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NOD2 Genotype (nod2 + genotype)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population

INFLAMMATORY BOWEL DISEASES, Issue 5 2008
Georgia E. Hume MD
Abstract Background: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD. We aimed to investigate the relationship between TLR4 A299G and TLR5 N392ST, and an Australian inflammatory bowel disease cohort, and to explore the strength of association between TLR4 A299G and CD using global meta-analysis. Methods: Cases (CD = 619, ulcerative colitis = 300) and controls (n = 360) were genotyped for TLR4 A299G, TLR5 N392ST, and the 4 major NOD2 mutations. Data were interrogated for case-control analysis prior to and after stratification by NOD2 genotype. Genotype,phenotype relationships were also sought. Meta-analysis was conducted via RevMan. Results: The TLR4 A299G variant allele showed a significant association with CD compared to controls (P = 0.04) and a novel NOD2 haplotype was identified which strengthened this (P = 0.003). Furthermore, we identified that TLR4 A299G was associated with CD limited to the colon (P = 0.02). In the presence of the novel NOD2 haplotype, TLR4 A299G was more strongly associated with colonic disease (P < 0.001) and nonstricturing disease (P = 0.009). A meta-analysis of 11 CD cohorts identified a 1.5-fold increase in risk for the variant TLR4 A299G allele (P < 0.00001). Conclusions:TLR 4 A299G appears to be a significant risk factor for CD, in particular colonic, nonstricturing disease. Furthermore, we identified a novel NOD2 haplotype that strengthens the relationship between TLR4 A299G and these phenotypes. (Inflamm Bowel Dis 2007) [source]

Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis

ARTHRITIS & RHEUMATISM, Issue 1 2009
Ikuo Okafuji
Objective Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-,B activity predict the Blau syndrome/EOS clinical phenotype. Methods Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-,B activity, which was defined as the ratio of NF-,B activity without a NOD2 ligand, muramyldipeptide, to NF-,B activity with muramyldipeptide. Results All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-,B activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-,B activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment. Conclusion NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS. [source]

NOD2/CARD15 genotype influences MDP-induced cytokine release and basal IL-12p40 levels in primary isolated peripheral blood monocytes

INFLAMMATORY BOWEL DISEASES, Issue 8 2008
Vanessa Beynon MD
Abstract Background: The functional link between mutations in NOD2 and Crohn's disease (CD) has not been entirely elucidated. The 1007fs mutation results in loss of NF-,B activation in response to muramyl dipeptide (MDP) but has also been linked to an increased IL-1, processing and IL-12 release. Methods: We investigated the basal and MDP-triggered mRNA expression and protein release for TNF-,, IL-10, IL-1,, and IL-12p40 in peripheral blood monocytes from 40 CD patients and 15 healthy individuals with different NOD2 genotypes. Results: Monocytes from individuals with 2 mutated NOD2 alleles (homozygous and compound-heterozygous individuals) displayed an impaired release of TNF-, and IL-10 but also of IL-1, and IL-12p40 in response to MDP. In contrast to other NOD2 variants, the presence of at least 1 1007fs allele in double-mutated individuals completely abrogated NOD2 receptor function. Interestingly, monocytes from CD patients with 2 mutated NOD2 alleles displayed significantly higher basal levels of IL-12p40 in cell culture supernatants compared to wildtype CD patients and control individuals (P = 0.002 and P = 0.008, respectively). This was regardless of the IL23R genotype and was not mirrored by increased IL-12p40 plasma levels in these individuals. Conclusions: The CD-associated NOD2 variants lead, in a dose- and mutation-dependent manner, to an impaired release of TNF-,, IL-10, IL-1,, and IL-12p40 in response to MDP. The finding of increased basal levels for IL-12p40-related cytokines in monocytes with 2 mutated NOD2 alleles is likely to set a new link between NOD2 mutations and the inflammatory mechanisms underlying CD. (Inflamm Bowel Dis 2008) [source]