Perianal Crohn’s Disease: Predictive Factors and Genotype-Phenotype Correlations

Abstract

Aim: To investigate genotype-phenotype correlations in patients with perianal Crohn’s disease (PCD) in order to determine which factors predispose to development of perianal disease in Crohn’s patients. Methods: Seven-hundred and ninety-five Caucasian individuals (317 CD patients and 478 controls without inflammatory bowel disease, IBD) were prospectively enrolled into a clinical/genetic database. Demographic and clinical data, as well as peripheral blood leukocyte DNA were obtained from all patients. The following were evaluated: three NOD2/CARD15 polymorphisms: R702W, G908R, and 1007insC; five IL-23r risk alleles: rs1004819, rs10489629, rs2201841, rs11465804, and rs11209026; a well-characterized single-nucleotide polymorphism (SNP) on the IBD5 risk haplotype (OCTN1) and two peripheral tag SNPs (IGR2060 and IGR3096). Results: PCD occurred in 147 (46%) of CD patients. There was no significant difference in the age at disease diagnosis between non-PCD and PCD patients (33 vs. 29 years, respectively). PCD patients were more likely to have disease located in the colon and ileocolic regions (79 PCD vs. 57% non-PCD; n = 116 vs. n = 96; p < 0.001), whereas patients with non-PCD were more likely to have Crohn’s within the terminal ileum and upper gastrointestinal tract (43% non-PCD vs. 21% PCD; n = 73 vs. n = 31; p < 0.05). Thirty-four percent of patients with PCD required a permanent ileostomy (n = 50) compared to only 4% of non-PCD patients (n = 6; p < 0.05). Mutations in CARD15/NOD2 and IL-23r were risk factors for CD overall; however, in contrast to prior reports, in this patient population, OCTN1 and IGR variations within the IBD5 haplotype were not significant predictors of PCD. Conclusion: Colon/ileocolic CD location appears to be a significant predictor of perianal manifestations of CD. Patients with PCD are more likely to require permanent fecal diversion. We did not identify any genetic variations or combination of clinical findings and genetic variations within the CARD15/NOD2, IL-23r, and OCTN1 genes or IGR that were predictive of PCD.

Predicting Outcomes to Optimize Disease Management in Inflammatory Bowel Diseases

“…Identification of risk factors at an earlier stage of disease may guide more intensive medical intervention, preventing the development of strictures and fistulae that ultimately result in the need for irreversible surgery. In our review of the evidence [primarily in patients with perianal and/or colonic CD], the most frequent factors independently associated with a permanent stoma were: complex perianal fistulae, 55,56 anal-canal stricture, 57 perineum involvement and perineal granulomas, 58 perianal sepsis, 59 faecal incontinence, 55 colonic CD 59 and distal colonic involvement. 57,60 Additionally, patients undergoing rectal resection or temporary faecal diversion for perianal disease control have a higher rate of permanent faecal diversion.…”

Combined Medical and Surgical Approach Improves Healing of Septic Perianal Crohn's Disease

“…34,35 These findings have been difficult to fully replicate. 36 However, our subset genetic analysis appeared to suggest a role of SLC22A5/OCTN2 …”

CARD15 Gene 3020insC Mutation with Inflammatory Bowel Diseases Patients in the Black Sea Region of Turkey

“…However, the candidate genes did not show a definitive association with this pathology [1,3]. Recent articles proposed a gene on chromosome 16q12, known as CARD15 (NOD2) is possibly responsible for CD [4][5][6][7][8]. Identified nucleotide oligomerisation domain (NOD2) as the IBD gene and recently, the nomenclature of NOD2 has been changed to caspase activating recruitment domain (CARD15).…”

“…Identified nucleotide oligomerisation domain (NOD2) as the IBD gene and recently, the nomenclature of NOD2 has been changed to caspase activating recruitment domain (CARD15). CARD15/NOD2 has a role in inflammatory response to bacterial triggers, especially lipopolysaccharides (LPS), and is expressed exclusively in monocytes and it has structural homology with R protein which is a class of plant disease resistance gene product [8]. CARD15/NOD2 comprises an amino terminal effector domain, a nucleotide-binding domain and leucine-rich repeats (RRs) and regulates apoptosis and/or nuclear factor (NF)-B activation [9].…”