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P659. Crohn's disease in an Irish population - a pilot genotype–phenotype analysis

B. Hall1,2, G. Holleran1,2, S. O'Sullivan3, S. Smith2, C. Medina3, D. McNamara1,2, 1Trinity College Dublin, Department of Clinical Medicine, Dublin, Ireland, 2Adelaide and Meath Hospital, Department of Gastroenterology, Dublin, Ireland, 3Trinity College Dublin, Dublin, Ireland, School of Pharmacy and Pharmaceutical Sciences, Dublin, Ireland

Background

Loss of function mutations in NOD2 (G908R, R702W, 1007fs) have been associated with Crohn's disease (CD) and, in particular, with severe phenotypes. Earlier identification of severe disease may allow for tailoring of treatment. NOD mutations are thought to occur less frequently in Celtic populations and their association with phenotype is unclear. Our aim was to assess NOD2 mutation status in an Irish cohort.

Methods

Following informed consent, the frequency of selected NOD2 mutations in blood were compared using genotyping analysis between subjects with established CD and controls. Montreal phenotype was recorded for CD subjects. Individuals with a normal surveillance ileo-colonoscopy, negative histology and lack of symptoms were recruited as controls. The frequency of mutations was compared between groups and among phenotypes using McNemar's test.

Results

To date, 40 subjects have been enrolled: 30 (75%) with CD, 24 (60%) women with a mean age of 37 years. Ileo-colonic, ileal, colonic, stricturing and penetrating phenotypes occurred in 18 (60%), 8 (26%), 4 (13%), 16 (53%) and 5 (16%) respectively, while 19 (63%) had undergone surgery. In total, 7 (23%) CD patients and no controls displayed a NOD2 mutation (p < 0.001). Table 1. No patient had more than one mutation. Stricturing and ileocolonic phenotype and surgery were strongly correlated with a NOD2 mutation (OR 10, p < 0.01, 12, p < 0.01 and 7, p < 0.01 respectively).

Table 1. Genotype–phenotype comparison
Montreal ClassificationG908RR702W1007fs
1. A1/L3/B2 HZ
2. A2/L3/B2 HZ
3. A2/L3/B2HH
4. A2/L3/B3pHH
5. A2/L3/B2HH
6. A1/L3/B2 HZ
7. A1/L1/B1 HZ
HH, homozygous; HZ, heterozygous.

Conclusion

In our cohort, NOD 2 mutations appear more prevalent than previously described in the Celtic population. Single NOD2 SNP's are associated with complicated disease and may be a useful biomarker of disease severity. Genetic testing in a larger cohort is warranted to further assess genetic influence on CD phenotypes.