The causes of Crohn’s disease
January 31, 2011 1 Comment
The Causes of Crohn’s disease are still unknown. However, statistical studies (that do not give causative explanations but only strong suggestions) indicate that Crohn’s disease may be caused by both genetic and environmental factors (in other words a genetic predisposition may enhance the effects of an environmental factor). Today, I don’t want to just list the causes but I want also try to explain the scientific method used to achieve this knowledge.
1) To determine whether a disease has genetic causes the first thing to do is to statistically study the frequency of a disease first in a population (as shown in the previous post) and subsequently compare with the frequency in a specific family whose members show the pathology. If the frequency of the disease within the family members is higher than the average frequency of the general population, a genetic cause of the disease is highly probable (because the genetic errors are transmitted from parents to the offsprings).
Þ As reported by Satsangi and colleagues (see the paper here), statistical studies from clinical data show that 5-10% of Crohn’s disease patients have a first-degree relatives with the same pathology with a concordance for disease type (see previous post) of about 70-80%. Therefore, the risk of developing Crohn’s disease for a person with a first-degree relative with the disease is about 15 times higher than the average risk in the population. Particularly important studies involve twins: a much higher correlation of Crohn’s disease is calculated in monozygotic twins (37%; twins with identical genome) than in dizygotic twins (7%; twins with non-identical genome).
2) The second step is to find the gene or the genes responsible for the pathology that have been transmitted from parents to their children. One of the most common strategies used by scientist is the Genome Wide Scan to identify susceptibility loci (or region) in the Chromosomes. This approach consists in sequencing small regions (marker sequences such as micro-satellites, SNPs, RFLPs, etc…) throughout genome of all the members of an affected family in order to identify chromosomal loci transmitted with high frequency to the sick members of the family and with less frequency to the healthly members. The analysis of those frequencies using dedicated algorithms is called genetic linkage (for more technical information check here) and allow to find susceptibility loci where it is possible to identify and subsequently study several genes.
Þ Using this approach, no single locus has been found but many susceptibility loci have been described on chromosomes 1, 3, 5, 6, 12, 14, 16 and 19 (for references see Baumgart and Carding). This result implicates that Crohn’s disease is a polygenic disease making even more difficult the challenge to describe the causes. More detailed studies have linked specific genes to the diseases: Nod2/Card15 a pattern recognition receptor involved in immune response against microbes present in the intestinal tract and its mutations have been associated with Crohn’s disease in white population; Mhc (major hystocompatibility complex) receptor responsible for the presentation of intracellular proteins to lymphocytes.
3) Once the responsible genes are identify by statistical analysis, the scientists start studying the function of the proteins (codify by the genes) within the cell and how its disruption may affect the cell and the immune-response as whole. The possible experiments to be performed are in such a big number (depending also from the function of the protein its-self) that it is not possible to list them all. However, some common approaches are often very informative. One example is the disruption of the homologue gene (gene with the same function in a different specie) in a mouse model called “knockout” that allows to subsequently study the phenotype of the animal and the molecular outcome.
Þ Structural studies of NOD2 have shown that it consists of 3 domains: a CARD domain responsible for activation of a signaling protein NFkB, a NOD domain responsible for the oligomerisation of the protein and a Leucine-rich region responsible for bacterial recognition (typical example of the modular structure of the proteins).
Þ The knockout mouse model for NOD2 do not fully fit the human Crohn’s disease (further suggesting the multi-factorial causes for this disease) but it gives important notions. The absence of a functional NOD2 alter normal signaling within the intestinal cells leading to abnormal activation of NFkB and production of pro-inflammatory cytokines (which may be one cause of the chronic inflammation). It will be interesting also understand if and how a deregulation of NOD2 in intestinal cells may influence the activity of so called T helper 1 lymphocytes.
The evidences for environmental factors rely entirely on statistical analysis and therefore have to be intended only as suggestion of causes (for references see Baumgart and Carding).
The LIFE STYLE may be one of the major factors:
- Smoking drastically aggravates the course of Crohn’s disease accelerating the need for surgical intervention.
- Bacterial or viral infection may trigger an excessive immune-reaction
- Excessive sanitation may reduce the exposure of children and adults to microbial and other environmental antigen limiting the fully maturation of mucosal immune system that subsequently may over-react to safe bacteria or antigen.
- Stress seems to increase the incidence of relapse in patient with quiescent disease.
- Diet may play a role although weak data are presented so far.
Many other studies will be required for a fully understanding of the molecular mechanism involved and the cells interaction. Remained tuned on E-ducereX to be updated!
- The Crohn’s Disease (educeredotcom.wordpress.com)
- Is the Risk of Crohn’s Higher If a Sibling Has It? (everydayhealth.com)