Post by kickingfrog on Feb 7, 2011 14:21:00 GMT
CLINICAL OUTLOOK
DNA Testing: Another Piece of the Puzzle
By Kelly Fordon
NFCA Volunteer
Two years ago I had never even heard of celiac disease. Then my son Peter (who was two at the time) started throwing up and couldn’t stop. A year after Peter’s diagnosis a biopsy revealed that I had celiac disease (CD) as well. Later that month, my husband Fred tested positive. According to the pathology report, he had “Stage III CD.”
Our gastroenterologist was baffled. He couldn’t believe we both suffered from the same disease. (If 1 in 133 people have CD then the chance of two CD’s marrying is 1 in 17,000).
Because Fred and I are both celiacs, naturally we were concerned that we’d passed on the genetic marker to our three unaffected children. Our pediatrician administered the blood antibody test. All three tested negative. This did little to diminish our concern. CD has been nicknamed the “great pretender” because the symptoms are varied and range from mild to debilitating.
Early diagnosis and treatment are crucial to reduce the risk of developing other auto-immune disorders or even cancer. We worried because nobody knows when (or what) might trip the CD switch. What if one of our children developed asymptomatic CD? They might suffer for years without knowing they had the disease. What if we didn’t catch it and it affected their growth and development? We thought it was time to consider the gene test.
Our pediatrician didn’t think that the gene test would alleviate our anxiety.
“30% of the population has a genetic marker for CD and only 1% of the population actually gets it,” he said, “Even if the kids are positive, you still won’t know if they’re ever going to develop it.”
If 30% of the population has it and Fred and I both have it, does that mean the kids have the marker?”
“Probably,” he said.
“Does it make a difference if they get it from both parents instead of one?” I asked. “That seems like a double whammy.”
He didn’t know.
There had to be more to it. I started to investigate the genetics behind CD. In order to understand it, it would have been helpful to have an advanced degree in molecular biology.
Luckily, Annette Taylor and Danielle Young of Kimball Genetics both stepped in to provide much needed guidance. (In the interest of brevity and because the terminology is so obscure, the explanations below are geared toward parents and patients with no medical background.)
WHEN DNA TESTING CAN HELP:
1) If your Family is At-Risk: The DNA test for CD involves analysis for the celiac-associated variations in specific HLA (human leukocyte antigen) genes that code for the molecules DQ2 and DQ8. One of these markers must be present for in an individual’s genetic make-up for the disease to develop.
Here’s a little refresher on genetics from Danielle Young:
We all have two sets (23 pairs) of chromosomes, which means we have a total of 46 chromosomes. Children inherit one (23 chromosomes) from their father and one from their mother.
The markers for CD--DQ2 and DQ8--are located on chromosome 6. 90% of CD sufferers carry the DQ2 marker, while 8-10% have the DQ8 marker. The DQ2 and DQ8 markers are composed of two parts—one encoded on our DNA on an alpha site and one on a beta site.
Here are some (but not all) of the possible combinations:
I: A child inherits the alpha half of the DQ2 marker from one parent and the beta half of the marker from the other parent. He ends up with one whole marker (1/2 from each parent) and his risk of developing CD is elevated.
II: A parent has the entire DQ2 marker on one of their chromosomes and they pass on the other unaffected chromosome to their child. The child does not inherit the marker!
III: Alternatively, a parent might have the entire DQ2 marker on one chromosome and he/she might pass that one on to their child. In this case the child would inherit the entire DQ2 marker from that parent (who would also be positive for DQ2) and the risk would increase.
IV: The parent is positive for CD but he has ½ the DQ2 marker on one of his chromosomes and ½ on the other. Since he only passes on one of the two chromosomes, the child only inherits 1/2 the marker. In this situation, the child will be positive for only ½ of the DQ2 marker, making their risk of developing the disease fairly small.
There’s a substantial chance that given all of the various permutations, the child has not inherited the marker or that they have only inherited ½ of the marker. If they only have one ½ of the DQ2 marker then they have less than 1% risk of developing CD.
Conversely, if they carry the marker and they have a family history of CD, then their risk of developing CD can be as high as 40%, according to Young. The only way to know is to test.
There is only one genetic arrangement that has been associated with severe symptoms including early onset diagnosis, refractory sprue and in some cases T-Cell Lymphoma.
This happens if a person is DQ2 positive on both chromosomes (homozygous for DAB1*2 in DQ2-positive at the beta sight.) Of course this means little to the layperson, but it is worth noting. I, for one, will want to know if my children have inherited this particular combination so that we can be mindful of possible complications. For this reason alone, DNA testing might be invaluable for a family-at-risk.
If an asymptomatic relative is positive for the DQ2 or DQ8 marker, they should be monitored (antibody testing/possible small bowel biopsy) every three to five years for the rest of their lives. If they do not have the marker then THEY NEVER HAVE TO WORRY ABOUT CELIAC DISEASE AGAIN!
2) In the Absence of Gluten: The standard testing for CD includes an antibody blood test and a possible small bowel biopsy depending on the antibody blood test results. The blood test looks for celiac-associated antibodies to see whether your body produces antibodies against gluten (gliadin).
An important aspect of the blood testing is that you MUST be exposed to gluten for the testing to be accurate. Sometimes family members are on a low-gluten diet due to other family member’s restrictions. Sometimes people choose to follow a gluten-free diet because it alleviates symptoms.
In either case, when a person doesn’t want to perform a one to three month “gluten challenge” prior to a small bowel biopsy, the DNA test is a viable option. DNA is not altered by diet, therefore there’s no need to be on a gluten free diet prior to testing.
3) If you have a Borderline or Ambiguous Blood or Small Bowel Biopsy Result: If a person has a positive blood antibody test but the small bowel biopsy is negative, the genetic test will determine whether a person has the genetic marker associated with CD. Perhaps the disease is not advanced enough to induce villous atrophy. If the person has the genetic marker associated with gluten sensitivity then villous atrophy might occur in the future—especially if the blood test was positive. If they don’t have the marker, then CD is not the problem.
4) If a person is not responding to the gluten-free diet: In this situation, the diagnosis of CD is in question. Negative DNA results would indicate that the individual does not have CD and would explain lack of response to the gluten-free diet. Positive results could help motivate these individuals to continue on the gluten-free diet, examine their diet for hidden sources of gluten or address the possibility of refractory sprue.
Empirical studies suggest that other gene variants may play a role in the onset and severity of CD. No one knows why some people with the gene markers manifest CD and others don’t.
Research is also being done into the complex interplay of genes and environment in activating CD. In the meantime DNA testing for DQ2 and DQ8 markers may provide much needed clues for patients and family members. It may not be as helpful for the general population, many of whom carry the marker, because most will never (the reasons are still unknown) test positive for CD.
Kimball Genetics is located in Denver, Colorado and offers the Celiac Disease DNA Test on cheek cell samples.
Turnaround takes one day. Family discounts and insurance billing applies.
The test includes detailed reports with genetic interpretation, recommendations and education as well as genetic counseling for physicians, patients and families. Other labs offering the test include Prometheus, Enterolab and Labcorp, among others. Check with your insurance provider concerning coverage…
www.celiaccentral.org/About-NFCA/19/
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