Pediatric-onset Crohn's Disease Research Articles

Clinical Features Affecting Final Adult Height in Patients With Pediatric-Onset Crohn's Disease

Clinical Features Affecting Final Adult Height in Patients With Pediatric-Onset Crohn's Disease

Association Between Genetic Variants in theIL-23RGene and Early-Onset Crohn's Disease: Results From a Case-Control and Family-Based Study Among Canadian Children

Interleukin (IL)-23 is a key regulator of inflammation and influences the activities of T-helper 17 (Th-17) lymphocytes. Recent reports indicate that variants in the gene coding for its receptor (IL-23R) are strongly associated with Crohn's disease (CD). We investigated whether DNA variants in the IL-23R gene determine susceptibility for CD in Canadian children. A case-control and case-parent trio design was implemented at three pediatric centers across Canada. Cases of CD (</=20 yr) along with their parents and controls were recruited. DNA samples were collected and genotyped for 10 single nucleotide polymorphisms (SNPs) in the IL-23R gene and three common SNPs in the CARD15 gene. Transmission disequilibrium-based tests were applied to the case-parent data and logistic regression models to the case-control data to study the association between the SNPs and CD. A total of 259 CD cases, 139 controls, and 232 families (167 trios and 65 dyads) were studied. The mean age at diagnosis was 13.3 yr (range 2.6-20 yr). The majority of the patients were Caucasian. Case-control analysis revealed significant associations with three SNPs (rs1004819, rs7517847, and rs11209026 [R381Q]) and borderline nonsignificant associations with three other SNPs (rs10489629, rs10889697, and rs11465804) in the IL-23R gene. Having any CARD15 variant was associated with a significant risk for CD (P < 0.0001). Analyses of case-parent data confirmed the findings from the case-control analysis including significant associations with the R381Q SNP (P= 0.002). The common variant in this SNP conferred risk for CD. These associations were largely independent of the CARD15 gene. Our findings confirm recently reported genome-wide associations between the IL-23R gene and CD. They suggest that the gene is also associated with pediatric-onset CD among Canadian children.

Evaluation of the Interleukin‐23 Receptor Gene Coding Variant R381Q in Pediatric and Adult Crohn Disease

Pediatric-onset Crohn disease (CD) may differ in genotype or phenotype from adult-onset CD. Genome-wide screening recently identified a protective mutation (R381Q) in the interleukin-23 (IL-23) receptor gene located on chromosome 1. The aims of our study were to evaluate whether this mutation is associated with CD in our population and to find whether it may have an impact on age of onset or a specific location phenotype in a pediatric- and adult-onset CD population. A total of 438 individuals (143 with pediatric-onset CD [age <18 years], 139 with adult-onset CD, and 157 control subjects) evaluated for age at onset and disease location were genotyped for the R381Q mutation in the IL-23 receptor gene by pyrosequencing. Mutant allele incidences were 5.7% in the normal cohort and only 2.28% in the CD cohort (P = 0.01). Carriers were found to constitute 8.9% of the normal cohort and only 4.6% of the CD cohort (P = 0.029). Homozygotes were found in only the control cohort. The mean age of onset for all of the patients with the mutation (including both age groups) was 17.8 +/- 6.1 years versus 21.3 +/- 12.4 years for patients without the mutation (P =0.08). The mutation was not associated with differences in sex, site of disease, or ethnicity. We did not find evidence of allelic interaction with CARD15. We confirmed the findings that the IL-23 receptor gene coding variant allele R381Q appears to decrease susceptibility to CD in an Israeli Jewish population. We found a trend toward earlier age of onset, but no interactions with CARD15 or modifying effect on disease location.

Genetic susceptibility has a more important role in pediatric-onset Crohnʼs disease than in adult-onset Crohnʼs disease

Genetic susceptibility may play a more important role in the etiology of early-onset inflammatory bowel disease (IBD) than in late-onset IBD, and therefore pediatric-onset IBD patients can be expected to have a higher frequency of gene mutations. We aimed to determine genotypes and phenotypes of patients with pediatric-onset IBD, to compare them with those of patients with adult-onset IBD and with controls, and to identify genotype-phenotype associations. Polymorphisms R702W, G908R, and 3020insC of CARD15 (caspase activating recruitment domain 15); Asp299Gly and Thr399Ile of TLR4; -207G-->C, 1672C-->T (L503F), rs3792876, rs274551, rs272893, and rs273900 of SLC22A4/5; and 113G-->A as well as rs2289311, rs1270912, and rs2165047 of DLG5 (Drosophila discs large homologue 5) were assessed in 103 pediatric-onset and 696 adult-onset IBD patients. Phenotypic classification was based on disease localization and behavior. Homozygosity for 3020insC in CARD15 was significantly higher in patients with pediatric-onset Crohn's disease (CD) than in patients with adult-onset CD (4.2% versus 0.6%, 95% confidence interval [CI] 1.2-42.0). Homozygosity for single-nucleotide polymorphism (SNP) rs3792876 in SLC22A4/5 was significantly higher in patients with pediatric-onset CD than in patients with adult-onset CD (6.1% versus 1.1%, P=0.02). Polymorphism 3020insC in CARD15 was associated with ileal involvement (1.9% versus 13.3%, CI 1.0-53.8) and a positive family history (6.1% versus 20%, CI 1.2-9.0). DLG5 SNP rs2165047 was significantly associated with perianal disease (50% versus 21.2%, CI 1.4-4). Polymorphisms 3020insC in CARD15 and SNP rs3792876 in SLC22A4/5 occurred statistically significantly more often in patients with pediatric-onset CD than in patients with adult-onset CD. Polymorphisms 3020insC in CARD15 and SNP rs2165047 in DLG5 were associated with specific phenotypes in this pediatric-onset CD cohort.

Pediatric onset Crohnʼs colitis is characterized by genotype-dependent age-related susceptibility

Pediatric onset Crohn's disease (CD) is associated with more colitis and less ileitis compared with adult onset CD. Differences in disease site by age may suggest a different genotype, or different host responses such as decreased ileal susceptibility or increased susceptibility of the colon. We evaluated 721 pediatric onset CD patients from 3 cohorts with a high allele frequency of NOD2/CARD15 mutations. Children with isolated upper intestinal disease were excluded. The remaining 678 patients were evaluated for interactions between age of onset, NOD2/CARD15, and disease location. We found an age-related tendency for isolated colitis. Among pediatric onset patients without NOD2/CARD15 mutations, colitis without ileal involvement was significantly more common in first-decade onset patients (P = 4.57 x 10(-5), odds ratio [OR] 2.76, 95% confidence interval [CI] 1.72-4.43). This was not true for colonic disease with ileal involvement (P = 0.35), or for isolated colitis in patients with NOD2/CARD15 mutations (P = 0.61). Analysis of 229 patients with ileal or ileocolonic disease and a NOD2/CARD15 mutation disclosed that ileocolitis was more prevalent through age 10, while isolated ileitis was more prevalent above age 10 (P = 0.016). NOD2/CARD15 mutations were not associated with age of onset. In early-onset pediatric CD, children with NOD2/CARD15 mutations demonstrate more ileocolitis and less isolated ileitis. Young children without NOD2/CARD15 mutations have an isolated colonic disease distribution, suggesting that this phenotype is associated with genes that lead to a specific phenotype of early-onset disease.

Pediatric inflammatory bowel disease: Clinical and molecular genetics

Pediatric-onset inflammatory bowel disease (IBD) is characterized by distinct phenotypic differences compared to adult-onset IBD. This raises the question whether early (pediatric) onset IBD represents the same disease process occurring in adults but merely at an earlier age or does IBD in children have a very different etiology and pathogenesis but with the same clinical presentation as adults. The use of techniques such as whole genome association studies to perform broad, unbiased screening for the contributions of common genetic variations to complex disease has rapidly assisted in the identification of several novel susceptibility loci associated with pediatric-onset Crohn's disease such as IL23R and ATG16L1. These genes join the already confirmed IBD susceptibility genes such as NOD2/CARD15, IBD5, and DLG5. Therefore, there is hope that advances in the field of clinical and molecular genetics will assist in answering the fundamental question of whether pediatric IBD has a different etiology and pathogenesis compared to adult IBD. This review examines the current status of clinical and molecular genetics of pediatric IBD, and highlights the differences between pediatric and adult IBD in disease phenotypes and genotypes. Finally, the future directions of genetic investigations in pediatric IBD are discussed.

DLG5 R30Q Variant Is a Female-Specific Protective Factor in Pediatric Onset Crohn's Disease

A significant association between the DLG5 variant (R30Q) and inflammatory bowel disease (IBD) has been confirmed in several independent adult IBD cohorts. There is growing evidence that gender significantly influences R30Q susceptibility in Crohn's disease (CD). Pediatric onset CD features a significantly lower incidence for female children compared with male children. We, therefore, studied the influence of gender on R30Q susceptibility in an exclusively pediatric onset IBD cohort. A total of 281 CD (181 trios) and 479 population-based controls were genotyped for DLG5 R30Q using Taqman assay. Association was tested by case-control and transmission disequilibrium testing analysis. Multivariate logistic regression was performed to investigate gene-gene and gene-gender interactions, as well as genotype-phenotype correlations. Overall allele frequency for R30Q was 8.5% in CD and 10.3% in controls. Logistic regression showed R30Q had no association with CD (OR 0.81, 95% CI 0.55-1.20, P= 0.3) when the cohort was analyzed as a whole. Stratified by gender, a significant negative association was detected for R30Q in female children (OR 0.39, 95% CI 0.2-0.77, P= 0.006), but not in male children. Gender was found to be an effect modifier of the association between R30Q and CD as the odds ratios in female children and male children differed significantly. The gender-specific association of R30Q and CD was independent of additional CD risk factors such as CARD15 and IBD5. DLG5 has a gender-specific role in the susceptibility of pediatric CD. Specifically, the significant negative association found between DLG5 R30Q and CD in female children suggests DLG5 may have a protective effect in CD susceptibility for female children.

Clinical Features Affecting Final Adult Height in Patients With Pediatric-Onset Crohn's Disease

Growth failure is a recognized complication of pediatric-onset Crohn's disease, but there are few data on final adult height. Our purpose with this work was to determine adult height and the clinical features that influence long-term growth impairment. We retrospectively studied 123 patients with Crohn's disease (65 male and 58 female) who had reached adult height. All of the case subjects were diagnosed before age 16.0 years. Heights were converted to SD scores and univariate analysis performed of factors postulated to influence final height, that is, interval from onset of symptoms to diagnosis, prepubertal onset of symptoms, gender, jejunal disease present at diagnosis, systemic steroid therapy, intestinal surgery, and midparental height SD scores. Significant univariate factors were additional analyzed in regression models. Mean height deficit at diagnosis was -0.50 SD scores, which improved to -0.29 SD scores at final height. Mean final height compared with target height, calculated from parental height, was -2.4 cm (range: -20.0 to 9.0 cm). Nineteen percent of the case subjects achieved a final height >8.0 cm below target height. The length of the interval between symptom onset and diagnosis correlated negatively with height SD scores at diagnosis. Height SD scores at diagnosis were related to final height SD scores, independent of midparental height. The presence of jejunal disease was negatively related to final height. Mean final adult height showed a modest deficit compared with target height, but in one fifth of patients, final height was significantly less than target height. Earlier diagnosis and improved treatment of jejunal disease would be likely to improve final height.

Contribution of OCTN Variants Within the IBD5 Locus to Pediatric Onset Crohn's Disease

The IBD5 locus on chromosome 5q31 is a confirmed Crohn's disease (CD) susceptibility locus in adults. Recently, two polymorphisms in the organic cation transporter (OCTN) gene cluster within the IBD5 locus have been found to be associated with CD. Although the original report of significant linkage to IBD5 was in families with at least one case of early age at onset CD, there are no published reports on the role of OCTN genes in pediatric onset CD. We performed a comprehensive analysis of OCTN variants in an independent, exclusively pediatric onset CD cohort and examined the genotype/phenotype correlations. 264 Caucasian CD children (172 of them were trios) were genotyped along with 527 controls for OCTN1 (SLC22A4 C1672T), OCTN2 (SLC22A5 G-207C), and two haplotype-tagging SNPs (IGR2230 and IGR2198). TDT confirmed the association of SLC22A4 and SLC22A5. Case-control analysis of the SLC22A4 1672T, SLC22A5-207C diplotype showed significant association (p=0.04) with CD susceptibility compared with controls. Little correlation was seen with regard to clinical phenotype and the SLC22A4/SLC22A5 diplotype. There was no significant interaction between the SLC22A4/SLC22A5 diplotype and the three CD-associated CARD15 SNPs. We confirm the association of the OCTN variants (SLC22A4 and SLC22A5) in pediatric onset CD as seen in adult CD cohorts. However, when an extended IBD5 haplotype was examined, no independent association between OCTN variants and pediatric onset CD can be demonstrated. Compared with adults, a relatively weak association of the OCTN variants was observed in our CD cohort. No definitive genotype-phenotype correlation or gene-gene interactions with CARD15 were observed. Although the IBD5 locus is associated with pediatric onset CD, no definitive conclusions can be drawn about OCTN variants as causative genes in pediatric CD at this point.

Investigating the Hygiene Hypothesis as a Risk Factor in Pediatric Onset Crohn's Disease: A Case-Control Study

Evidence for the hygiene hypothesis in the etiology of Crohn's disease (CD) is unclear. We investigated the relationship between infection-related exposures and risk for CD in children. A hospital-based case-control was carried out. Newly-diagnosed cases of CD (n = 194), less than 20 yr of age were recruited from the gastroenterology clinic of a large-pediatric inflammatory bowel disease (IBD) center in Montreal, Canada. Orthopedic patients pair-matched (n = 194) for timing of diagnosis and area of residence were recruited as controls. Information on infection-related exposures between birth and disease diagnosis was ascertained by administering a structured questionnaire to the mother and the index subject. The relationship between the frequency and timing of infection-related exposures with CD was studied. The mean age (SD) at diagnosis was 12.3 (5.1). CD was more common after 10 yr of age. Gender distribution was similar between comparison groups. In multivariate conditional logistic regression, family history of IBD (odds ratio (OR) = 4.6; 95% confidence interval (CI) = 1.6-13.3), age (OR = 1.2; 95% CI = 1.1-1.3), and owning a pet (OR = 2.0; 95% CI = 0.9-4.5) were associated with risk for CD, whereas regular use of a personal towel (OR = 0.5; 95% CI = 0.2-0.9) and lesser crowding in homes (OR = 0.3; 95% CI = 0.1-0.8) were protective. Day-care attendance during the first 6 months of life and "physician-diagnosed infections" between 5 and 10 yr of age were associated with increased risks for CD. Infection-related exposures seem to enhance risk for CD in children. The timing of these exposures during early childhood may be relevant to the etiology of pediatric CD.

TNF Promoter Polymorphisms and Modulation of Growth Retardation and Disease Severity in Pediatric Crohn's Disease

Delayed growth is common in pediatric Crohn's disease (CD). Multiple factors have been shown to affect growth in this situation, the most prominent being the presence and severity of inflammation and inadequate nutritional intake. Inflammation, anorexia, and weight loss are all manifestations of circulating TNF-alpha, which is elevated in CD. The ability to secrete TNF-alpha may be affected by polymorphisms in the TNF-alpha promoter. The aim of our study was to determine whether growth retardation and disease severity in pediatric onset CD are affected by TNF promoter genotype. Genotyping for TNF-alpha and NOD2/CARD15 single nucleotide polymorphisms was performed in 87 patients with detailed growth records. Parameters including disease location and disease severity were recorded, and the effect of these polymorphisms on Z-scores for height and weight at disease onset and during follow-up were analyzed. Lower age of onset was linked to more height retardation, while the presence of colonic disease and the absence of ileal disease were more likely to predict the absence of growth retardation. The presence of two polymorphisms thought to decrease circulating TNF-alpha was associated with higher mean Z-scores for height and a trend toward less growth retardation. Two other polymorphisms were modestly associated with disease severity. Polymorphisms in the TNF-alpha promoter may independently modulate growth and disease severity in pediatric onset CD. The effect of these polymorphisms does not appear to be mediated via weight loss, and is relatively modest.

TNF PROMOTER POLYMORPHISMS MODULATE GROWTH RETARDATION AND DISEASE SEVERITY IN PEDIATRIC CROHN??S DISEASE

Background and Aims: Delayed growth is common in pediatric Crohn's disease (CD). Multiple factors have been shown to affect growth in this situation, the most prominent being presence and severity of inflammation and inadequate nutritional intake. Inflammation, anorexia and weight loss may are all manifestations of circulating TNF alpha, which is elevated in CD. The ability to secrete TNF alpha may be affected by polymorphisms in the TNF alpha promoter. The aim of our study was to determine whether growth retardation and disease severity in pediatric onset Crohn's disease are affected by TNF promoter genotype. Methods: Genotyping for TNF alpha single nucleotide polymorphisms (SNPs) was performed in 87 patients with detailed growth records. Parameters including disease location, disease severity and were recorded, and the effect of these polymorphisms on z-scores for height and weight at disease onset and during follow-up until age 16 for height and 18 for weight were analyzed. Results: Z scores for height <1 S.D. occurred in 44% of patients, <2 SD in 19%. Lower age of onset was linked to more height retardation, while presence of colonic disease and absence of ileal disease were more likely to predict absence of growth retardation (p = 0.004). Mean height scores were increased with 238 G/A (p = 0.003) while Height retardation was reduced by two polymorphisms reported to decrease circulating TNF(−238 G/A, −863 C/A).The effect on height was not associated with lower z scores for weight. Disease severity was modestly associated with the pro-inflammatory polymorphisms −308 G/A and inversely associated with 857 C/T. Conclusion: Polymorphisms in the TNF alpha promoter may modulate disease severity and growth retardation in pediatric onset CD, though this effect appears to be modest. The effect of genotype on growth retardation is not associated with TNF mediated weight loss.

CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn’s disease

The risk for Crohn's disease (CD) is determined in part by genetic factors. Three recently described mutations in the CARD15(NOD2) gene have been associated with adult-onset CD. We investigated the effect of CARD15 mutations on disease manifestation, disease progression, and the risk for early surgery in childhood-onset CD. Genotyping for 3 CARD15 mutations: R702W, G908R, and 3020insC, was performed in 186 children with CD from a prospective cohort. A transmission-disequilibrium test was used to test for association with CD. Genotype with disease location and behavior was tested with logistic regression analysis. The effect of mutations on surgical outcome was evaluated using a Cox proportional hazard analysis. The mean age at CD diagnosis was 12.4 years. The frequency of allelic mutations observed was 6.6% for R702W, 6% for G908R, and 13.1% for 3020insC. Of Caucasian CD children, 42% had at least one CARD15 mutation. None of the non-Caucasian children with CD had any CARD15 mutation. A significant association was detected for 3020insC (P = .0045). Ileal location (odds ratio, 4.3; P = .003) and stricturing disease (odds ratio, 6.6; P = .0001) was more frequent and the risk for surgery was higher (hazard ratio, 5.8; P < .0001) and surgery occurred earlier (hazard ratio, 2.24) in those children with 3020insC mutation compared with those without 3020insC. In children with pediatric-onset CD, early development of stricturing behavior leading to surgical resection is influenced by ileal location and 3020insC variant of the CARD15 mutation. Genetic testing may identify children with CD who are at risk for early surgery.

CARD 15 / NOD 2 in Paediatric Onset Crohn's Disease

CARD 15 / NOD 2 in Paediatric Onset Crohn's Disease

Changing patterns in pediatric-onset Crohn's disease: A 30 year epidemiologic study

Changing patterns in pediatric-onset Crohn's disease: A 30 year epidemiologic study