Gastroduodenal Crohn's Disease Is Associated With NOD2/CARD15Gene Polymorphisms, Particularly L1007PHomozygosity

Abstract

Limited data exist on the specific association between gastroduodenal Crohn's disease (GDCD) and NOD2/CARD15 gene polymorphisms. The aim of this study was to assess the association between NOD2 polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702W and the clinical features of Crohn's disease. We retrospectively reviewed the records of 202 patients with confirmed Crohn's disease and complete data was performed. Seventy-one patients (35%) had at least 1 allelic variant: 55 had 1 variant, 4 were homozygous for L1007fs, 2 homozygous for R702W, and 10 were compound heterozygous. Eighteen patients with confirmed GDCD were identified; 10 (56%) had wild type, 4 (22%) had 1 variant, and 4 (22%) had 2 allelic variants (2 were L1007P homozygous and 2 compound heterozygous). Compared to patients without gastroduodenal involvement, those with GDCD were more likely to have 2 allelic variants (22% vs. 6%; odds ratio [OR] 2.7; 95% confidence interval [CI] 1.6-7.3) and to be homozygous for L1007P (11% vs. 1%; OR 5.2; 95% CI 2.5-9.4). G908R heterozygosity was associated with ileal involvement (OR 1.4; 95% CI 1.1-2.9) and smoking habits (OR 2.4; 95% CI 1.2-3.8), whereas L1007P homozygosity was associated with GDCD (OR 5.8; 95% CI 2.6-10.8). L1007P variation was associated with younger age at diagnosis as well. There was no specific association between R702W homo- or heterozygosity and any of the characteristics examined. In conclusion, GDCD is associated with double dose of the NOD2/CARD15 gene variants, particularly L1007P homozygosity. There is evidence of specific variant-phenotype associations. G908R heterozygosity is associated with ileal involvement and smoking, whereas L1007P homozygosity is strongly associated with GDCD and younger age at diagnosis.

Macrophage migration inhibitory factor (MIF) −173G/C promoter polymorphism influences upper gastrointestinal tract involvement and disease activity in patients with Crohnʼs disease

“…This is in contrast to a recent study that demonstrated that patients with gastroduodenal CD involvement were more likely to carry 2 allelic CARD15 variants and to be homozygous for the 1007fs mutation. 37 In contrast, in our study CARD15 1007fs homozygotes were overrepresented among MIF GC heterozygous carriers, the group with the lowest upper GI involvement (11.1% compared to 2.7% with the MIF wildtype GG genotype; P ϭ 0.035). However, the observed lack of upper GI involvement was independent of the CARD15 genotype since there was no significant difference in the frequency of upper GI involvement between carriers and noncarriers of CARD15 variants in the GC heterozygous group (P ϭ 0.585).…”

“…However, the observed lack of upper GI involvement was independent of the CARD15 genotype since there was no significant difference in the frequency of upper GI involvement between carriers and noncarriers of CARD15 variants in the GC heterozygous group (P ϭ 0.585). Similar to our study, the analysis by Mardini et al 37 was performed retrospectively. To avoid selection and ascertainment biases, we therefore prospectively analyzed the MIF and CARD15 genotype status of all 13 CD patients diagnosed To compare expression levels between inflamed and noninflamed colonic lesions, mRNA expression in noninflamed tissue was arbitrarily set to 1.0.…”

“…For example, CARD15 mutations are significantly associated with ileal location. [32][33][34][35][36] In contrast, there are currently, with the exception of one preliminary report, 37 no studies on genetic risk factors for upper GI tract involvement in CD patients. In addition, the exact incidence and prevalence of CD in the upper GI tract is still unknown, because adequate population-based studies are lacking, although upper GI tract involvement is associated with a worse prognosis.…”

Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up

“…[29][30][31][32][33][34][35] All samples were analyzed in one laboratory (Dr de Villiers, University of Kentucky Medical Center). For NOD2, the allelic variants G908R, L1007P, and R702W were assayed by polymerase chain reaction (PCR), amplification of the entire sequence of exon 8 and exon 11, and the relevant segment of the large exon 4 of the NOD2/CARD15 gene, followed by restriction fragment length polymorphism analysis.…”

Crohn’s Disease: a Role of Gut Microbiota and Nod2 Gene Polymorphisms in Disease Pathogenesis

“…They frequently need a surgical intervention and have a high risk of restenosis. This mutation is also associated with gastroduodenal involvement (26)(27)(28). In addition to CD, three missense mutations (R334W, R334QQ an L469F) in the nucleotide-binding domain of Nod2 confer susceptibility to another granulomatous disorder affecting the eyes, skin, and joints known as Blau syndrome (29) and early onset sarcoidosis (30).…”