Genome Wide Association Study (GWAS)
Professor David van Heel's group carried out the first ever coeliac disease genome wide association study, published in the journal Nature Genetics.in June 2007. The primary study was performed on a British sample collection, with replication of the major finding in a Dutch and an Irish sample collection.
310,605 single nucleotide polymorphisms (SNPS) were tested for association using Illumina's beadchip technology in samples from 778 coeliac disease individuals and 1,422 population controls (British 1958 Birth Cohort). Genetic varaints in the IL2 / IL21 gene region were identified as risk factors predisposing to coeliac disease.
The Guardian newspaper published an article about this project.
Genome Wide Association Study Follow Up
We followed up 1,020 top associated SNPS from the British GWAS in a further set of 1,643 coeliac and 3406 population control samples from Britain, The Netherlands and Ireland. This study was published in Nature Genetics in March 2008.
We identified seven further gene regions predisposing to coeliac disease. There are now nine coeliac gene regions identified, including the 2007 IL2-IL21 finding and the long-recognised HLA-DQ association. Of the nine regions, eight contain likely candidate genes involved in immune system function. This agrees nicely with what we know about the immunology of coeliac disease. We know how genetic variation influences biological function for HLA-DQ, and we reported possible mechanisms for two of the new findings: SH2B3 and IL18RAP.
Interestingly there seems to be substantial overlap of gene regions with other autoimmune diseases, particularly four of the nine coeliac regions also predispose to type 1 (early onset) diabetes. We have been awarded a grant from the Juvenile Diabetes Research Foundation to study potential common mechanisms of these diseases.
The Daily Telegraph newspaper published an article about this project.
Current Research
Finding more disease genes will require analysis of thousands more samples. We have formed a large collaborative group to enable this, and have been awarded (Feb 2008) a major collaborative grant by the Wellcome Trust charity. Our current collaborators are based in the UK, the Netherlands, Ireland, Finland (genome scan samples), Spain, US, Hungary, Italy, Sweden, Norway (replication samples).
We currently aim to:
- precisely localise from each region the disease causing genetic change ('fine-mapping'). The current markers we have identified for each region are probably just tagging (i.e. correlated with) the true causal variant.
- discover more coeliac disease predisposing genetic variants
- understand how the coeliac disease genetic variants are influencing biological function
Ethics note
All our research is performed on human samples (we do no animal based research). Our studies have all been approved by independent research ethics committees from the UK National Research Ethics Service.