Diverse effects of the CARD15 and IBD5 loci on clinical phenotype in 630 patients with Crohn's disease.
ABSTRACT Genetic variants at the CARD15 and IBD5 loci are strongly associated with Crohn's disease (CD), but evidence of the effect of these variants on the clinical expression of CD is conflicting and has often been hampered by small sample sizes. We studied 630 well-characterized patients to clarify the genotype/phenotype relationship in CD.
Patients and healthy controls were genotyped for three common mutations in CARD15 and a marker of the IBD5 risk haplotype. Allele frequencies were compared between phenotypic subgroups using chi2 or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors.
The mean age at diagnosis was significantly lower in carriers of the CARD15 or IBD5 risk alleles. After correction for age and smoking, CARD15 mutations were strongly associated with both ileal disease (P=8.8 x 10(-6)) and stenotic disease (P=0.003), but the association with stenotic disease appeared to be due to a confounding effect with ileal disease. CARD15 mutations were also associated with the presence of granulomas (P=5.7 x 10(-5)), which remained significant after adjustment for age at diagnosis and disease location (P=0.0047). The IBD5 risk haplotype frequency was significantly elevated in cases with perianal disease (P=0.028) and axial spondyloarthropathy (P=0.012).
Genetic variants at the CARD15 and IBD5 loci have diverse effects on clinical expression in CD. CARD15 mutations are significantly correlated with the presence of granulomas.
SourceAvailable from: Kelvin K F Tsoi[Show abstract] [Hide abstract]
ABSTRACT: Inflammatory bowel diseases (IBD) result from an interaction between genetic and environmental factors. Preliminary findings suggest that susceptibility genes differ between IBD patients in Asia and the West. We aimed to evaluate disease-predisposing genes in Asian IBD patients. A systematic review and meta-analysis were performed of published studies from 1950 to 2010 using keyword searches in MEDLINE, EMBASE, EBM Reviews, and BIOSIS Previews. In all, 477 abstracts were identified and data extracted from 93 studies, comprising 17,976 IBD patients and 27,350 age- and sex-matched controls. Major nucleotide oligomerization domain (NOD)-2 variants in Western Crohn's disease (CD) patients were not associated with CD in Han Chinese, Japanese, South Korean, Indian, and Malaysian populations. New NOD2 mutations were, however, associated with CD in Malaysians (JW1), Han Chinese, and Indians (P268S). Autophagy-related protein 16-linked 1 (ATG16L1) was not associated with CD in East Asians (odds ratio [OR] 0.97; 95% confidence interval [CI] 0.84-1.13). Interleukin (IL)-23R was associated with CD in South Koreans (OR 1.8; 95% CI 1.16-2.82) and a single nucleotide polymorphism in IL-23R (Gly149Arg) was protective of CD in Han Chinese (OR 0.3; 95% CI 0.15-0.60). Tumor necrosis factor (TNF) superfamily gene-15 (SF15) polymorphisms were associated with CD (OR 2.68; 95% CI 1.86-3.86), while TNF-308 polymorphisms (OR 1.82; 95% CI 1.15-2.9), cytotoxic T lymphocyte antigen (CTLA)-4 (OR 2.75; 95% CI 1.22-6.22) and MICA allele (OR 2.41; 95% CI 1.89-3.07) were associated with ulcerative colitis in Asians. Genetic mutations of IBD in Asians differ from Caucasians. New mutations and susceptibility genes identified in Asian IBD patients provide an opportunity to explore new disease-associated mechanisms in this population of rising incidence.Inflammatory Bowel Diseases 01/2012; 18(6):1164-76. DOI:10.1002/ibd.21845 · 5.48 Impact Factor
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ABSTRACT: BACKGROUND:: Ileal intubation is being increasingly performed at colonoscopy and has in turn lead to an increasingly recognized subgroup of patients-those with mild terminal ileal inflammation, an entity that we have coined isolated active ileitis (IAI). The aims of this study were to define the natural history of IAI and determine if IAI shares a similar genetic and serologic profile with Crohn's disease (CD). METHODS:: Patients with IAI were identified from our institution's histopathology and endoscopy databases. Cases attended for repeat colonoscopy and blood were analyzed for the expression of antineutrophil cytoplasmic antibody, anti-OmpC, anti-Saccharomyces cerevisiae antigen (ASCA) IgA, ASCA IgG, and anti-CBir antibodies and NOD2 genotyping. Age and sex-matched healthy controls, CD, and UC cases were also recruited. RESULTS:: Sixty-three patients with IAI were recruited. There was no significant difference in the prevalence of antibodies between IAI cases and healthy controls for antineutrophil cytoplasmic antibody, OmpC, ASCA IgA, or ASCA IgG. The presence of all 5 antibodies was significantly higher in the CD group than the IAI group, P < 0.05. There were 28.6% of CD cases that carried one or more NOD2 variants, compared to 26.2% of the IAI cohort and 6.1% of healthy controls. Forty-three cases underwent follow-up ileocolonoscopy. Six of 43 cases (14%) had definite CD. CONCLUSIONS:: A majority of IAI cases developed persistent symptoms and terminal ileal abnormalities; however, only 14% developed classical, histological, or radiological features of CD. Although patients with IAI have a low level of seropositivity, similar to healthy controls, they do share an excess of NOD2 mutations with CD cases.Inflammatory Bowel Diseases 06/2013; DOI:10.1097/MIB.0b013e31828dc68b · 5.48 Impact Factor
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ABSTRACT: BACKGROUND:: Up to 70% of patients requiring surgery for Crohn's disease (CD) develop recurrence within 10 years. Unequivocal markers predicting recurrence are needed to tailor postoperative therapy appropriately. NOD2 (nucleotide-binding oligomerization domain 2) polymorphisms increase the risk of developing CD; however, their ability to predict recurrence is uncertain. This study aims to determine the association between NOD2 variants and surgical recurrence after initial disease-modifying surgery. METHODS:: A comprehensive search for published series comparing the effect of NOD2 polymorphisms on postoperative surgical recurrence in patients with CD was performed. Random-effects methods were used to combine data. RESULTS:: Six cohort studies comprising 1003 patients with CD were included. A total of 340 patients (33.9%) expressed at least 1 of the 3 common NOD2 polymorphisms. The 1003 patients underwent surgical resection with 335 (33%) developing surgical recurrence. Of 340 NOD2-expressing patients, 130 (39%) required further resection, whereas 202 of 663 patients (30.5%) without the variant underwent repeat resection. NOD2 was not significantly associated with surgical recurrence (odds ratio: 1.58, 95% confidence interval: 0.97-2.57, P = 0.064), most likely because of study heterogeneity (Cochran Q: 12.36, P = 0.030, I: 59.6%). The sensitivity of any mutation in predicting disease recurrence was 39.7% and specificity was 69%, with the area under the receiver operating characteristic curve being 0.64. CONCLUSIONS:: Patients with CD with a NOD2 polymorphism do not have an increased risk of surgical recurrence compared with patients without the variant. These data provide insufficient evidence to support postoperative medical prophylaxis based solely on the presence of NOD2 polymorphism.Inflammatory Bowel Diseases 03/2013; DOI:10.1097/MIB.0b013e3182813391 · 5.48 Impact Factor