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Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease

a technology of fibrostenosis and mutations, which is applied in the field of mutations in nod2 that are associated with fibrostenosis in patients with crohn's disease, can solve the problems of delayed optimal treatment, increased risk of intestinal cancer, and increased risk of ibd

Inactive Publication Date: 2004-03-18
CEDARS SINAI MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, patients with IBD are at increased risk for the development of intestinal cancer.
The extensive and often protracted clinical testing required to diagnose Crohn's disease and disease subtypes may delay optimal treatment and involves invasive procedures such as endoscopy.
Crohn's disease also can include extra-intestinal complications such as inflammation of the eye, joints and skin; liver disease; kidney stones or amyloidosis; and is associated with an increased risk of intestinal cancer.
Mismatches between a probe and allele reduce the efficiency of both probe hybridization and cleavage by Taq polymerase, resulting in little to no fluorescent signal.

Method used

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  • Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease
  • Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease
  • Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease

Examples

Experimental program
Comparison scheme
Effect test

example ii

Patients with Crohn's Disease Have an Increased Frequency of Rare Allelic Variants of NOD2 / CARD15

[0100] This example describes the association of a "2" allele at SNP 8, SNP 12, or SNP 13 within the NOD2 / CARD15 locus (rare allelic variants of NOD2 / CARD15) with Crohn's disease in a North American population.

[0101] In order to determine whether the North American Crohn's disease patient populations in Cohorts 1 and 2 expressed allelic variants of NOD2 / CARD15, Cohort 1 (hypothesis-generating) and Cohort 2 (hypothesis-confirming) were genotyped for the rare allelic variant of SNP 8 (R675W), SNP 12 (G881R) and SNP 13 (3020insC). A cohort of ulcerative colitis patients was used for comparison.

[0102] Genotyping was performed using a genotyping assay employing 5'-exonuclease technology, the TaqMan MGB.TM. assay (PE Biosystems; Foster City, Calif.). Primers were designed using the software PrimerExpress 1.5.TM. (PE Biosystems) and sequence information found in dbSNP for NOD2 / CARD15 SNP 5, 8, ...

example iii

Rare Variant Alleles in the NOD2 / CARD15 Locus are Associated with the Fibrostenosing Subtype of Crohn's Disease in Cohort 1

[0106] This example demonstrates that a "2" allele at SNP 8, SNP 12, or SNP 13 is significantly associated with fibrostenosing disease in Cohort 1.

[0107] Patients with Crohn's disease express diverse clinical phenotypes that can be due to differences in underlying genetic factors. In order to determine whether rare variant alleles at the NOD2 / CARD15 locus were associated with specific Crohn's disease-related clinical phenotypes or disease-related serum immune markers, univariate analysis was performed. The univariate analysis evaluated the association between NOD2 / CARD15 allelic variants at SNP 8, SNP 12, or SNP 13 and predefined clinical characteristics, including age of onset, disease location, and disease phenotype (fibrostenosing disease, internal-perforating disease, perianal fistulizing disease or ulcerative colitis-like disease). The association between N...

example iv

Rare Variant Alleles in the NOD2 / CARD15 Locus are Associated with the Fibrostenosing Subtype of Crohn's Disease in Cohort 2

[0110] This example demonstrates that a "2" allele at SNP 8, SNP 12, or SNP 13 of the NOD2 / CARD15 locus is significantly associated with fibrostenosing disease in Cohort 2.

[0111] The results obtained with Cohort 1 in Example III indicated that NOD2 / CARD15 rare variant alleles were positively associated with fibrostenosing Crohn's disease, small bowel involvement, ASCA positivity, and younger age of onset, and negatively associated with UC-like disease (see Table 5). These hypotheses were further tested using Cohort 2; the results are shown in Table 6. As with Cohort 1, Cohort 2 demonstrated a significant association between a "2" allele at SNP 8, SNP 12, or SNP 13 of the NOD2 / CARD15 locus and fibrostenosing disease (p=0.002, with Bonferroni correction p=0.01; see Table 6). These results indicate that a "2" allele at SNP 8, SNP 12, or SNP 13 of the NOD2 / CARD15 lo...

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Abstract

The present invention provides a method of diagnosing or predicting susceptibility to a clinical subtype of Crohn's disease characterized by fibrostenosing disease by determining the presence or absence in an individual of a fibrostenosis-predisposing allele linked to a NOD2 / CARD15 locus, where the presence of the fibrostenosis-predisposing allele is diagnostic of or predictive of susceptibility to the clinical subtype of Crohn's disease characterized by fibrostenosing disease. In a method of the invention, the clinical subtype of Crohn's disease can be, for example, characterized by fibrostenosing disease independent of small bowel involvement. The invention also provides a method of optimizing therapy in an individual by determining the presence or absence in the individual of a fibrostenosis-predisposing allele linked to a NOD2 / CARD15 locus, diagnosing individuals in which the fibrostenosis-predisposing allele is present as having a fibrostenosing subtype of Crohn's disease, and treating the individual having a fibrostenosing subtype of Crohn's disease based on the diagnosis.

Description

[0001] This application claims the benefit of priority of provisional application serial No. 60 / 407,391, filed Aug. 30, 2002, and which is incorporated herein by reference.[0003] 1. Field of the Invention[0004] The invention relates generally to the fields of genetics and autoimmune disease and, more specifically, to mutations linked to the NOD2 / CARD15 gene and genetic methods for diagnosing clinical subtypes of Crohn's disease.[0005] 2. BACKGROUND INFORMATION[0006] Inflammatory bowel disease (IBD) is the collective term used to describe two gastrointestinal disorders of unknown etiology: Crohn's disease (CD) and ulcerative colitis (UC). The course and prognosis of IBD, which occurs world-wide and is reported to afflict as many as two million people, varies widely. Onset of IBD is predominantly in young adulthood with diarrhea, abdominal pain, and fever the three most common presenting symptoms. The diarrhea may range from mild to severe, and anemia and weight loss are additional co...

Claims

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Application Information

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IPC IPC(8): C07H21/04C12Q1/68G01N
CPCC12Q1/6883C12Q2600/172C12Q2600/156C12Q2600/112
Inventor ABREU, MARIA T.TAYLOR, KENT D.ROTTER, JEROME I.YANG, HUIYINGSUGIMURA, KAZUHITOTARGAN, STEPHAN R.
Owner CEDARS SINAI MEDICAL CENT
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