The genetics of Crohn’s disease decoded

We’re not searching blindly through the three billion letters of the genome”, explains Emilie Theâtre, a Giga Research researcher. “The sequences tested by the chip are either genes that have already been identified for their role in Crohn’s disease, or genetic sequences that produce proteins known for their role in the inflammatory process of the digestive system, or genes associated with other inflammatory diseases such as diabetes or psoriasis.” The study published in Nature confirms the genetic relationship of several inflammatory immune diseases: Crohn’s, ulcerative colitis, diabetes, rheumatoid arthritis, psoriasis, etc. In some rare cases, patients can develop two or three of these diseases at the same time. And epidemiological studies show that some families are more affected than others by these inflammatory immune diseases: an uncle has diabetes, a nephew has Crohn’s, a first cousin, develops psoriasis, a great-aunt had ulcerative colitis, etc. For instance, there is extensive genetic overlap between diabetes and Crohn’s disease. Out of the 39 genetic variants identified in diabetes, 20 of them can also be found in Crohn’s disease. In that case, how can it be that the majority of people only develop one of these inflammatory diseases? In reality, genetics only rarely explains a single disease. The medical destiny of identical twins (who have exactly the same genetic heritage) provides a good example. In the case of Crohn’s disease, for instance, it is common for only one of the twins to develop the disease. The person’s environment and history must also be taken into account.
As we said, the genetic map of Crohn’s disease is now very complete: 163 variants are associated with the disease. The map is certainly precise, but none of these variants alone explains the disease, which clearly results from a “losing combination”. But is it a combination of two, three, four, five genetic variants? Or more? Mathematically, there are an almost infinite number of possible combinations. The solution is beyond the reach of the current models. So much so, that this wealth of genetic information can’t be used to develop diagnostic tools. In any case, the usefulness of developing a diagnostic tool is currently limited because there is no preventive treatment for the disease.

Instead, the aim is rather to understand the physiopathology of the disease in order to develop new treatments. The researchers are endeavouring to understand the molecular cascade that leads these genetic variations to the clinical manifestation of the disease. Thanks to the mouse knockout technique, for instance, it is possible to observe the consequence of precise genetic suppression. Another avenue consists of taking immune cells from the intestine, studying the genetic expression within these cells and seeing if these active genes correspond to one or other of the 163 known variations. But this type of research is very time-consuming. The first gene in Crohn’s disease was identified in 2001 and we still don’t really know how it causes the disease. One of the immediate stakes of this work on the physiopathology of the disease is sorting between patients who develop a benign form of the disease (40%) and who should avoid the serious side effects of immune system suppressors, and those who develop the most severe form of the disease (60%) and who must be treated as quickly as possible.

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