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Prometheus NOD2 / CARD15 Test

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Prometheus NOD2 / CARD15 Test

The Prometheus NOD2 / CARD15 Gene blood test is a genetic test that looks for any of 3 different gene mutations in the gene most commonly associated with Crohn's Disease, the NOD2 / CARD15 gene.

Although there are more than these three mutations in the NOD / CARD15 gene that may increase a person's likelihood of developing Crohn's Disease, these three are among the most commonly associated with Crohn's and are an indicator of patient prognosis.

What Does Prometheus NOD2 / CARD15 Test For?

The Prometheus NOD2 / CARD15 Test specifically looks for the three following mutations (discussed below): R702W [C2104T]; G908R [G2722C]; 1007fs [3020insC] (Please see Figure 1):


[pos]1a[/pos]

Figure 1: NOD2 / CARD15 Domains and Crohn's Disease - Associated Mutations

About NOD2 / CARD15

- The NOD2 / CARD15 (Nucleotide-Binding Oligomerization Domain-Containing Protein 2 / CAspase Recruitment Domain 15) gene is located on Chromosome 16q12 UGID: 2061083; UniGene Hs. 592072.

The NOD2 / CARD15 protein is 1040 amino acids long and is expressed at highest levels in White Blood Cells (WBC), or Leukocytes, of the immune system. Specific mutations in the gene, and corresponding change the amino acid sequence in the NOD2 / CARD15 protein are associated with Crohn's Disease (see Figure 1).
NOD2 / CARD15 Domains
There are 3 specific types of Domain important to proper NOD2 / CARD15 function. A domain is a region on the protein that folds in a very stereotyped way and usually carrys out a specific job important to proper protein function.

The important domains in the NOD2 / CARD15 protein are:
1. The CARD Domain(s). The CAspase Recruitment Domain (CARD). These domains activate signaling via the NOD/2CARD15 proteins.

2 .The NACHT Domain. The NACHT [NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein)] domain binds to other NACHT domains (on NOD2 or other protein containing a NACHT domain). This NACHT - NACHT binding between proteins brings the two proteins close together so other domains on the proteins may interact with each other. [3]

3. The LRR Domain(s). The Leucine - Rich Repeat Domain recognizes certain patterns specific to the bacterial cell wall.
NOD2 / CARD15 Crohn's Disease - Associated Mutations
Crohn's disease related mutations in the NOD2 / CARD15 gene has been suggested to correlate with age of symptom onset. This idea is controversial, although recent research has indicated an age-of-onset factor related to some gene mutations. Crohn's disease is generally well-accepted to be a multifactorial disease with complex interactions between gene mutation(s) causing immune response dysregulation and environmental influences.

For pediatric onset Crohn's disease, symptoms are thought to be mainly due to effects of gene mutation(s) since envitonmental influences have not yet had time to play a substantial role. In contrast, adult-onset symptoms are thought to be due to both genetic and environmental influences.
R702W SNP 8
The first polymorphism the Prometheus NOD2 / CARD15 test is R702W [C2104T]. A single base change in the NOD2 / CARD15 gene from C to T at nucleotide 2104 conferrs a substitution from R (Arginine) to W (Tryptophan) at amino amino acid 702 along the protein (See Figure 1).
- The R702W polymorphism is found at slightly higher rates in adult-onset Crohn's disease versus childhood onset.
G908R SNP 12
The G908R polymorphism, amino acid substitution 908, R (Arginine) for G (Glycine) is due to a point mutation at nucleotide 2722 in which C is sutstituted for G in the DNA. See Figure 1.
- The G908R polymorphism in the NOD2 / CARD15 gene was found at slightly higher rates in adult onset patients versus childhood symptom onset.
1007fs SNP 13
The 1007fs [3020insC] polymorphism, a result of a nucleotide insertion (C) at residue 3020 results in a frame-shift in the protein at amino acid 1007.
- The 1007fs variant is significantly correlated with childhood onset of the disease over adult onset. See Figure 1.

- All three polymorphisms correlate with symptomology involving ileitis and ileocolitis. In patients with Greek background, there was no correlation with stricturing phenotype.

- In Crohn's Disease patients of italian descent, any one of these three mutations correlated significantly with small bowel obstruction, acute intestinal obstruction at diagnosis, strictures, fistulas, and increased number of surgeries. [2]

- In persons that have one of these three gene mutations on only one DNA strand, the risk of developing Crohn's Disease increases 1.5 to 3 fold.

- In persons that have more than one of the three NOD2/CARD15 mutations, or have the same mutation on both DNA strands, the risk of developing Crohn's Disease increases between 10 to 40 fold.

- Crohn's Disease patients carrying at least one of the three NOD2/CARD15 mutations are at higher likelihood of having ileal Crohn's Disease symptoms.
- This has been suggested to be due to effects in NOD2/CARD15-expressing ileal Paneth cells, which secrete defensins (part of the innate immune response).

- NOD2/CARD15 mutations increase Crohn's Disease susceptibility primarily in in Caucasian persons.

How do NOD2/CARD15 Mutations Cause Increased NFkB Activation?

- Mutations in NOD2/CARD15 result in reduced signaling in response to microbial infection and decreased NFkB activation. However, NOD2/CARD15 is a feedback inhibitor of the Toll-Like Receptor 2 (TLR-2) pathway which activates NFkB.

- NOD2/CARD15 mutations decrease the efficacy of the feedback inhibitory pathway on NFkB, leading to the overactivation of NFkB and pro-inflammatory symptoms seen in Crohn's Disease.

Things to Know About Prometheus Labs NOD2 / CARD15 Genetic Test

- A positive test for one ore more of the three genes tested for in the Prometheus NOD2 / CARD15 genetic test is not a guarantee that a person will develop Crohn's Disease

- The Prometheus Labs NOD2 / CARD15 genetic testing is by no means an exhaustive measure of all possible gene mutations that can increase susceptibility risk for Crohn's Disease. Within the NOD2 / CARD15 gene itself, there are multiple other mutations that correlate with Crohn's Disease or other diseases. Furthermore, there are a large number of genes that are involved in Crohn's Disease, and mutation in any one of them can confer increased risk of Crohn's Disease or even protection from Crohn's Disease.

CPT Codes Charged by Prometheus NOD2 / CARD15 Test

The Current Procedural Terminology codes, or CPT codes, are used for medical billing / insurance purposes. Medical bills submitted to your health insurance company typically use CPT codes rather than a description of a procedure. They may often be used for health insurance pre-authorization purposes as well.
CPT Codes for Prometheus NOD2 / CARD15 Genetic Testing
- 83907, Lysis of cells prior to nucleic acid extraction
- 83896(X6), Nucleic acid probe, each DNA marker
- 83898(X3), Amplification of patient nucleic acid, each DNA marker
- 83912, Interpretation and report

- The CPT Codes listed above for the Prometheus NOD2 / CARD15 Test may not be an exhaustive list of charges applied by Prometheus. In addition, you will likely incur charges for the blood draw services at your laboratory, you may be charged shipping of the sample, and when your doctor receives the test result you will be charged for the visit for your results.

Life Insurance, Disability Insurance, and Long Term Care Insurance: Very Important Issues to Consider Before You Undergo Genetic Testing

-Gene testing for disease-causing mutations is not something to be taken lightly. In addition to the emotional toll a positive test result can impart, there is the possibility of a major financial toll regarding Insurance that many people are not aware of.

In the United States, it is legal for an Insurance company to turn you down for Life Insurance, Disability Insurance, or Long Term Care Insurance simply based on your genetic testing results.

Some Insurance companies may choose to instead charge premiums that are so high many people are unable to afford them.

It is legal for Life, Disability or Long Term Care Insurance companies to discriminate against you regarding any genetic test showing a mutation in a disease-causing gene (including mutations for the NOD2 / CARD15 gene associated with Crohn's Disease).

This stumbling block shocked many people who obtain positive gene test results, even if they have no symptoms of the disease. Some highly discriminated against gene mutations include: BRCA1 / BRCA2 genes, associated with breast/ovarian cancer susceptibility (even in men) 4 ; Huntington's gene, a dominant inherited degenerative disease causing progressive loss of controlled movement 5; APO-e4 / ADAD genes, increase risk of developing Alzheimer's Disease, a progressive degenerative disease causing memory loss and dementia 6.

It may be legal for Insurance Companies to discriminate against you if you are seeking Disability Insurance or Long Term Care Insurance based on your genetic test result.

It is not legal for your Health Insurance Company to discriminate against you based on your genetic testing results.

It is not legal fo your Employer to discriminate against you based on your genetic test results as long as your Employer has 15 or more Employees.

The Genetic Information Nondescrimination Act was passed in 2008 (P.L. 110-233, 122 Stat. 881) is a United States Federal Law that protects persons from being descrimited against by Health Insurance Companies and Employers (with 15 or more employees) due to genetic testing results.7,8

References

1. Prometheus Laboratories Inc. Sample NOD2 / CARD15 Test Result.

2. Guagnozzi D, Cossu A, Viscido A, et al. Acute intestinal obstruction and NOD2/CARD15 mutations among italian Crohn's disease patients. Eur Rev for Med and Pharmacol Sci. 2004; 8:179-185. http://www.europeanreview.org/pdf/129.pdf

3. Damiano JS, Oliveira V, Welsh K, and Reed JC. Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses. Biochem J. 2004;381(1):213–219. http://www.ncbi.nlm.nih.gov/pmc/arti.../bj3810213.pdf

4. BRCA1 and BRCA2 Fact Sheet NCI: National Cancer Institute at the NIH, National Institutes of Health. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

5. Huntington's Disease Society of America http://www.hdsa.org

6. Alzheimer's Association http://www.alz.org/alzheimers_diseas...alzheimers.asp

7. Genetic Information Nondescrimination Act (GINA) of 2008. H.R. 493. Retrieved April 16, 2012 http://www.gpo.gov/fdsys/pkg/STATUTE...-122-Pg881.pdf

8. The National Human Genome Research Institute. GINA: The Genetic Information Nondiscrimination Act of 2008: Information for Researchers and Health Care Professionals. Retrieved April 16, 2012 http://www.genome.gov/Pages/PolicyEt...INAInfoDoc.pdf

9. Gazouli M, Pachoula I, Panayotou I, et al. NOD2/CARD15, ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn’s disease. 2010; 16(14):1753-1758. http://www.ncbi.nlm.nih.gov/pmc/arti...JG-16-1753.pdf

10. http://www.springerlink.com/content/086124v331512179

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04-16-2012, 05:17 PM   #1
David
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Wow, incredible article. Very informative. Thank you Judith!
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04-16-2012, 09:11 PM   #2
Judith
 
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Thanks! There is still a TON more I would like to add......
04-21-2012, 02:00 AM   #3
Aura
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Hi

Once again, thank you for the information. The discrimination issues are complex in the US - and probably elsewhere as well. What if you have the genetic predisposition evident in the test - yet it is not physically manifested? It may not manifest. To what extent can the categorical state it will happen?


We have a Human Rights Act here that protects us

http://en.wikipedia.org/wiki/New_Zea...ights_Act_1993

But there still is unseen discrimination
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