ERC Advanced Grant for Cisca Wijmenga

The European Research Council (ERC) has awarded an Advanced Grant to Cisca Wijmenga, professor of human genetics and head of the Department of Genetics, UMCG. The grant is to fund her further research into celiac disease. This is a disease that affects approx. 1% of the population. It is triggered by gluten in the diet, which is found in foods containing wheat, rye and barley. For example, gluten is present in bread, pastas, pizzas and biscuits, and many ready-to-consume items. More knowledge on the disease's biomedical background will aid it's correct diagnosis, prevention and treatment.

Cisca Wijmenga is going to study the disease mechanisms responsible for celiac disease, making use of genes that confer susceptibility to the disease and identifying specific genetic variants. Her studies, which have already identified 39 risk genes for celiac disease, suggest that there is a mechanism causing a deregulation of the gene expression in patients.

More information on her personal webpage, her research

ERC Proposal -- Celiac disease: from lincRNAs to disease mechanism (CD-LINK)

Genome-wide association studies (GWAS) have provided important new insights into mechanisms underlying complex diseases. To date, over 2,000 genetic loci have been associated by single nucleotide polymorphisms (SNPs) to more than 250 common diseases, including celiac disease. Yet, most disease-SNPs are not located within protein-coding genes, providing a challenge in interpreting GWAS findings. This project examines how SNPs associated to celiac disease, with a focus on those outside the coding part of the genome, contribute to disease etiology. The results will provide the basis for new strategies for early detection and prevention of celiac disease and its complications.

Aim

This project investigates the disease mechanisms underlying celiac disease by using predisposing genes and disease-associated genetic variations as disease initiating factors. Specifically, we will investigate if lincRNAs are causally involved in celiac disease pathogenesis by regulating protein-coding genes and pathways associated with celiac disease. Since it is clear that celiac disease is driven by T cells, I will focus on those genes and lincRNAs from the 39 loci that are expressed in T cells.

Impact

Uncovering the specific mechanism by which genetic variation results in a disease phenotype will foster new biological insights and pinpoint the biological pathways involved in celiac disease. These discoveries may have direct clinical application as they may uncover potential therapeutic targets. We will provide a solid scientific basis for new diagnostic markers, particularly biomarkers, based on genetics and genomics.

Summary

Celiac disease affects at least 1% of the world population. Its onset is triggered by gluten, a common dietary protein, however, its etiology is poorly understood. More than 80% of patients are not properly diagnosed and they therefore do not follow a gluten-free diet, thereby increasing their risk for disease-associated complications and early death. A better understanding of the disease biology would improve the diagnosis, prevention, and treatment of celiac disease. This project investigates the disease mechanisms in celiac disease by using predisposing genes and genetic variants as disease initiating factors. Specifically, it will investigate if long, intergenic noncoding RNAs (lincRNAs) are causally involved in celiac disease pathogenesis by regulating protein-coding genes and pathways associated with the disease.

This project is based on two important observations by my group: (1) Our genetic studies, which led to identifying 39 celiac disease risk loci, suggest that the mechanism underlying the disease is largely governed by dysregulation of gene expression. (2) We uncovered a previously unrecognized role for lincRNAs that provides clues as to exactly how genetic variation causes disease, as this class of biologically important RNA molecules regulate gene expression. The research will be performed in CD4+ T cells, a severely affected cell type in disease pathology. I will first use celiac disease-associated protein-coding genes to delineate their regulatory pathways and then study the transcriptional programs of lincRNAs present in celiac disease loci. Next I will combine the information and investigate if the expressed lincRNAs modulate the pathways and affect T cell function, thereby discovering if lincRNAs are a missing link between non-coding genetic variation and protein-coding genes. Our findings may well lead to potential therapeutic targets and provide a solid scientific basis for new diagnostic markers, particularly biomarkers, based on genetics