Genetic testing - questions

[BunnyMummy]

Hi all

I'm pretty sure I don't currently have celiac disease based on recent serology. I have (probably) IBS and autoimmune thyroid disease so celiac keeps popping up every few years as something to consider. I did a genetic test, hoping that it would show negative and I'd then never need to think of it again. My results have come back consistent with (but not diagnostic for) celiac disease, so I guess that didn't turn out as I'd hoped.  

Is anyone able to help me understand these results a bit better? I've done lots of reading but I don't really know enough about it to draw any conclusions except that I think it puts me into a somewhat higher risk than average of developing celiac disease, but still overwhelmingly most likely never to develop it.

I will, of course, discuss it with the doctor, but my next appointment is in a month or so and it doesn't seem urgent enough to bring that forward.

HLA DQ2 Alleles

DQA1 *05 Detected

DQA1 *02 Not Detected

DQB1 *02 Detected

HLA DQ8 Alleles

DQB1 *0302 Not Detected

 

Many thanks, Bunny

[knitty kitty]

Welcome to the forum, @BunnyMummy!

Having genes that code for Celiac Disease does not mean that you have active Celiac Disease, however, since you have autoimmune thyroid disease and IBS symptoms (which overlap with Celiac symptoms) proper testing for active Celiac Disease should be done.  

Some people invalidate their antibody tests by not eating sufficient gluten prior to testing blood for Celiac antibodies.  Some of us with Celiac Disease are seronegative, like me.  Anemia, diabetes and Thiamine deficiency can cause seronegative test results.  Thiamine deficiency is also seen in autoimmune Thyroid disease.

I found some articles for you.  

HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: practical implications of the HLA molecular typing

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482388/

And...

HLA DQ Gene Dosage and Risk and Severity of Celiac Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2175211/

And...

HLA-DQA1 and HLA-DQB1 Alleles, Conferring Susceptibility to Celiac Disease and Type 1 Diabetes, Are More Expressed Than Non-Predisposing Alleles and Are Coordinately Regulated

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678473/

And instructions for the Gluten Challenge prior to antibody testing for Celiac Disease.

According to recent research, updates to the gluten challenge are being implemented.

Recommended intake of gluten should be increased to 10 grams of gluten per day for at least two weeks. Or longer.

While three grams of gluten will begin the immune response, ten grams of gluten is needed to get antibody levels up to where they can be measured in antibody tests and changes can be seen in the small intestine.  

Keep in mind that there are different amounts of gluten in different kinds of bread and gluten containing foods.  Pizza crust and breads that are thick and chewy contain more gluten than things like cake and cookies.  

References:

https://www.beyondceliac.org/celiac-disease/the-gluten-challenge/

And...

Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878429/?report=reader

 "In our study, limited changes in Vh:celiac disease (villi height vs crypt depth - aka damage to the small intestine)  following 14-day challenge with 3 g of gluten were observed, in accordance with Sarna et al.  While the 3 g dose was sufficient to initiate an immune response, as detected by several biomarkers such as IL-2, the 10 g dose was required for enteropathy within the study time frame. Based on our data, we would suggest that gluten challenge should be conducted over longer durations and/or using doses of gluten of ≥ 3 g/day to ensure sufficient histological change can be induced."
Keep us posted on your progress!

[BunnyMummy]

Thank you Knitty Kitty.

I was on a gluten including diet, though not necessarily every day. I increased the gluten intake for about 4.5 weeks (breakfast cereal, sandwiches etc) and then did the serology test which came back negative. I've had two other tests in the past, which were also negative. I did call it at 4.5 weeks because I was very uncomfortable, but I also had milk, which could be the culprit. I think a low FODMAP diet with a set of proper challenges will be useful.

This was a quote from one of your links - "Ninety-seven percent of celiac disease patients carried both of the HLA alleles, DQA1*05 and DQB1* 02. Those who carried a second allele of DQB1*02 were 5 times more likely to have celiac disease as those with just one (95% CI:1.4-18.1). The carriage of 2 copies of DQB1*02 did not predict either an earlier age of onset or severity of disease."

How might one know if they have a second copy of DQB1*02? My results just say "detected".

Cheers

Bunny

[knitty kitty]

You would have two copies of DQB1*2 instead of having one of each of DQB1*2 and DQA1*5.

[BunnyMummy]

Ah, I see - two only regardless of the distribution? (So could also have been two DAQ1*05?)

Sorry, really not familiar with any of this. Thank you.

[knitty kitty]

You can have lots of different combinations as discussed in those articles.  But you only need one of those alleles  (not two together) to be susceptible to CeD.

[BunnyMummy]

The articles, being medical, assume some knowledge that I don't have. Will read carefully and search for various terms.

I keep seeing reference to one combination being higher risk than other combinations.

[BunnyMummy]

Based on the table on this page:

I think my results fall on the second row - DQ2 +DQ2 OR DQ2 Homozygous DQB1*02

Cheers
Bunny

 

[knitty kitty]

I'm sure there are more complete genetic tests available if you were interested in finding out exactly your Celiac genes.  And people who can decipher the results better!  

Do pursue more thorough testing for Celiac Disease with a proper gluten challenge.  

Let us know what you find out!  

[BunnyMummy]

I will follow up but I think the negative serology was probably accurate as I was eating gluten already, and added more for the last month or so. Will see if I can find an IBS 'specialist' GP to talk to.

 

Cheers and thanks for your help.

[knitty kitty]

There are a lot of people who have been misdiagnosed as having IBS when they actually had Celiac Disease and, in the average of ten years to be properly diagnosed, their health suffers unnecessarily.  

Have you started a gluten free diet yet?  Did your IBS symptoms resolve?

Which antibody tests for Celiac Disease did you have?  Specifically, did you have a total IgA and tTg IgA?   Autoimmune thyroid disease can affect the production of Celiac antibodies.  

There's some evidence that anti-gluten antibodies can attack the thyroid.  

There's a genetic overlap between Celiac Disease and autoimmune thyroid disease.  

"The prevalence of autoimmune thyroid disease in patients with celiac disease is four times greater than that in the general population, and this may be due to the common genetic predisposition."

https://www.beyondceliac.org/celiac-disease/related-conditions/thyroid-disease/

Celiac Disease and Autoimmune Thyroid Disease: The Two Peas in a Pod

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312543/

Celiac Disease and Autoimmune Thyroid Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2111403/

Best wishes

[BunnyMummy]

I haven't cut out gluten at this stage. I have eliminated milk (but not cheese) and the bowels have been dramatically better. Not perfect, but it's much more manageable. Lactose must be an issue for me which was a bit of a surprise. 

The celiac testing done was Deamidated Gliadin IgG and Tissue Transglutaminase IgA. Both results were <1. This is the standard celiac screening test at this lab. I don't know about other labs.

 

[knitty kitty]

Ideally, a Total IgA test should be done to make sure you are producing sufficient IgA antibodies in general, because we make lots of different kinds of IgA antibodies.  A test for tTg IgA is looking for the specific antibodies against gluten.

If the Total IgA is below "normal" limits, then the specific tTg IgA test is not accurate.  This can result in a false negative.  

If the Total IgA is within "normal" range, and specific tTg IgA is not there, then possibly a negative diagnosis may be diagnosed.  However, some people in the early stages of CeD produce tTg IgA antibodies, but they stay in the intestines where they are produced and don't get into the bloodstream.  This can be a false negative.

Diabetes, anemia and Thiamine deficiency can affect tTg IgA antibody production, resulting in seronegative Celiac Disease.  This would be a false negative.

The "Gold Standard" of Celiac diagnosis is an endoscopy with biopsy sampling from the different areas of the small intestine.  Damage to the small intestine can be patchy and easily missed or beyond the reach of the endoscopy scope.  Much of the damage can be microscopic, (especially in the early stages of CeD), which requires special staining and examination by a pathologist experienced with CeD.  Again, this can result in false negatives if inexperienced doctors don't take biopsy samples from the right areas, and if the pathologist isn't well versed in CeD damage.  

DGP IgG antibodies are frequently found in children and young adults because their immune systems are less mature.  Older adults may not have these.

The tTg IgA antibodies attack gluten, but also cause collateral damage to the villi in the small intestine.  Villi absorb nutrients from our food, but villi also produce lactase, an enzyme that breaks down lactose, the sugar in dairy.  After being damaged, villi can no longer produce lactase.  This results in lactose intolerance, a symptom commonly found in CeD.  

Antigluten antibodies can affect the Thyroid, possibly complicating your Autoimmune Thyroid disease.  

Genes never change. 

It would be a disservice not to pursue further discussion with your doctor about a Celiac diagnosis.  

No one wants to be a member of the Celiac club, but knowing how to improve our health improves our quality of life.  

[BunnyMummy]

On 12/22/2023 at 2:40 PM, knitty kitty said:

You would have two copies of DQB1*2 instead of having one of each of DQB1*2 and DQA1*5.

Hi again

Looking back on my test, it simply says 'detected' (or 'not detected'). I suspect the test wasnt specific enough to identify how many copies. At this stage, I'm making an appointment, hopefully with a GP who helped family members - do you think it is worth having the same test at a different lab? Family members were advised single/double of the allele, so I assume the lab they used was more detailed.