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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn's disease
T Heliö1, L Halme, M Lappalainen
1Department of Medicine, Helsinki University Hospital, Helsinki, Finland. tiina.helio@hus.fi
Insights
The 1007fs variant of the CARD15/NOD2 gene is linked to Crohn's disease (CD) in Finnish individuals. CARD15 variants also predict disease location and complications in CD patients.
Area of Science:
- Genetics
- Gastroenterology
- Immunology
Background:
- The caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene is implicated in Crohn's disease (CD) susceptibility.
- Specific CARD15 variants have been associated with increased risk of developing CD.
Purpose of the Study:
- To determine the allele frequencies of CARD15 variants (R702W, G908R, 1007fs) in Finnish patients with inflammatory bowel disease (IBD).
- To investigate associations between CARD15 variants and familial or complicated forms of CD.
Main Methods:
- Genotyping for CARD15 variants R702W, G908R, and 1007fs.
- Study population included sporadic CD patients, familial CD cases, CD patients from mixed IBD families, ulcerative colitis (UC) patients, and healthy controls.
Main Results:
- The 1007fs variant was significantly more frequent in CD patients (4.8%) compared to controls (1.7%).
- Familial CD cases showed a higher frequency of the 1007fs allele (10.9%) than non-familial CD.
- CD patients with at least one CARD15 variant had a higher incidence of ileal disease, stricturing/penetrating complications, and increased need for surgery.
Conclusions:
- NOD2 gene variant frequencies were lower in the Finnish population compared to other groups.
- The 1007fs variant is associated with Crohn's disease in this cohort.
- Presence of CARD15 variants is predictive of ileal disease and complicated CD phenotypes.
Background:
Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn's disease (CD).
Aim:
Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD.
Patients And Methods:
We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs.
Results:
In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery.
Conclusions:
The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.
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