Pediatric Crohn's Disease and Growth Retardation: The Role of Genotype, Phenotype, and Disease Severity

Wine, Eytan; Reif, Shimon; Leshinsky‐Silver, Esther; Weiss, B; Shaoul, Ron; Shamir, Raanan; Wasserman, Dror; Lerner, Aaron; Boaz, Mona; Levine, Arie

doi:10.1542/peds.2004-0417

Cited by 78 publications

(69 citation statements)

References 36 publications

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“…The IL-6 -174 genotype conferred no propensity toward developing the disease, confirming other work describing a lack of association of the IL-6 gene with Crohn's disease (51). This effect of the IL-6 promoter is in marked contrast to polymorphisms in the NOD-2 gene which are increased in Crohn's disease (52,53), yet do not affect growth (54).…”

Section: Discussionsupporting

confidence: 79%

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Sawczenko

Azooz

Paraszczuk

et al. 2005

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

111

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Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzenesulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P ‫؍‬ 0.023) and increased IGF-I (P ‫؍‬ 0.05). In humans, the IL-6 ؊174 G͞C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 ؊174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growthretarded than those with the GC or CC genotypes (height SD score, ؊0.51 vs. ؊0.10; P ‫؍‬ 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg͞dl, P ‫؍‬ 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P ‫؍‬ 0.7). Thus, the IL-6 ؊174 genotype mediates growth failure in children with Crohn's disease.Crohn's disease ͉ height ͉ insulin-like growth factor I ͉ C-reactive protein ͉ food intake

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Section: Discussionsupporting

confidence: 79%

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Sawczenko

Azooz

Paraszczuk

et al. 2005

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

111

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“…Reports of pediatric series to date available have been limited to mainly CARD15 variants [11][12][13][14][15][16][17][18][19] , small number of subjects [11,12,15,16,18,19] , and scarce information on UC patients [13,15,41] . T he car riag e rate of CARD15 variants in our pediatric population was 38% for CD patients and 20% for UC patients, not significantly different from figures in adult Italian population (36% for CD and 15% for UC, respectively) [51] .…”

Section: Discussionmentioning

confidence: 99%

“…Paradoxically, in contrast to the data in adults, there are studies mainly looking at CARD15 polymorphisms [11][12][13][14][15][16][17][18][19]40] , while being scarce and conflicting on OCTN1/2 and DLG5 genes [41][42][43][44] . Moreover, many pediatric series are flawed by a small sample size [11,12,15,16,18,19,43,44] , little information on UC patients [13,15,41] , and lack of control populations [11,12,16,17,19] . In this study we have investigated the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in IBD predisposition in a large Italian pediatric cohort.…”

Section: Concerning the Dlg5 Gene Hampe Et Almentioning

confidence: 98%

“…CARD15 major variants are mostly associated with ileal disease and stricturing behaviour [7] . In pediatric series, a correlation with ileal localization [11][12][13][14] , stricturing behaviour [12,13,15] early surgery [12,13] growth delay [13,14] , and higher disease activity [13,16] has been reported, although with conflicting findings [17][18][19] . Functional polymorphisms in the carnitine organic cation transporter cluster (OCTN1/2) [20] on chromosome 5q31 and mutations in disc large gene 5 (DLG5) [21] on www.wjgnet.com the long arm of chromosome 10 (10q23) have also been reported to be associated with CD.…”

Section: Introductionmentioning

confidence: 99%

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Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases

Cucchiara

Latiano

Palmieri

et al. 2007

WJG

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AIM:To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predisposition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS:Two hundred patients with Crohn's disease (CD), 186 ulcerative colitis (UC) patients, 434 parents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS:Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001).Homozygosis for both OCTN1/2 variants was more common in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an increased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was more frequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed.

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“…In the study of Wine et al it was observed that the presence of NOD2/CARD15 mutation carries a risk of a more severe course of the disease, which in turn may slow down the growth. However, no direct correlation of this mutation with growth retardation has been demonstrated [7]. A similar role is ascribed to IBD5 gene polymorphism, presence of which is associated with growth retardation.…”

Section: Etiology and Frequency Of Growth Disturbances In Children Wimentioning

confidence: 99%

Growth retardation in pediatric inflammatory bowel diseases – pathogenesis and treatment

Pytrus¹,

Iwańczak²

2013

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Pediatric Crohn's Disease and Growth Retardation: The Role of Genotype, Phenotype, and Disease Severity

Abstract: Severity of disease is correlated with growth failure for both height and weight. Location of disease is a weaker predictor of disordered growth and is correlated with growth retardation but not growth failure. The NOD2 genotype was not correlated with growth retardation or growth failure.

Cited by 78 publications

References 36 publications

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases

Growth retardation in pediatric inflammatory bowel diseases – pathogenesis and treatment

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