Overview 

Coeliac disease is a prevalent autoimmune disorder that is triggered when you eat gluten, a protein commonly found in carbohydrates. At least 1 in 100 people in the UK and Europe have coeliac disease. However, only 36% of people with the condition are clinically diagnosed, highlighting the need for more awareness of this condition. This article delves into the genetic background of coeliac disease to help improve your understanding of the condition and how it can impact your health. 

What is coeliac disease?

Coeliac disease (pronounced see-li-ac), is an autoimmune disorder. Autoimmunity is where the body’s immune system attacks healthy tissues by accident, causing inflammation and damage. In the case of coeliac disease, the body has an autoimmune response to gluten. 

Gluten is a compound composed of nearly 40 different types of proteins which are classified under two subtypes, Glutenins and Gliadins.¹ Glutenins are fibrous proteins that contain high levels of cysteine, a key amino acid.² In contrast to this, gliadins are rich in two types of amino acids, proline and glutamine.² These amino acids function as building blocks of proteins, allowing them to create function-specific structures.

The ingestion of gluten triggers an immune reaction that damages the lining of the small intestines, specifically the villi.³ Villi are tiny hairlike structures on the lining of your small intestines. These projections increase the surface area of your gut, allowing for nutrient absorption. However, an individual with untreated coeliac disease has either damaged or no villi (villous atrophy).⁴ This makes the gut unable to absorb nutrients from food, so no matter how much you eat, you can’t get enough nutrients (malabsorption). 

Coeliac disease can affect the growth and development of your children due to the lack of nutrition absorption. In addition to these issues, the damage to your intestines also causes symptoms such as diarrhoea, bloating, weight loss, fatigue, or anaemia. There is no cure for the disease, however, the majority of individuals with the condition follow a gluten-free diet to help protect and improve intestinal health. Gluten isn’t essential for your diet, so it can be replaced by other foods to supplement the necessary nutrients and vitamins you need. If you need more guidance on what foods include gluten, the NHS has an informative webpage for this (NHS). 

Genetic basis 

The genetic basis of coeliac disease can be pinpointed to specific genetic variations that predispose individuals to develop the condition. 

HLA

The strongest genetic associations with coeliac disease are found within the Human Leukocyte Antigen (HLA) complex, specifically the HLA-DQ2 and HLA-DQ8 associated genes.⁵ The majority of individuals with the condition express either HLA-DQ2 or HLA-DQ8 complex proteins. These complexes are made from two subunits (dimers) which are coded for by a range of associated genes. The subunits can either be the same (homodimers) or different (heterodimers). HLA complexes are responsible for binding to proteins found on the surface of different compounds. These proteins can also be called antigens. 

Antigens are like name tags that help your body’s immune system identify whether something is a friend or foe. These name tags are composed of proteins and are found on the surface of all types of molecules. HLA complexes act as a messenger that brings attention to these name tags by presenting them to different immune cells, which helps identify whether something is harmful or not. HLA-DQ2 and HLA-DQ8 genes produce HLA proteins that specifically bind to gluten, allowing them to stimulate gluten-specific T cells.^6,7 These T cells function as one of the key players in inducing an autoimmune response towards gluten in an individual with coeliac disease. 

HLA proteins bind to their antigens with a high level of specificity based on the structure of the antigens. Certain genetic variants of HLA-DQ2 and HLA-DQ8 genes bind much better to gluten than others. Hence, you can consider the severity of coeliac disease like a spectrum. Some individuals may have a much stronger autoimmune response to gluten in comparison to others, depending on the genetic variation of their HLA-DQ2 and HLA-DQ8 genes. 

Alleles 

Your genetic information is inherited from your parents as alleles. An allele is a variant of a gene. Each individual receives two alleles, one from each parent for every gene where possible. If the two alleles you receive from your parents are the same for a particular gene, you are considered to be homozygous for that allele. If the alleles are different, you are heterozygous for that allele. 

Researchers have investigated the effects of homozygous and heterozygous alleles on the risk of developing coeliac disease. They have identified that individuals with homozygous HLA-DQ2 alleles had a very high risk and a homozygous pair of HLA-DQ8 alleles had a high risk of developing coeliac disease in comparison to heterozygous alleles.^8,9 The increased risk is attributed to the enhanced ability of homozygous HLA alleles to produce proteins that bind to gluten with more affinity and stimulate aberrant immune responses. Despite the lower risk compared to homozygous alleles, heterozygotes still contribute to disease susceptibility. However, the presence of these genes alone is not sufficient for the development of the disease. The risk of developing coeliac disease for a person who has these HLA risk alleles is estimated to be only 36-53%.¹⁰ 

Other genes associated with coeliac disease 

In addition to HLA genes, other genes have also been observed to be present in individuals with coeliac disease. Genome-wide association studies or GWAS are extensive studies that look at all the genetic information of a large number of individuals within a specific population. Multiple GWAS have been conducted to identify additional genes involved in the development of coeliac disease.^11,12,13 One study was able to identify 54 genetic variations in 5 genes that were associated with the condition.¹⁴ However, the exact function and underlying mechanisms of these genes and their involvement in the development of coeliac disease are not fully understood, highlighting the need for more research. 

Is coeliac disease hereditary? 

Coeliac disease is a genetic disease that can be inherited and has been observed to run through families. If you have a close relative with the condition, such as a parent, brother, or sister, you have an increased chance of developing the disease. Mutations in the HLA genes are common, suggesting there are additional factors that induce the development of coeliac disease in certain individuals. 

Environmental factors - epigenetics 

Environmental factors or epigenetics are also a plausible reason for the onset and development of coeliac disease. Your behaviours and environment can influence how your genes work. These changes are reversible, however, they can still impact genetic expression. The exact mechanisms of how epigenetics influences coeliac disease are still unclear.¹⁵ The main epigenetic changes are as follows:^15,16,17 

• DNA Methylation: This process involves adding chemical groups called ‘Methyl’ to specific places on your DNA. This group blocks proteins from ‘reading’ your DNA, essentially ‘turning off’ your gene. Methyl groups can be removed in a process called demethylation to allow the genes to be read and turned ‘on’. Studies have shown that there is an increased DNA methylation for specific regions in the DNA of patients with coeliac disease
• Histone Modification: DNA is wrapped around protein complexes called histones. When your DNA is tightly wrapped around these histones, the proteins that ‘read’ your DNA can’t be read. These genes are then turned ‘off’. When the DNA is loosely wrapped, the proteins can ‘read’ your DNA, and the gene is turned ‘on’. Similar to DNA methylation, chemical groups can be added or removed from histones to make the DNA more tightly or loosely packed. The relationship between these modifications and coeliac disease has also been investigated, however, no definitive conclusions have been made so far

Other health conditions

Several other health conditions have also been associated with the onset and development of coeliac disease. It is currently unclear how these conditions cause or increase the risk of developing coeliac disease. However, individuals with these underlying health conditions have been observed to also develop coeliac disease. The NHS and Coeliac UK have listed individuals with the following health conditions as more likely to develop coeliac disease: 

• Type 1 Diabetes 
• Thyroid conditions
• Down’s Syndrome
• Turner Syndrome 
• Lactose Intolerance

Summary 

The underlying genetic background of coeliac disease unveils a complex infrastructure of multiple genes. Central to this network of genes are the HLA-DQ2 and HLA-DQ8 genes, whose variants significantly influence the development of the condition. Homozygous alleles amplify the risk of development, whilst heterozygous alleles also play a substantial role.

Beyond the HLA genes, genome-wide association studies have also uncovered a range of additional genetic and epigenetic factors that contribute to the disease's predisposition. Underlying health conditions have also been associated with the increased risk or development of coeliac disease. Despite multiple remaining unanswered questions, researchers strive to broaden our understanding and help uncover the bigger picture behind the genetic basis of coeliac disease.