Celiac Genes: How to Check Your Raw Data

Celiac disease is an autoimmune disorder in which gluten causes damage to the villi in the small intestines. Gluten is a protein found in wheat, barley, rye, and spelt. When people with celiac disease consume even very small amounts of gluten, their body mounts a response that causes damage to the intestines.

Celiac disease is caused by a combination of environmental factors (eating gluten, other factors) and having genetic variants that cause susceptibility to the disease. Without genetic susceptibility, you won’t have celiac.

What is celiac disease?

Celiac disease (spelled coeliac in Britain) is an autoimmune disorder in which gluten, a protein found in wheat and other grains, leads to your body attacking its own cells.

Inside the small intestines, there are little projections called villi. In celiac disease, the body attacks those cells, causing the villi to shorten and not absorb nutrients very well.

Symptoms of celiac disease:

There are a variety of symptoms associated with celiac disease – and not everyone with celiac will have all of the symptoms. Symptoms include:[ref]

  • gastrointestinal upset
  • tiredness/ fatigue
  • nutrient deficiencies even when eating a good diet
  • anemia or iron deficiency
  • reduced bone density, early osteoporosis
  • oral ulcers (canker sores)
  • a skin rash – dermatitis herpetiformis
  • in children, poor growth and short stature

Is celiac disease hereditary?

Genetic diseases that are hereditary are caused by inheriting a genetic variant or mutation from your parents.

While there isn’t just one specific genetic variant that causes everyone who carries it to get celiac disease, it is hereditary and based on genetic variants.

For celiac disease to be possible, there are genetic variants that must be present in order for a person to be susceptible. So if the celiac variants (listed below) are not present, you can nearly always rule out the disease.

Almost everyone with Celiac disease has either the HLA-DQ2 or HLA-DQ8 alleles. Specifically,  90-95% of people with celiac disease have HLA-DQ2.5, and 5 – 10% of people have HLA-DQ8. Some studies also list HLA-DQ2.2 as a possibility for celiac, with about 1% of celiac patients carrying HLA-DQ2.2.

Not everyone with the HLA types will get celiac disease, though. In fact, almost 25% of the population has HLA-DQ2.5, and that percentage grows to about 30% when adding in HLA-DQ8.[ref]

With only about 1% of the population having celiac disease, you can see that just having the HLA type doesn’t mean that you will get celiac disease.

Thus, looking at your genetic variants can help you rule out celiac disease, but not tell you if you have it.

Genetics is just part of the picture. Talk with your doctor for a diagnosis. Your doctor can order tests such as a blood test or a small intestine biopsy to accurately diagnose or rule out celiac disease.

What is an HLA serotype?

Serotypes, discovered in 1933 by Rebecca Lancefield, are variations within species (bacteria and viruses) or variations among immune cells in people. The typing is based on their cell surface antigens. In humans, the human leukocyte antigen (HLA) determines the serotype. HLA serotypes can be used in determining transplant matches.

One HLA type is HLA-DQ, which is a protein found on antigen-presenting cells. DQ is involved in the immune system by stimulating T-cells, which then signal B-cells to produce antibodies.

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 its tolerance to self-proteins, triggering autoimmune diseases such as celiac, lupus, and type 1 diabetes.

Diagnosing Celiac Disease:

There are blood tests that can show whether you carry antibodies against gluten. The test is not 100% accurate, and some people may have false-negative results (e.g., a blood test shows that you don’t have celiac when you do).

Genetics can help you rule out celiac. If you don’t carry the HLA type (below) and also have a negative antibody test, then celiac is highly unlikely.

The ‘gold standard’ is an intestinal biopsy, where a gastroenterologist takes a small snip out of your intestines to see if there is damage to the villi.


Celiac Genotype Report

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HLA-DQ2.5:

Approximately 90-95% of celiac patients have HLA-DQ2.5, which can be determined by looking at rs2187668 (T).[ref] This genetic variant is fairly common and is found in about 25% of European Caucasians.  Thus, having the genetic variant 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 genetic data for rs2187668 (23andMe v4, v5; AncestryDNA):

  • C/C: typical (no risk for celiac unless HLA-DQ8)
  • C/T: one allele for HLA-DQ2.5 (Celiac disease is possible)
  • T/T: two alleles for HLA-DQ2.5 (Celiac disease is possible)

Members: Your genotype for rs2187668 is .

HLA-DQ8:

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

Check your genetic data for rs7454108 (23andMe v4, v5; AncestryDNA):

  • C/C: two alleles for HLA-DQ8 (Celiac disease is possible)
  • C/T: one allele for HLA-DQ8 (Celiac disease is possible)
  • T/T: typical (no risk for celiac unless HLA-DQ2)

Members: Your genotype for rs7454108 is .

HLA-DQ2.2:

The SNPs above cover most people (~98%) with Celiac, but not quite all. The HLA-DQ2.2 variant is found in 1-2% of people with celiac disease.[ref][ref]

To determine your HLA-DQ2.2 status, you must have all three of the following risk alleles listed as “HLA-DQ2.2 possible”.

Check your genetic data for rs4713586 (23andMe v5, AncestryDNA):

  • A/A: HLA-DQ2.2 possible if you also have rs2395182 T, and rs7775228 C
  • A/G: not HLA-DQ2.2
  • G/G: not HLA-DQ2.2

Members: Your genotype for rs4713586 is .

Check your genetic data for rs2395182 (23andMe v4, v5, AncestryDNA):

  • T/T: HLA-DQ2.2 possible if you also have rs4713586 A/A, and rs7775228 C
  • G/T: HLA-DQ2.2 possible if you also have rs4713586 A/A, and rs7775228 C
  • G/G: not HLA-DQ2.2

Members: Your genotype for rs2395182 is .

Check your genetic data for rs7775228 (23andMe 4, v5; AncestryDNA):

  • C/C: HLA-DQ2.2 possible if you also have rs4713586 A/A, and rs2395182 T
  • C/T: HLA-DQ2.2 possible if you also have rs4713586 A/A, and rs2395182 T
  • T/T: not HLA-DQ2.2

Members: Your genotype for rs7775228 is .

 


Other genes involved in celiac risk (only for people who carry the HLA type from above):

The HLA genotypes (above) are necessary for celiac disease, but they aren’t the only factors involved. Recent studies have looked into other genetic variants, 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.[ref][ref]

SH2B3 gene: encodes a lymphocyte adapter protein that regulates signaling pathways related to inflammation.

Check your genetic data for rs3184504 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: increased relative risk of celiac (with HLA type above)
  • T/T: increased relative risk of celiac (with HLA type above)[ref][ref]

Members: Your genotype for rs3184504 is .

LPP gene:

Check your genetic data for rs1464510 (23andMe v4 only):

  • A/A: increased relative risk of celiac (with HLA type above)[ref]
  • A/C: increased relative risk of celiac (with HLA type above)
  • C/C: no increased risk

Members: Your genotype for rs1464510 is .

TAGAP gene:

Check your genetic data for rs1738074 (23andMe v4; AncestryDNA):

  • T/T: increased relative risk of celiac (with HLA type above)[ref]
  • C/T: increased relative risk of celiac (with HLA type above)
  • C/C: no increased risk

Members: Your genotype for rs1738074 is .

REL gene:

Check your genetic data for rs842647 (23andMe v4; AncestryDNA):

  • A/A: increased relative risk of celiac (with HLA type above)[ref]
  • A/G: increased relative risk of celiac (with HLA type above)
  • G/G: no increased risk

Members: Your genotype for rs842647 is .

Check your genetic data for rs2816316 (23andMe v4, v5):

  • A/A: increased relative risk of celiac (with HLA type above)[ref]
  • A/C: increased relative risk of celiac (with HLA type above)
  • C/C: no increased risk

Members: Your genotype for rs2816316 is .

IL-18 receptor: A meta-analysis showed a T-allele (23andMe orientation) on rs917997  increased the relative risk of celiac disease by 5%, The same study showed a T-allele on rs6441961 increased the risk of celiac by 6%.[ref]

Check your genetic data for rs917997 (23andMe v4, v5; AncestryDNA):

  • T/T: slightly increased relative risk of celiac (with HLA type above)[ref]
  • C/T: slightly increased relative risk of celiac (with HLA type above)
  • C/C: no increased risk

Members: Your genotype for rs917997 is .

Check your genetic data for rs6441961 (23andMe v4, v5; AncestryDNA):

  • T/T: slightly increased risk of celiac (with HLA type above)[ref]
  • C/T: slightly increased risk of celiac (with HLA type above)
  • C/C: no increased risk

Members: Your genotype for rs6441961 is .

A Finish study from 2012 found that FUT2 non-secretors are at an increased risk of celiac disease.  The A/A 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 genetic data for rs601338  (23andMe v4, v5):

  • A/A: increased risk of celiac
  • A/G: no increased risk
  • G/G: no increased risk

Members: Your genotype for rs601338 is .


Lifehacks:

Testing for celiac disease:

After learning about carrying the genetic variants linked with celiac disease, a lot of people immediately decide to try out a gluten-free diet. This can be a mistake!

For example, if you go on a gluten-free diet and feel great, you still don’t know if you have celiac disease or if you are just gluten intolerant.

For a person who has celiac disease, being 100% gluten-free is essential. This is an important difference from some people with gluten intolerance who may be able to handle small amounts of gluten.

Instead of jumping into a gluten-free diet, I highly suggest that you get tested first for celiac disease.

Your doctor is the place to start, and he/she can order testing for you.  If your doctor won’t order the test – or you don’t have a doctor – you can order the blood tests yourself online (UltaLab Tests – Celiac is one option).

Increased risk of other autoimmune diseases with the celiac genes:

People who have celiac disease are also more likely than normal to also have other autoimmune conditions such as Hashimoto’s thyroiditis and type 1 diabetes.[ref]


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References:

Canova, Cristina, et al. “Celiac Disease and Risk of Autoimmune Disorders: A Population-Based Matched Birth Cohort Study.” The Journal of Pediatrics, vol. 174, July 2016, pp. 146-152.e1. PubMed, https://doi.org/10.1016/j.jpeds.2016.02.058.

Huang, Shi-Qi, et al. “Association of LPP and TAGAP Polymorphisms with Celiac Disease Risk: A Meta-Analysis.” International Journal of Environmental Research and Public Health, vol. 14, no. 2, Feb. 2017, p. 171. PubMed Central, https://doi.org/10.3390/ijerph14020171.

Hunt, Karen A., et al. “Newly Identified Genetic Risk Variants for Celiac Disease Related to the Immune Response.” Nature Genetics, vol. 40, no. 4, Apr. 2008, pp. 395–402. PubMed, https://doi.org/10.1038/ng.102.

Izzo, Valentina, et al. “Improving the Estimation of Celiac Disease Sibling Risk by Non-HLA Genes.” PLoS ONE, vol. 6, no. 11, Nov. 2011, p. e26920. PubMed Central, https://doi.org/10.1371/journal.pone.0026920.

—. “Improving the Estimation of Celiac Disease Sibling Risk by Non-HLA Genes.” PloS One, vol. 6, no. 11, 2011, p. e26920. PubMed, https://doi.org/10.1371/journal.pone.0026920.

—. “Improving the Estimation of Celiac Disease Sibling Risk by Non-HLA Genes.” PLoS ONE, vol. 6, no. 11, Nov. 2011, p. e26920. PubMed Central, https://doi.org/10.1371/journal.pone.0026920.

—. “Improving the Estimation of Celiac Disease Sibling Risk by Non-HLA Genes.” PLoS ONE, vol. 6, no. 11, Nov. 2011, p. e26920. PubMed Central, https://doi.org/10.1371/journal.pone.0026920.

Leccioli, Valentina, et al. “A New Proposal for the Pathogenic Mechanism of Non-Coeliac/Non-Allergic Gluten/Wheat Sensitivity: Piecing Together the Puzzle of Recent Scientific Evidence.” Nutrients, vol. 9, no. 11, Nov. 2017, p. 1203. PubMed Central, https://doi.org/10.3390/nu9111203.

Megiorni, Francesca, and Antonio Pizzuti. “HLA-DQA1 and HLA-DQB1 in Celiac Disease Predisposition: Practical Implications of the HLA Molecular Typing.” Journal of Biomedical Science, vol. 19, no. 1, Oct. 2012, p. 88. BioMed Central, https://doi.org/10.1186/1423-0127-19-88.

Monsuur, Alienke J., et al. “Effective Detection of Human Leukocyte Antigen Risk Alleles in Celiac Disease Using Tag Single Nucleotide Polymorphisms.” PLoS ONE, vol. 3, no. 5, May 2008, p. e2270. PubMed Central, https://doi.org/10.1371/journal.pone.0002270.

Parmar, A. S., et al. “Association Study of FUT2 (Rs601338) with Celiac Disease and Inflammatory Bowel Disease in the Finnish Population.” Tissue Antigens, vol. 80, no. 6, Dec. 2012, pp. 488–93. PubMed, https://doi.org/10.1111/tan.12016.

“Symptoms of Celiac Disease.” Celiac Disease Foundation, https://celiac.org/about-celiac-disease/symptoms-of-celiac-disease/. Accessed 16 Dec. 2021.

Ting, Yi Tian, et al. “A Molecular Basis for the T Cell Response in HLA-DQ2.2 Mediated Celiac Disease.” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 6, Feb. 2020, pp. 3063–73. PubMed Central, https://doi.org/10.1073/pnas.1914308117.

Trynka, Gosia, et al. “Dense Genotyping Identifies and Localizes Multiple Common and Rare Variant Association Signals in Celiac Disease.” Nature Genetics, vol. 43, no. 12, Nov. 2011, pp. 1193–201. PubMed Central, https://doi.org/10.1038/ng.998.

Tye-Din, J. A., et al. “Appropriate Clinical Use of Human Leukocyte Antigen Typing for Coeliac Disease: An Australasian Perspective.” Internal Medicine Journal, vol. 45, no. 4, Apr. 2015, pp. 441–50. PubMed Central, https://doi.org/10.1111/imj.12716.

Yang, Guang, et al. “Systematic Review and Meta-Analysis of the Association between IL18RAP Rs917997 and CCR3 Rs6441961 Polymorphisms with Celiac Disease Risks.” Expert Review of Gastroenterology & Hepatology, vol. 9, no. 10, 2015, pp. 1327–38. PubMed, https://doi.org/10.1586/17474124.2015.1075880.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.