Researchers:
dr. S. Withoff
V. Kumar
prof. dr. C. Wijmenga
Type of project: Stage Wetenschap / Research project
Nature of the research:
Previous analysis implicated miRNAs in celiac disease. Interested students will investigate how changes in miRNA regulation affect the expression of genes involved in celiac disease and other autoimmune diseases.
Genome wide association studies (GWAS) have been very successful in identifying genetic changes that predispose to autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis (RA), celiac disease (CeD), and multiple sclerosis (MS). An unexpected finding was that a variety of immune-related diseases share genetic disease susceptibility factors, implying that these diseases share mechanistic features.
Our lab has focused focuses on CeD. CeD is a chronic inflammation of the small intestines that results from a T-cell mediated immune response to ingested gluten (gluten is a constituent of many common grains like wheat, rhye, etc). A characteristic feature of CeD is damage of of the small intestine (villous atrophy, crypt hyperplasia, symptoms of malabsorption). The genetic make-up of an individual contributes to CeD susceptibility. In a recent GWAS, aimed at identification of susceptibility genes for CeD, we have identified 57 independent genetic alterations in 40 loci to be strongly associated with CeD (Trynka et al., Nature Genetics, In Press). Subsequent fine-mapping of these alterations suggest that most of them do not affect the sequence of protein-encoding genes in these loci, but that they probably affect gene regulatory regions (promoters, 3’-UTRs, miRNA bindingsites).
We are part of an international consortium that developed the so-called immuno-chip. We were the first to publish results using this chip and we have found several novel genetic variants involved in CeD, that no one has observed before (Trynka et al. Nature Genetics, 2011, In Press). Careful analysis of some of the genetic alterations associated with CeD seem to affect the expression of genes that encode miRNAs or affect potential miRNA bindingsites in the 3’-UTR of CeD susceptibility genes. We are studying how these changes in miRNA expression or binding affects CeD. Because many of the genetic variants are shared with other autoimmune diseases the results will contribute broadly to our understanding of autoimmune diseases etiology.
Research question / problem definition
To investigate how changes in miRNA regulation affect autoimmune disease genes and pathways.
Workplan
Students will be involved in ongoing research on the role of miRNAs in CeD and other autoimmune diseases.
References
• Celiac disease: update from the 14th International Celiac Disease Symposium 2011. Kumar V, Wijmenga C. Expert Rev Gastroenterol Hepatol. 2011 Dec;5(6):685-7.
• Pervasive sharing of genetic effects in autoimmune disease. Cotsapas C, et al. PLoS Genet. 2011 Aug;7(8):e1002254.
• A genetic perspective on coeliac disease. Trynka G, Wijmenga C, van Heel DA. Trends Mol Med. 2010 Nov;16(11):537-50.
• miRNAs in the spotlight: Making ‘silent’mutations speak up. Salzman DW & Weidhaas JB. Nature Med. 2011, 17:914-5
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