June 26, 2003 Access past issues

Reviewed by: Sarah E. Dodson, MSPH Rollins School of Public Health Emory University

The Health Outcome

An estimated one million Americans live with inflammatory bowel disease (IBD) (1). Crohn’s disease (CD) is a type of IBD that affects about 1-3 per 1,000 people in Western countries. Common symptoms of CD include abdominal pain, diarrhea, and rectal b lee ding. CD is often clinically characterized by location, type, and behavior of the disease (2).

The Finding

Hampe et al. investigated the relation between several NOD2 genotypes (SNP8, SNP12, and SNP13) and phenotypic characteristics of patients with CD (3). Characteristics of the clinical course of the disease included the presence of stenoses, fistulae, arthritis, or other extraintestinal complications; resections; relapse frequency; and location of disease (ileal, right colon, left colon).

The investigators used a two-stage study design. First, a retrospective case series of German CD patients (n=446) was assembled for the purposes of hypothesis formation. Hypotheses that emerged as potentially important from studying associations in the case series were then tested in a second, prospectively established case series, both in Germany (n=106) and in Norway (n=55). The investigators used these case series of CD patients to perform a case-control study to obtain estimates of the haplotype frequencies of the three SNPs in both CD patients and the general population.

In the retrospective case series, six clinical characteristics showed noteworthy haplotype associations (p=0.1): fistulae, stenosis, resection, and all three locations of disease. In the German prospective case series, these haplotype associations could be replicated for ileal (p=0.006) and right colonic disease (p ³ 0.001). The investigators stated that a similar trend was noted in the Norwegian case series (3).

Previous studies of stenoses, fistulae, extraintestinal involvement, and relapse frequency have also failed to demonstrate significant associations with any of these NOD2 mutant haplotypes (4-6). However, the association with ileal disease is similar to the findings of Ahmad et al., in that possession of a NOD2 variant was significantly associated with ileal disease (RR=3.3 for a single variant to RR=23.1 for more than one variant, with the greatest RR SNP13 carriers) (7). Additionally, Cuthbert et al. found that the frequency of each mutant NOD2 haplotype was significantly increased in ileum-specific disease (OR=2.04, 95% CI=1.23-3.38), indicating a twofold increased risk for ileal disease in patients who carry a NOD2 mutation (8). Finally, most previous studies did not differentiate between right and left colonic disease, so the association with right colonic disease is novel and needs to be replicated.

Public Health Implications

Identification of genetic risk factors that contribute to complex disorders such as CD provides opportunities for researchers to further analyze and understand these disorders. Studies such as this one, linking genetic traits with the clinical characteristics of a condition, may one day allow for more stable and detailed characterization and classification of heterogeneous diseases like CD. Previous classification schemes, relying on clinical characteristics alone, change over time and depend on many environmental factors. The information that practitioners extract from these studies may help them identify patients at risk for the development of certain complications and therefore also help them develop tailored preventative programs.

References

1. Crohn’s and Colitis Foundation of America. Q & A about Crohn’s disease. Accessed on February 15, 2003
2. Andres PG, Friedman LS. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterol Clin North Am 1999 Jun;28(2):255-81.
3. Hampe J, Grebe J, Nikolaus S, Solberg C, Croucher PJ, Mascheretti S , et al. Association of NOD2 (CARD 15) with clinical course of Crohn’s disease: a cohort study. Lancet 2002 May 11;359(9318):1661-5.
4. Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 2002 Apr;70(4):845-57.
5. Vermeire S, Wild G, Kocher K, Cousineau J, Dufresne L, Bitton A , et al. CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. Am J Hum Genet 2002 Jul;71(1):74-83.
6.   Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA, Belaiche J. Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease.
   Gut 2001 Dec;49(6):777-82.
7. Ahmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR , et al. The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology 2002 Apr;122(4):854-66.
8. Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Croucher PJ, Mascheretti S , et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.  Gastroenterology 2002 Apr;122(4):867-74