A SEQUENTIAL STUDY IN THE SCREENING OF COELIAC DISEASE AMONG FIRST DEGREE RELATIVES?

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Introduction: Coeliac disease (CD) is a complex genetic disorder.Besides the environmental factor gluten and the HLA-DQ2 and 8 proteins, other unknown genetic factors are involved.Several genome-wide screens have been performed to locate the regions with genes involved in CD.In the Dutch population this has led to the discovery of two susceptibility regions, 6q21-22 and 19p13 (CELIAC4).The region on 19p13 is only limited to 3.5 Mb, but since it is a region with a high density of genes, it still contains 92 candidate genes.Aim: We set out to fine-map this region with microsatellite markers and single nucleotide polymorphisms (SNPs) to search for association between genes and CD.Methods: We started with a cohort of 216 cases and 216 controls and expanded this to 311 cases and 540 controls.Microsatellites and SNPs were used.Results: Association testing using microsatellite markers has revealed a small region of interest of around 450 kb.Further fine-mapping with SNP shows association in a 150 kb region, encompassing a limited number of genes.Adding more SNPs led to the discovery of MYO9B as the gene on 19p13 most strongly associated to CD.This gene, which is a singleheaded motor myosin, shows association in its 3' part.This part of the gene contains the most interesting domains, which also differentiate the role of this myosin from the other family members.The Rho-Gap and Dag-Pe domains indicate that this gene is involved in signal transduction.We are now elucidating the specific role of this gene in signal transduction and trying to incorporate it in our models for CD.Conclusion: Finemapping the Dutch CD linkage region on chromosome 19p13 has led us to the gene MYO9b which is associated with the disease.

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