Abstract
Abstract: :
Purpose: CARD15/NOD2 mutations have been found to cause a rare autosomal–dominant form of uveitis called familial juvenile systemic granulomatosis (also called Blau syndrome or Jabs disease). Mutations in CARD15/NOD2 distinct from those found in familial juvenile systemic granulomatosis predispose individuals to Crohn’s disease (CD). CD is an inflammatory condition which sometimes includes uveitis. The presence of specific CARD15/NOD2 mutations has an affect on the phenotypic presentation of CD. Since both familial juvenile systemic granulomatosis and CD are granulomatous diseases associated with uveitis, we tested the hypothesis that CARD15/NOD2 mutations influence the presence of uveitis in a CD population. Methods: Uveitis patients diagnosed with CD seen at the Casey Eye Institute Uveitis clinic and CD patients with no ocular involvement seen at the Gastroenterology clinic at Oregon Health & Science University were recruited into the study. All 12 exons of CARD15/NOD2 were genotyped either by direct sequencing or by denaturing HPLC analysis. Statistical analyses were performed by the Fisher’s Exact Test. Results: A total of 35 CD patients were genotyped. Ten patients (7 female, 3 male) suffer from uveitis related to their CD, whereas the other 25 have no ocular involvement reported with their disease (17 female, 8 male). All patients were Caucasian, including 1 Hispanic and 2 patients with mixed Caucasian and Native American ancestry. The group with uveitis was older (age range 35–79, mean age 51) compared to the patients without uveitis (age range 19–70, mean age 39). Of the 10 patients with both CD and uveitis, 7 had colitis and 3 had ileocolitis. Among 25 CD patients without uveitis, there were 12 with small bowel inflammation, 7 with small bowel and colon CD and 6 with colitis alone. CD–associated mutations were present in this cohort of patients. The 3 most common CD mutations (corresponding to amino acid changes R702W, G908R and 1007fs) were identified in 10/25 patients without uveitis (at a combined allele frequency of 26%), but were not found in any of the 10 patients with uveitis. This difference, i.e. 26% vs. 0%, was statistically significant with a P = 0.014. Conclusions: Mutations in CARD15/NOD2 that contribute to the genetic predisposition to CD are strikingly absent from the subset of CD patients who develop uveitis. Colitis, a clinical component of CD that is independent of CARD15/NOD2 mutations, tends to be more common in CD patients with uveitis compared to patients with CD in general.
Keywords: inflammation • genetics • candidate gene analysis