%

Glucocorticoids in Pediatric Gastrointestinal Disorders

Iudicibus

Martelossi

Decorti

2015

Systemic Corticosteroids for Inflammatory Disorders in Pediatrics

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Pediatric Inflammatory Bowel Disease\ud Inflammatory bowel diseases (IBDs) are the most frequent chronic gastrointestinal disorders in pediatric age. They include two disease entities – Crohn’s disease (CD) and ulcerative colitis (UC) – which, although different in their pathogenesis, show common clinical characteristics such as chronic inflammation at different levels of the gastrointestinal tract and alternation between active and inactive phases. The incidence of IBD is increasing in recent years, particularly among children and adolescents, and it is currently estimated that 20–30 % of patients with IBD experience the onset of symptoms when they are under 20 years of age [1–3]. In childhood, IBDs are gener- ally more extended, more severe, and progress more rapidly than in adulthood. Moreover, therapy in children with IBD is more aggressive than in adults: Indeed, about 80 % of children need steroids, and about 30 % are subjected to an intestinal resection during a 5-year follow-up. Quality of life is severely affected in IBD, espe- cially for pediatric patients, owing to the chronic character of the disease that implies frequent hospitalizations and aggressive therapies, with a significant risk of side effects and a considerable impact on health care costs. IBD can result in loss of education and difficulty in gaining employment or insurance; overall, 15 % of patients with IBD are unable to work after 5–10 years of disease. Depressive disorders and low social func- tioning are also common among these patients, and the disease can also cause growth failure or retarded sexual development in young people [4–7]. It was recently reported that the mean individual annual costs in European countries amount to US$6,000 for CD and $4,600 for UC, and pediatric cases cost even more than adult ones [8]

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Section: Gr Gene Polymorphismssupporting

confidence: 49%

Glucocorticoids in Pediatric Gastrointestinal Disorders

Iudicibus

Martelossi

Decorti

2015

Systemic Corticosteroids for Inflammatory Disorders in Pediatrics

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“…Clinical activity, inclusive of clinical and inflammatory markers evaluation, was assessed by 'Pediatric Crohn's Disease Activity Index' (PCDAI) for patients with CD, and by 'Pediatric Ulcerative Colitis Activity Index' (PUCAI) for patients with UC: clinical remission was defined as PCDAI < 10 or PUCAI < 10, while clinical improvement was defined as a reduction of at least 15 points from baseline score for PCDAI and of at least 20 points from baseline for PUCAI. Patients were classified on the basis of their clinical response into three groups: steroid-resistant (SR), patients who have active disease despite treatment with prednisone 2 mg/kg/day (max 50 mg/day) for 4 weeks; steroid-sensitive (SS) patients who did not relapse when therapy was discontinued after tapering and did not need GCs for at least 1 year, and steroid-dependent (SD) patients, who experienced disease relapse during steroid tapering or within 3 months after the steroid was stopped [21].…”

Section: Methodsmentioning

confidence: 99%

Role of the Long Non‐Coding RNA Growth Arrest‐Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease

Lucafò

Silvestre

Romano

et al. 2017

Basic Clin Pharma Tox

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Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side-effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non-coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, to confirm the sensitivity and specificity of these lncRNAs. These cells showed a different sensitivity to GCs and revealed differential expression of GAS5 after treatment. GAS5 was up-regulated in GC-resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knock-down reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up-regulation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy.Due to their anti-inflammatory and immunosuppressive properties, glucocorticoids (GCs) are widely used in the treatment of many inflammatory and autoimmune diseases [1,2]. In particular, they play a critical role in the treatment of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), where they are used to induce remission in patients with moderate to severe disease [3]. However, a considerable interindividual variability in GC response has been documented [4,5]: close to 20% of patients are resistant to these agents, while 40% of patients become dependent from GCs for maintaining clinical remission. Presently, there are no means to predict patients' response to GCs in advance [6,7].GCs diffuse across the cell membrane and exert their biological effects primarily by binding to the cytoplasmic GC receptor (GR) [8,9], which translocates into the nucleus and interacts, through its DNA-binding domain (DBD) [10,11], with steroid-responsive genes promoter regions known as GC responsive elements (GREs) [12][13][14].Recent reports have shown that the growth arrest-specific 5 (GAS5) gene encodes for a long non-coding RNA (lncRNA) which can act as a riborepressor of the GR [15]. In particular, GAS5 exon 12-derived sequence has been shown to structurally mimic the GREs, preventing the binding of the activated GR complex to its target DNA sequences [16].In previous studies conducted i...

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“…Concomitant occurrence of multiple autoimmune diseases in some patients is well known (3)(4)(5) and results from shared genetic and perhaps environmental risk factors among these different diseases (6)(7)(8). Polymorphisms of the nuclear localization leucine-rich-repeat protein 1 (NLRP1) gene encoding the NACHT (NAIP, CIITA, HET-E, TP1) domain of NLRP1 have been associated with a number of autoimmune diseases, including vitiligo (9, 10), Addison disease (11,12), type 1 diabetes (11), celiac disease (13), systemic lupus erythematosus (14), rheumatoid arthritis (15), systemic sclerosis (16), Kawasaki disease (17), as well as steroid responsiveness in inflammatory bowel disease (18), although the specific biological mechanism underlying these genetic associations remains unknown.…”

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confidence: 99%

NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome

Levandowski

Mailloux

Ferrara

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

196

132

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Nuclear localization leucine-rich-repeat protein 1 (NLRP1) is a key regulator of the innate immune system, particularly in the skin where, in response to molecular triggers such as pathogenassociated or damage-associated molecular patterns, the NLRP1 inflammasome promotes caspase-1-dependent processing of bioactive interleukin-1β (IL-1β), resulting in IL-1β secretion and downstream inflammatory responses. NLRP1 is genetically associated with risk of several autoimmune diseases including generalized vitiligo, Addison disease, type 1 diabetes, rheumatoid arthritis, and others. Here we identify a repertoire of variation in NLRP1 by deep DNA resequencing. Predicted functional variations in NLRP1 reside in several common high-risk haplotypes that differ from the reference by multiple nonsynonymous substitutions. The haplotypes that are high risk for disease share two substitutions, L155H and M1184V, and are inherited largely intact due to extensive linkage disequilibrium across the region. Functionally, we found that peripheral blood monocytes from healthy subjects homozygous for the predominant high-risk haplotype 2A processed significantly greater (P < 0.0001) amounts of the IL-1β precursor to mature bioactive IL-1β under basal (resting) conditions and in response to Toll-like receptor (TLR) agonists (TLR2 and TLR4) compared with monocytes from subjects homozygous for the reference haplotype 1. The increase in basal release was 1.8-fold greater in haplotype 2A monocytes, and these differences between the two haplotypes were consistently observed three times over a 3-mo period; no differences were observed for IL-1α or TNFα. NLRP1 RNA and protein levels were not altered by the predominant high-risk haplotype, indicating that altered function of the corresponding multivariant NLRP1 polypeptide predisposes to autoimmune diseases by activation of the NLRP1 inflammasome.cytokine | DNA sequencing | interleukin-1beta

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Genetic Predictors of Glucocorticoid Response in Pediatric Patients With Inflammatory Bowel Diseases

Abstract: 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.

Cited by 56 publications

References 49 publications

Glucocorticoids in Pediatric Gastrointestinal Disorders

Glucocorticoids in Pediatric Gastrointestinal Disorders

Role of the Long Non‐Coding RNA Growth Arrest‐Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease

NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome

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