Newly discovered genetic risk factors could improve celiac disease detection

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Author: Benjamin Goudey, Research Scientist, Healthcare and Life Sciences, IBM Research

 About 1% of the Australian population need to abstain from gluten due to a condition called celiac disease, an autoimmune disease that inflames the small intestine when gluten is consumed. While around 1% of people in Western countries have celiac disease, up to 70% or more of these individuals are undiagnosed¹, with a substantial proportion of individuals asymptomatic. This is problematic given the wide range of long-term effects of undiagnosed celiac disease, including malabsorption of nutrients, osteoporosis, other autoimmune illnesses and cancer.¹

One reason why celiac disease remains under-detected lies in how difficult it is to diagnose – a challenge my family knows all too well. One of my sisters has long endured multiple blood tests and highly invasive testing procedures yet has never been able to reach a conclusive diagnosis.

 The diagnosis of celiac disease requires a potential celiac sufferer to eat gluten daily for one to three months, followed by a blood test that must be confirmed by a biopsy of the small intestines, a highly invasive procedure². For those with undiagnosed celiac disease already on a gluten-free diet, eating gluten every day can be painful. But if gluten is not consumed regularly, these tests can be inconclusive².

An alternative diagnostic approach is genetic testing, which doesn’t require gluten intake. These tests look for gene variants in two genes, HLA-DQA1 and HLA-DQB1² , that cause susceptibility to celiac disease. For anyone without versions of these genes that cause the disease, a diagnosis of celiac can be excluded.² But if you do test positive for the genetic variants which are associated with the condition, there is still a good chance you may not have it.¹  While up to 50% of the population carries the HLA genes linked to celiac disease, only 1% actually has the disease.¹

IBM Research and the University of Melbourne

I was recently part of a collaboration between IBM Research in Australia and the University of Melbourne, examining how improved statistical modelling can boost the predictive power of genetic information already collected clinically. As detailed in new research in the European Journal of Human Genetics, we analysed genetic data from almost 15,000 individuals from four different countries, with and without celiac disease. We demonstrated a new degree of accuracy to the genetic prediction of celiac disease, with an accuracy of 86-90% depending on the individual’s country of origin.

The improved approach to genetic testing of celiac disease further allowed us to uncover two novel genetic risk factors. These gene variants, present in just 1-6% of people, occur within the two genes and have not been previously associated with the disease. Although we still haven’t uncovered the biological role of these particular genetic variants in celiac disease, we have been able to better understand the genetic underpinnings of the disease as well as improve testing of the condition.

The key to better health

Building on these findings, our study explores the impact of adjusting the guidelines about which genetic risk factors indicate a positive test. With the negligible impact on detecting actual cases, we could double the number of people who can be excluded from a potential diagnosis of celiac disease compared to existing clinical testing. This spares them from extensive clinical testing currently needed to provide a definitive diagnosis.

Ultimately, if put into the hands of doctors and clinicians, we hope that the testing for celiac disease can be much simpler, and the number of people with undetected celiac disease can be reduced – in turn giving them the key to better health. While the results may not resolve my sister’s ongoing quest to confirm her celiac status, they may make the diagnostic journey a little easier for others in the near future.

[Paper published in the European Journal of Human Genetics ]

1. Lindfors, K., Ciacci, C., Kurppa, K., Lundin, K.E., Makharia, G.K., Mearin, M.L., Murray, J.A., Verdu, E.F. and Kaukinen, K., 2019. Coeliac disease. Nature Reviews Disease Primers, 5(1), pp.1-18. doi.org/10.1038/s41572-018-0054-z
2. Rubio-Tapia, A., Hill, I.D., Kelly, C.P., Calderwood, A.H. and Murray, J.A., 2013. American College of Gastroenterology clinical guideline: diagnosis and management of celiac disease. The American journal of gastroenterology, 108(5), p.656. doi:10.1038/ajg.2013.79