Diverse effects of the CARD15 and IBD5 loci on clinical phenotype in 630 patients with Crohn's disease

TY - JOUR

T1 - Diverse effects of the CARD15 and IBD5 loci on clinical phenotype in 630 patients with Crohn's disease

AU - Onnie, Clive M.

AU - Fisher, Sheila A.

AU - Prescott, Natalie J.

AU - Mirza, Muddassar M.

AU - Green, Peter

AU - Sanderson, Jeremy

AU - Forbes, Alastair

AU - Lewis, Cathryn M.

AU - Mathew, Christopher G.

PY - 2008/1

Y1 - 2008/1

N2 - Objectives Genetic variants at the CARD15 and lBD5 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.Methods 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 chi(2) or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors.Results 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).Conclusion 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.

AB - Objectives Genetic variants at the CARD15 and lBD5 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.Methods 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 chi(2) or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors.Results 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).Conclusion 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.

KW - Crohn's disease

KW - NOD2 VARIANTS

KW - IBD5

KW - SUSCEPTIBILITY

KW - phenotype

KW - NOD2/CARD15 GENE

KW - FUNCTIONAL VARIANTS

KW - GRANULOMAS

KW - RISK-FACTOR

KW - CHROMOSOME 5Q31

KW - CARD15

KW - INFLAMMATORY-BOWEL-DISEASE

KW - ASSOCIATION

KW - CATION TRANSPORTER GENES

U2 - 10.1097/MEG.0b013e3282f1622b

DO - 10.1097/MEG.0b013e3282f1622b

M3 - Article

VL - 20

SP - 37

EP - 45

JO - European Journal of Gastroenterology and Hepatology

JF - European Journal of Gastroenterology and Hepatology

IS - 1

ER -