Original articles—alimentary tract
Genetic Risk Profiling and Prediction of Disease Course in Crohn's Disease Patients

https://doi.org/10.1016/j.cgh.2009.05.001Get rights and content

Background & Aims

Clinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated.

Methods

Complete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7–22). Fifty CD-associated polymorphisms were genotyped. Kaplan–Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time.

Results

Homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60–18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13–69.78; P = .04 and OR, 0.56; 95% CI, 0.38–0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present.

Conclusions

CD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach.

Section snippets

Patient Selection, Study Design, and Data Collection

We reviewed patient files of 970 unrelated IBD patients of Western European origin, recruited in the framework of the IBD genetics study that started in October 1996 until now at the IBD unit of the University Hospital in Leuven, Belgium. The control group consisted of 367 unrelated healthy volunteers without a family history of IBD or other immune-related disorders. Diagnosis of IBD was based on accepted clinical, endoscopic, radiologic, and histologic criteria.17, 18 After thorough review of

Patient Characteristics at Diagnosis and at Last Follow-Up

A total of 755 patients were studied. Patient characteristics are presented in Table 1. At diagnosis, 637 patients (84%) had pure inflammatory disease without strictures, non-perianal or perianal fistulae. During follow-up, 236 of these (37%) developed strictures, 157 (25%) developed non-perianal fistulae, and 177 (28%) developed perianal penetrating disease.

By the time of last follow-up, 253 patients of the total study group (34%) had not developed strictures or non-perianal or perianal

Discussion

Several studies have shown that the implementation of biologic therapies in active refractory CD is associated with mucosal healing and a reduced number of hospitalizations and surgeries.32 This suggests that an early introduction of such therapies might prevent a disabling disease course.33 Therefore, it becomes increasingly desirable to define patients at high risk for such an evolution in an early stage. Previous studies have shown that clinical and demographic markers alone poorly predict

Acknowledgments

The authors thank Vera Ballet for swift administrative assistance and Karolien Claes, Tamara Coopmans, Sophie Organe, and Nele Van Schuerbeek for the excellent technical and scientific support for sample selection, DNA extraction, and genotyping.

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    Conflicts of interest The authors disclose no conflicts.

    Funding L. Henckaerts is a doctoral fellow and S. Vermeire is a clinical researcher of the Fund for Scientific Research (FWO), Flanders, Belgium. A. Franke was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) and received infrastructure support through the DFG excellence cluster “Inflammation at Interfaces.”

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