A UK-led international study has identified four types of genetic disturbance in the immune system that lead to celiac disease, bringing to 40 the total number of known inherited factors that increase a person’s risk of developing the disease. The researchers hope the findings will help to improve diagnostic tools and treatments for celiac disease, and it may also give new clues about related autoimmune diseases such as type 1 diabetes.

You can read about the discovery in a study published in the 28 February online issue of the journal Nature Genetics, by lead investigator Dr David van Heel, Professor of Gastrointestinal Genetics at Barts and The London School of Medicine and Dentistry, and colleagues. The research was funded by the Wellcome Trust, and supported by the patient charity Coeliac UK.

Celiac or coeliac disease affects about 1 in 100 people living in the Western world. It is an autoimmune disease triggered by an intolerance to gluten, a protein that is present in wheat, barely, rye and foods prepared with these grains. When triggered, the disease stops the normal absorption of nutrients, and if left undiagnosed, eventually leads to severe health problems like anaemia, fatigue, weight loss, and poor bones.

In an earlier study, van Heel discovered an overlap between coeliac disease and type 1 diabetes risk regions of the human genome, as well as coeliac disease and rheumatoid arthritis.

He told the media that in this latest study they discovered how the body’s T cells react to toxic wheat proteins, how the thymus gland eliminates them in infancy, and how the body responds to viral infection. (T cells are a type of white blood cell that start life in bone marrow and mature in the thymus, a gland that sits between the heart and the sternum).

“We can now shed light on some of the precise immune disturbances leading to coeliac disease,” said van Heel.

“We now understand that many of these genetic risk factors work by altering the amounts of these immune system genes that cells make. The data also suggests that coeliac disease is made up of hundreds of genetic risk factors, we can have a good guess at nearly half of the genetic risk at present,” he added.

For the study, van Heel and colleagues performed a “second generation genome-wide association study” that included 4,533 people with celiac disease, and 10,750 people who did not have the disease (the controls). They also genotyped over 130 sequences of DNA (single-nucleotide polymorphisms, or SNPs) in a separate group of 4,918 people with the disease and 5,684 controls.

By comparing what they found in the genomes of people with the disease to those of the people without the disease, they concluded there is robust evidence of SNP variants in 13 new regions of the genome (they “reached genome-wide significance”), most of which contained genes with immune functions and four having “key roles in thymic T-cell selection”.

The researchers also found evidence to suggest there is a shared risk between the gene linked to celiac disease and many other common chronic diseases involving the immune system.

“Multiple common variants for celiac disease influencing immune gene expression.”
Patrick C A Dubois, Gosia Trynka, Lude Franke, Karen A Hunt, Jihane Romanos, Alessandra Curtotti, Alexandra Zhernakova, Graham A R Heap, Róza Adány, Arpo Aromaa, et al.
Nature Genetics Published online: 28 February 2010.

Source: Queen Mary, University of London.

Written by: Catharine Paddock, PhD