Coeliac disease & HLA genes

Celiac/Coeliac disease (CD) is an inherited autoimmune condition where gluten proteins found in grains trigger an immune system attack the lining of the small intestine. 

The strict definition of coeliac disease - specific damage to the small intestine which can be identified as flattened villi - is linked with genes DQ2 and DQ8.

Symptoms include diarrhoea, fatigue, anaemia, weight loss, abdominal distension; and less frequently - osteoporosis, irritable bowel, chronic fatigue and miscarriage.

There are several risk factors for coeliac disease:

  • Genetics - HLA DQ8 and HLA DQ2 genotypes
  • Family history -  relative with CD or other autoimmune diseases
  • Genetics AND family history - if family member has same HLA variants and CD (70% in identical twins, 30% in HLA identical siblings)
  • Existing intestinal injury 
  • Degree of exposure to gluten (how frequent and how much) 
  • Lifestyle triggers - stress, trauma, surgery, puberty
  • Other gene variants, including FUT2

I. Genetics

The HLA (Human Leukocyte Antigen) family of genes help the immune system distinguish the body's own proteins from proteins made by foreign invaders, such as viruses and bacteria. 

HLA DQ variants increase risk of loss of tolerance/recognition of self-proteins, triggering autoimmune conditions such as coeliac disease, rheumatoid arthritis, type 1 diabetes and lupus. Two HLA gene variants are the biggest genetic risk factor for Coeliac Disease - 

1. HLA-DQA1/ HLA DQ Alpha 1, also known as CELIAC1 

SNP rs2187668 [C/T] tags the DQ2 (DR3) genotype (T is the risk allele).

HLA DQ2 is the highest risk indicator but is very common - 25-30% of Caucasians have a T variant but only 3% of those develop the disease.

2. HLA-DQB1/ HLA DQ Beta 1

SNP rs7454108 [T/C] tags the DQ8 (DR4) genotype (C is the risk allele) - also the biggest risk factor for Type 1 Diabetes.

Overall 1 in 112 Europeans are diagnosed with Coeliac Disease.

II. FAQ: What is the difference from testing HLA-DQA1 as opposed to HLA-DQ2 & DQ8?

HLA-DQA1 and HLA-DQB1 are the  gene names.
HLA-DQ2 and HLA-DQ8 are the genotypes - or description of the version of the gene (based on the variance/ SNP result)
HLA-DQA1 gene
The rs2187668 SNP 'tags' the 'DQ2' genotype. If you have a CC result (that's the 'wild', or default - no variance) genotype. If you have a TT result that would be DQ2/DQ2 or 0202, which is the highest risk (single) SNP for coeliac disease (but it is not determinate). If you have a C/T (or T/C) result that would be DQ2.
HLA-DQB1 gene
The rs7454108 SNP 'tags' the 'DQ8' genotype. On this SNP, if you have a TT result (that's the 'wild', or default - no variance) genotype. If you have a CC result that would be DQ8/ DQ8. This is also a risk genotype for coeliac disease. The risk is lower than for the DQ2 genotype. If you have a T/C (or C/T) result that would be DQ8.
If you have both variances, the genotype would be described as DQ2/DQ8 (or DQ8/DQ2) which is the highest overall risk (still not determinate). As the genotypes aren't determinate (as in you can have the risk genes but never develop coeliac disease) you could have the risk HLA genotypes and have NCGS (Non-Coeliac Gluten Sensitivity) but not coeliac. 

The HLA genes are in the Nutrient Core report and in the Thyroid Balance report.

III. Diagnostic test 

There are several tools that can be used to detect coeliac disease but there isn’t one definitive diagnostic test. 

Tests include:

  • HLA Genetics 
  • Serum Blood tests: elevation of tissue transglutaminase (tTG), an enzyme (tTG > 000 mg/dl) 
  • Gastro examination and biopsy for villi flattening in the stomach
  • Gluten challenge tests/gliadin assays 
  • Relief of symptoms or reversion of an abnormal intestinal biopsy to normal on a gluten-free diet
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