3 Genes?

[beebs]

I was reading on facebook and someone said that their husband tested positive for 3 coeliac genes??? I thought we only had two copies of HLA DQ genes? What do you suppose it means?

[mushroom]

I don't understand the genetics, but I do understand that you can have half genes, and that in Europe there are more than two genes recognized as celiac genes.

[beebs]

This is here in oz - we only recognise DQ8 & DQ2 - man genetics is so complicated!

[ravenwoodglass]

This is here in oz - we only recognise DQ8 & DQ2 - man genetics is so complicated!

It is the same way here in the US. It seems to depend on what country you are in as to what genes are recognized. Research is showing that at least 9 but possibly many more genes are involved.

My genes are not celiac associated genes here in the US. They are thought to be genes associated with RA. Oddly enough some folks with RA respond quite well to the gluten-free diet. My RA symptoms resolved within 6 months. Now in the Middle East and Asia those same genes are recognized as being celiac associated genes.

Doctor put too much stress on a science that is in it's infancy. Genetics can not be used to firmly rule in or rule out celiac.

[beebs]

I totally get you raven, what I meant though was - don't we only have two copies of HLA DQ genes? One inherited from each parent?

So are you HLA DQ 9/HLA DQ 9?? I am also DQ 6 - which I heard was associated with RA also - but I could be wrong!

This gene stuff is way too smart for me

[Skylark]

HLA-DQ is made from two proteins, alpha and beta. You get two genes for alpha and two for beta, one from each parent. The genes are called HLA-DQA1 and HLA-DQB1. DQ2 and DQ8 are the so-called celiac HLA-DQB1 chains. The third so-called celiac gene is HLA-DQA1 *0505. It is possible to be unlucky enough to get all three.

[beebs]

Thank you Skylark! You always know the scientific stuff!

[mushroom]

beebs, it's way too smart for me too, having flunked chemistry and math in high school However I went on-line shopping with the Google department store and found this which may help some:

Open Original Shared Link

What does HLA mean?

HLA stands for Human Leukocyte Antigen which are certain molecules found on the surface of cells. More than 100,000 HLA molecules (many copies of some few variants; see below) can be expressed on the surface of a single cell. The genes which encode (i.e. determine the structure of) these HLA molecules are found on Chromosome 6 in humans.

HLA molecules are involved in immune regulation. They bind to small fragments(peptides) of bacteria, virus etc. and present these to particular cells (T-cells) of the immune system. T-cells patrol the body and are educated to inspect whether the HLA molecules display peptides that are foreign to the body. If a T-cell recognizes something foreign, it sends out an "alarm". This will result in an immune response and the immune system will start to attempt to defeat the presumed intruder in the body. It is likely that in Celiacs the immune system reacts to gluten and that the immune response which is initiated in the small intestine on contact with gluten results in alterations of the normal gut tissue.

Why only some individuals react to gluten is not completely understood. There exist a large number of different variants of HLA molecules. Which HLA molecules an individual manufactures is determined by the gene-variants the individual has inherited from his or her parents. It is conceivable that some particular varieties of HLA molecules (i.e. DQ2 and DQ8; see later) are particularly efficient in binding and presenting gluten fragments and that individuals who carry these particular HLA molecules are more prone to develop Celiac Disease. It is important to remember that the very same HLA molecules that present gluten fragments also are very efficient in presenting fragments of virus and bacteria and are thus of great importance for the body to survive from various infections.

How does one test for HLA markers? Where? How much does it cost? Will insurance cover it?

HLA typing can be done either by analyzing the genes which code for the HLA molecules or by analyzing the HLA molecules themselves. Today most laboratories perform HLA typing by analyzing the HLA molecules on the surface of cells. Conveniently the typing is done with leukocytes (white blood cells) that are isolated from a blood sample. In some few years gene-analysis may become the standard way of doing HLA typing.

Most large commercial laboratories can perform HLA typing. The cost varies, depending on where it is performed, and how many HLA markers are specified to be analyzed. The costs range from $160 to $800 in the few examples the Listowners have seen. Those who donate blood for celiac genetics studies typically get the HLA typing done for free.

Not only will insurance generally NOT cover HLA typing (at least in the US), but some patients are fearful that if their insurance company discovers that they have HLA markers implying a much higher risk for developing a serious disease, that in the future, coverage may be denied. This is topic on which heated discussion is occurring in the U.S. Some patients actually use a different doctor for their HLA typing and do not submit the invoice to their insurance company for this reason.

How many different types of HLA markers are there?

Your HLA type can be called your body type just as your particular ABO type is your blood type. HLA terminology is rather complex. To make matters worse, the coding has been changed several times by the immunologists. The following is an attempt to explain the HLA system in a simplistic way:

HLA molecules exist in two classes. HLA-A, HLA-B and HLA-C molecules make up the class I molecules and HLA-DR, HLA-DQ and HLA-DP molecules make up the class II molecules. All HLA molecules consist of two units; an alpha chain and a beta chain. For each chain there is a corresponding gene. The genes coding for HLA molecules (except the gene coding for the beta chain of class I molecules) are positioned on a stretch of chromosome 6 like pearls on a string. For each gene locus (each position) there exist a large number of variants or alleles (colors of pearls). For some loci there are more than 100 different variants described! Each individual has two chromosomes (pearl strings) which are inherited from the mother and the father. The composition of alleles on the two chromosomes (combination of colored pearls on the strings at different positions) are characteristic for each individual. Typically, the genes of one chromosome (the colored pearls on one string) code for one HLA-A molecule, one HLA-B molecule, one HLA-C molecule, two HLA-DR molecules, one HLA-DQ molecule and one HLA-DP molecule. Provided that the genes on the individual's two chromosomes code for different variants (i.e. there are different color of the pearls in the corresponding positions on the two strings) an individual may express as much as 14 different HLA molecules. (The number can be larger as in some instances alpha- and beta-chains of HLA-DQ and HLA-DP molecules that are coded for by genes on opposite chromosomes may form functional molecules).

Which alleles (color of pearls) that occur together at the various loci (positions) are not completely random. Some combinations are particularly frequent. Several combinations of alleles (color of pearls) are usually maintained together as gene blocks (segments of pearls). If you have one particular allele (color of pearl) at one locus (position) you very often have another distinct allele (color of pearl) at a neighboring locus (position). This phenomena is termed linkage disequilibrium and is very important for understanding association of certain diseases with particular HLA markers.

Which HLA markers are associated with Celiac Disease? I have been confused, sometimes reading about DQ2, at other times about DR3, B8 and other markers.

The three markers DR3, B8 and DQ2 are all associated with Celiac Disease. The reason for this is that the genes which code for B8, DR3 (also termed DRw17) and DQ2 are in linkage disequilibrium. They are part of a gene segment that is usually maintained as a gene block. This fact has posed a problem in the work to identify which molecules are actually involved in the development of Celiac Disease and which alleles are just associated with celiac disease because the genes coding for these molecules are usually linked with the predisposing genes. In other words: Which of B8, DR3 or DQ2 are actually involved in the development of Celiac Disease and which are just marker molecules?

Those Celiacs who are not DR3 positive very often are DR5/DR7 (DR5 is coded for by genes on the one chromosome and DR7 is coded for by genes on the other chromosome). Individuals who are DR3, almost always also are DQ2 (because the genes coding for DR3 and DQ2 are in linkage disequilibrium - they are in a conserved gene block). The names of the genes in this gene block that jointly code for DQ2 are DQA1*0501 (which codes for the alpha chain) and DQB1*02 (which codes for the beta chain). The DQA1*0501 gene also exists in a gene block that contains the gene coding for DR5, and the DQB1*02 gene exists in a gene block that contains the gene coding for DR7. Individuals who are DR5/DR7 may thus also possess the DQA1*0501 and DQB1*02 genes. In contrast to individuals who are DR3-DQ2 the DQ genes in DR5/DR7 individuals which code for DQ2 are located on two different chromosomes. This explains why DR5/DR7 individuals also have a predisposition to develop Celiac Disease and strongly indicates that it is DQ2 coded for by the DQA1*0501 and DQB1*02 genes that actually are involved in the development of Celiac Disease. About 95% of the Celiac population carry these particular genes.

In addition, another 4-5% of the Celiac population have genes that code for DR4 and DQ8 molecules (the genes coding for DR4 and DQ8 are maintained in block of genes). Probably it is the DQ8 molecule that mediates the disease predisposition in this subgroup of patients. Some very few Celiacs are neither DQ2 nor DQ8 implying that HLA typing is not a perfect predictor of risk for Celiac Disease.

If one has two copies of the Celiac-related markers instead of one, does it make a difference?

Recent results indicate that individuals who carry the DQA1*0501 and DQB1*02 alleles and in addition have an extra copy of the DQB1*02 allele have an increased risk of developing Celiac Disease. This is called a "gene-dosage effect". The DR types of individuals who usually carry these DQ genes are DR3/DR3 (i.e. DR3 homozygous) and DR3/DR7.

Are there non-HLA genes involved in determining if someone has the potential to get Celiac Disease?

Probably. The fact that there is a difference in the risk factors between identical twins (70%) and HLA-identical siblings (30-40%) implies that there are probably non-HLA genetic factors involved. Research on this topic is continuing.

Are there any known HLA or other genetic markers associated with gluten intolerance in autism?

Not much has been published on this topic. Dr. Reed Warren of Utah State University has published several studies on the genetics of autism in Northern Utah. Those studies did not show a significantly increased prevalence of DR3 in autism. Gene Stubbs of Ohio State University has stated in unpublished correspondence that he found substantially increased DR3 in the parents of autistic children.

Hope this helps some. Or not ??

[beebs]

:blink:

[Bubba's Mom]

LOL! Clear as mud to me. I was tested for the DQ2 and DQ8 only. My Dr. didn't entertain the idea of there being any other genes associated with Celiac. He said my genetic testing was negative for Celiac. I'd explain that info posted above to him if I knew what it meant. Maybe I should copy and print it off?

[beebs]

LOL! Clear as mud to me. I was tested for the DQ2 and DQ8 only. My Dr. didn't entertain the idea of there being any other genes associated with Celiac. He said my genetic testing was negative for Celiac. I'd explain that info posted above to him if I knew what it meant. Maybe I should copy and print it off?

:lol:

[mushroom]

Sorry about that, you two It was the nearest to layman's language I could find, where you didn't have to be Skylark to decode it

[Skylark]

Yeah, some of this stuff takes a doctorate to understand. Good thing I have one!

Bubba's Mom, some diagnostic labs like Enterolab only test B chain so they would only test for DQ2 and DQ8. Better labs like Prometheus also test for DQA *0505.

I wouldn't get too hung up on the genetic testing. You can be celiac without the so-called celiac genes, and also have the genes and not be celiac.

[nora-n]

I have two DQ5 , I had to get tested by enterolab to get any answer.

The first lab that tested me and reported negative gene tests, used a rapid test that only tells you the DQ2 or 8, of any are present.

Enterolab sends the gene tests out, I think to the American Red Cross, and chose to only order the beta chains to conserve costs.

Those of you earlier in the thread:

Nowadays usually labs test both the beta and alpha chains, but only report for DQ2 and 8 to the doctor since often doctors do not know what to do with all the surplus information.....often people have phoned the lab and gotten the complete report.

This is because there are some celiacs with half genes (usually meaning 05* in the alpha chain)

A few have posted here.

Actually, more people with suspicious symptoms and DQ2,2 have posted than those with half genes.

[researchmomma]

Skylark, what is the sero equivalent of this The third so-called celiac gene is HLA-DQA1 *0505. ?

This stuff is so interesting to me. My daughter had her gene testing at Prometheus but they only reported: Negative for DQ 2 or 8. So I am considering giving them a call to see if they have any further info.

She got glutened this weekend and the reaction WAS pretty strong so we continue to confirm via elimination that gluten is a problem for her.

The gene info is more for my own personal information. My grandmother died from potential Celiac related (or NCGI) diseases (duodenal cancer and pernicous anemia) and my Mom has Grave's and Parathyroid tumors. So the info is really interesting to me.

Edited to correct that the reaction to gluten WAS strong not wasn't.

[nora-n]

05* alone means half a DQ2,5 kind of

0501 is the alpha chain if DQ2,5 but it is possible to have that alone

0505, I do not remember anyone posting with an actual 0505 alpha chain but before they just called it 05* I think

[Skylark]

Skylark, what is the sero equivalent of this The third so-called celiac gene is HLA-DQA1 *0505. ?

Serology comes from B chain. A1*0505 is one of the A chains that is strongly linked to DQ7 so if they found DQ7 there is a chance she has A1*0505. A1*0501 is linked to DQ2.

Nora, A1*0505 is the allele linked to DQB1*0301 (as DQ7.5) and is occasionally found as the only celiac allele folks without DQ2 or DQ8 B chains. DQB1*0301 is not thought to confer risk. It is one nucleotide different from A1*0501 and translates to the same protein. Because of this, some labs are labeling A1*0501/5 as a celiac gene. (Since Beebs' friend has DQ2 and DQ8, he would have A1*0501. I didn't think of that when I typed *0505.)

[nora-n]

there are some charts with alpha and beta chains here

Open Original Shared Link

so 0505is simply DQ7....and DQ7 celiacs are described in literature, so one could say DQ2, 8 and 7 are celiac genes.

Hadjivassiliou found that 20% of his gluten ataxia patients had DQ1.

There are also interesting charts on the HLA DR page on wikipedia, with corresponding diseases

[Skylark]

so 0505is simply DQ7....and DQ7 celiacs are described in literature, so one could say DQ2, 8 and 7 are celiac genes.

The stuff I've been reading says that the DQ7 B1*0301 chain does not seem to confer risk if there is a different A chain with it. The risk is conferred by A1*0505 (or possibly other HLA genes in the DQ7.5 haplotype). Remember, DQ7.3 is reasonably common, does not confer celiac risk, and still can have B1*0301. Also A*05 jumps risk considerably in DQ2 folks.

[nora-n]

that was the article on sardinian or something celiacs with DQ7, and they probably meant DQ7,5. Of course it is the 0505 alpha chain that is the celiac gene.

By the way, 23andme only tests for 0501 alpha chain for celiac risk. I do not know if it is 0501 or 05* they test for.

[domesticactivist]

Wow! Thanks for that.

We has the kids reared by kimball genetics division of labcorp. They sent back a risk assessment based on both alpha and beta. Then I called the genetic councilor and they sent me the full report. I've heard (but not confirmed) that Prometheus can do the same

[nora-n]

interesting about the full report.

Here in Norway (and Sweden) they still only tell you if you are positive or negative for DQ2 or 8, so I had to order the test via Enterolab.

This is so expensive because it costs so much extra from europe for special shipping. I guess ordinary mail would do, but I am not sure.