Genetics of celiac disease…

The Genetics of Celiac Disease (1)One of my initial reasons for getting 23andMe testing done was to figure out if I could possibly have celiac disease.  I went gluten-free about seven years ago, and since I felt better, I didn’t want to go back to eating gluten in order to get the testing done for celiac. The ‘Catch-22’ of getting diagnosed with celiac disease is that you have to be eating gluten for a while before getting tested.   So I was hoping that the genetic testing would rule out the possibility of celiac for me (and my family).

First a little background information...
Celiac disease (also spelled coeliac) is an autoimmune disorder in which gluten triggers an immune response that damage to the villi in the small intestines.  Gluten is a protein found in wheat, barley, rye, and spelt. There are many resources on the internet with great information about celiac disease and the symptoms involved.  Celiac.org is a good starting point for anyone wanting to learn more.

The genetic components of Celiac…
There isn’t one genetic variant that causes everyone who has the variant to automatically get celiac disease, but there are genetic variations that must be present in order for a person to be susceptible to celiac disease.  So if the polymorphism isn’t present, you can nearly always rule out the disease.

Virtually everyone with celiac disease has either the HLA-DQ2 or HLA-DQ8 alleles. Specifically,  ~90-% of people with celiac disease have HLA-DQ2.5, and 5 – 10% of people have HLA DQ8 depending on the population. Some studies also show  HLA 2.2 as a possibility for celiac [study].

Almost 25% of the population has HLA-DQ2.5, and that percentage grows to about 30% when adding in HLA DQ8. [ref]  There are a couple of single nucleotide polymorphisms (SNPs) that you can look at (listed below) to determine if you have those HLA types.

With only about 1% of the population having celiac disease, you can see that just having the HLA type does not mean that you will get celiac disease, just that it is possible to get it.  So think of HLA typing as a way to rule out celiac disease instead of ruling it in.

Your doctor can order tests such as blood test or a small intestine biopsy to accurately diagnose or rule out celiac disease.  Most DNA test results that you order yourself, such as AncestryDNA and 23andMe, aren’t guaranteed to be 100% accurate, and the research studies could also have errors.

A little science background…
So what is an HLA serotype?  Serotypes, discovered in 1933 by Rebecca Lancefield, are variations within species (bacteria and viruses) or among immune cells of people.  The typing is based on the cell surface antigens.   In humans, the human leukocyte antigen (HLA) determines the serotype.

One HLA type is HLA-DQ, which is a protein found on antigen presenting cells.  DQ is involved in the immune system through stimulating T-cells which then signal B-cells to produce antibodies.  The HLA-DQ recognizes foreign antigens from pathogens, but it also recognizes common self-antigens.  This is where the problem begins when the HLA-DQ loses it tolerance to self-proteins, triggering autoimmune diseases such as celiac, lupus, and type 1 diabetes.

SNP’s involved in Celiac:
Approximately 90-95% of celiac patients have HLA-DQ2.5, which can be determined from the SNP rs2187668 (T). [ref] The SNP is fairly common and found in about 25% of European Caucasians.  So, again, having the SNP does not mean that you have celiac, only that it is possible for you to have it or develop it at some point.

Check your 23andMe results for rs2187668:

  • CC: wildtype
  • CT: one allele for HLA-DQ2.5 (Celiac disease is a possibility)
  • TT: two alleles for HLA-DQ2.5 (Celiac disease is a possibility)

HLA-DQ8 alone is found in about 5-10% percentage of Celiac patients.

Check your 23andMe results for rs7454108:

  • CC: two alleles for HLA-DQ8 (Celiac disease is a possibility)
  • CT: one allele for HLA-DQ8 (Celiac disease is a possibility)
  • TT: wildtype

The SNPs above cover most people with celiac, but not quite all.

The HLA-DQ2.2 variant, found by itself in a very small percentage of celiac cases, can also be determined if you have the newer version, v.5, of 23andMe testing (or AncestryDNA testing).  To determine HLA-DQ2.2, look at rs2395182, rs7775228, and rs4713586.  If you have a “T” on rs2395182, a “C” on rs7775228, and a “G” on rs4713586 should tell you if you carry the HLA-DQ2.2 variant. [study]

Other genes involved in celiac….
Since about 1% of those with European ancestry receive a diagnosis of celiac while 30% have the HLA types for it, something else must also be involved in a person’s risk for celiac.  Recent studies have looked into other genetic traits, as well as environmental aspects such as duration of breastfeeding, the timing of the introduction of wheat to an infant’s diet, and types of bacteria in the gut.

Below are a few of the current studies on other genetic factors influencing the risk of celiac disease.

A large study in 2011 looked at genetic differences between over 12,000 individuals with celiac compared to approximately the same number without celiac disease.

A sibling study from 2011 found three SNPs to be significant in increasing the risk of celiac disease among siblings where one sibling had been diagnosed with celiac.  The A-alleles of rs1464510, rs842647, and rs2816316 increased the risk of celiac disease in siblings in conjunction with the HLA type.

Check your 23andMe results for rs1464510:

  • AA: increased risk of celiac (only with HLA type, above)
  • AC: increased risk of celiac (only with HLA type, above)
  • CC: no increased risk
Check your 23andMe results for rs842647:

  • AA: increased risk of celiac (only with HLA type, above)
  • AG: increased risk of celiac (only with HLA type, above)
  • GG: no increased risk
Check your 23andMe results for rs2816316:

  • AA: increased risk of celiac (only with HLA type, above)
  • AC: increased risk of celiac (only with HLA type, above)
  • CC: no increased risk

An August 2015 meta-analysis showed that a T-allele (23andMe orientation) on rs917997  increased the risk of celiac disease by 5%, The same study showed that a T-allele on rs6441961 increased the risk of celiac by 6%.

Check your 23andMe results for rs917997:

  • TT: increased risk of celiac (only with HLA type, above)
  • CT: increased risk of celiac (only with HLA type, above)
  • CC: no increased risk
Check your 23andMe results for rs6441961:

  • TT: increased risk of celiac (only with HLA type, above)
  • CT: increased risk of celiac (only with HLA type, above)
  • CC: no increased risk

A Finish study from 2012 found that FUT2 non-secretors are at an increased risk of celiac disease.  The AA genotype for rs601338 determines a non-secretor.  The odds ratio for non-secretors for celiac is 1.28.  (Non-secretors are also resistant to the Norovirus.)

Check your 23andMe results for rs601338:

  • AA: increased risk of celiac (only with HLA type above)
  • AG: no increased risk
  • GG: no increased risk


More to read:
Another aspect that has recently been studied is the effect of the gut microbiome on the risk for celiac.  It is now thought that there is either a viral or bacterial component modifying the gut microbiome that must also be present.

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