Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn’s disease and active smoking status resulting in ileal stenosis requiring surgery

Abstract

Background NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. Methods 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotypephenotype analyses. Results Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p. Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10 −5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of

It is not NOD2 — genetic and clinical risk factors for postoperative complications following ileocolic resection in Crohn’s disease

“…In our cohort, rs2076756 was not assessed and the others were quite rare with only one homozygote Arg702Trp (rs2066844) and one p.Gly908Arg (rs2066845), respectively, but Kline et al also did not find one of the NOD2 SNPs to be associated with postoperative complications after ileocecal resection [21]. In our follow-up data, we could not detect significant differences in the need for further surgical therapy or increased need for immunosuppressive or immune-modulatory therapy over time regarding the risk factors identified by others [18][19][20]: homozygous NOD2 variant, smoking, or fistulating disease.…”

“…To our knowledge, this is the first study to investigate the impact of high-risk SNP p.Leu1007fsX1008 (rs2066847) status on postoperative surgical outcome in a CD cohort undergoing ileocecal resection. In a recent study, Schnitzler et al showed that homozygosity of this variant together with active smoking is associated with a 100% risk for developing ileal stenosis requiring surgery [18]. In our analysis, previous immunosuppressive therapy, the homozygous NOD2 variant p.Leu1007fsX1008 and positive microscopic inflammation margins were not associated with increased risk for severe complications.…”

Gene Polymorphisms of NOD2, IL23R, PTPN2 and ATG16L1 in Patients with Crohn’s Disease: On the Way to Personalized Medicine?

“…The tendency of an association with the ileal phenotype in NOD2 rs2066847 carriers is in accordance with the results from Schnitzler et al [26], who described that all homozygous carriers of this mutation in 1.076 CD patients presented with ileal CD, and if they were smokers, they developed ileal stenosis in all cases.…”

“…The risk allele frequencies of NOD2 rs2066844, NOD2 rs2066845, NOD2 rs2066847, ATG16L1 rs2241880, PTPN2 rs2542151 and PTPN2 rs7234029 were similar to the ones described in other studies [18,25,26].…”

Intestinal stricture in Crohn's disease: A 2020 update

“…Three major nucleotide‐binding oligomerization domain‐containing protein 2 ( NOD2 ) mutations, p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066845) and p.Leu1007fsX1008 (rs2066847), have been proposed to predict the formation of CD strictures 52 . One study 53 found that NOD2 mutation had a gene‐dose effect. There is a strong relationship between the number of affected alleles and the severity of CD, and patients with homozygous rs2066847 mutation have more severe symptoms than those with rs2066844 or rs2066845 mutation.…”