Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Three new chromosomal regions were identified, in addition to the already established HLA-B region by using DNA genotyping and sequencing of the largest ever Celiac disease patients DNA bank

The work carried out during this 3 year project has brought significant advances in our knowledge of the Coeliac genetic make-up associated with the disease.

Building on smaller studies where the size of the samples was the limiting factor for the accuracy of the analysis, we were able to build a pan-European data bank of unprecedented size that allowed for the required samples content.

The building of this data bank and the good spirit inside the Consortium made also this effort very enjoyable.

Several key results have been obtained:
- 88% of celiac patients are DQ2 positive; 6% are DQ8 positive and 5,6% have only half of the DQ2 heterodimer. Only 3 out of 1008 patients were to be classified in other HLA categories.

However the relative risk associated to DQ genotypes are clearly dissimilar between Northern and Southern European populations.

- Our data suggest that the DR2-B8 hp, close to the HLA-B region contain an additive factor affecting susceptibility to Coeliac disease. The MICA5.1, MICB15 and TNF2 (associated to MICBx10) region gives a substantial increase in the odds for the predisposition to the disease.

- A novel risk factor, denoted CELIAC2 is located in chromosome 5q31-33 region. This was demonstrated using a meta and mega analysis of the different individual studies carried out by each of the participants with their particular family sets. Although the IL12B locus could be dismissed as the particular genetic factor from the Consortium data, there are several other genes involved in the immunomodulation process linked to this region. Further work is on-going to identify more precisely this genetic factor.

- CELIAC3 is another genetic factor clearly identified during this study. It is located in the CTLA4-CD28-ICOS region of chromosome 2q33. It could be identical to the quantitative alteration of CTLA4 expression as shown in other autoimmune diseases as shown recently by the group of Todd.

- Other chromosomal regions on chromosome 11q, 15, 16q12 and 19q13 were dismissed.

Therefore at least 4 genetic regions are involved with the genotype associated with Celiac disease. The relative weight of each region could be different from one population to the other. Precise identification of the molecules involved in the expression of the disease will be of ultimate importance for confirming the exact importance of each of these regions.

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