Genetic Characterization of Indo-European and Indian Inflammatory Bowel Disease patients: similaraties with the Caucasian population and cross-ethnicity fine-mapping of risk loci.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder that presents as one of two sub-phenotypes: Crohn’s disease (CD) or ulcerative colitis (UC).(1) There is a strong genetic contribution to IBD, with high disease concordance rates in identical twins and a 10- to 25-fold increased disease risk in relatives of CD patients. However, IBD are complex diseases in which multiple genetic and environmental factors are likely to contribute to pathogenesis.(2) With improved genotyping technologies and the completion of the human genome project, genome-wide association studies (GWAS) have become possible. In the last few years, tremendous progress has been made in unravelling the genetic background of IBD, and more recently, meta-analyses and follow up studies have been performed within the international IBD genetics consortium that have confirmed a total of 99 IBD loci.(3,4) However for the larger part, the causal genes or variants within each locus remain unknown. So far, most genetic research has been performed in the Caucasian (CEU) population. There is virtually no reliable data from other ethnicities. We aim to genetically analyze two unique cohorts of IBD patients (one of Indo-Europeans from Iran, and a second cohort of Indians from the Punjab in India). We will then compare them both with the Caucasian IBD population. The differences and similarities in the genetic structure of IBD between different ethnicities will be of great value in expanding our understanding of the aetiology of these complex diseases and might partly explain (next to environmental factors) the difference in prevalence of IBD in different countries This proposal aims to study three aspects of the genetic susceptibility of IBD: 1. Validation of the IBD Montreal subphenotype classification. 2. Are the currently known IBD loci involved in non-Caucasian IBD? 3. Can the different haplotype structures seen between ethnicities help in identifying the causal genes in associated loci? 1) Validation of the IBD Montreal classification For genetic research it is important that the patients’ phenotypes are described in a consistent manner. The general diagnosis of CD and UC is standardized and internationally uniformly accepted. However the classification of CD and CU into sub-phenotypes is done using the Montreal classification, which describes the extent and behaviour of both diseases in more detail. Although this classification is widely used in research and clinical practice, there is virtually no information on how consistently it is applied in practice. We aim to validate the Montreal sub-phenotype classifications for both Crohn’s disease and ulcerative colitis by different individual professionals, different centres and different countries. 2) Are the known IBD loci involved in non-Caucasian IBD? We have genotyped the Indian and Iranian cohorts using a custom-made “Immunochip” containing approximately 200,000 single nucleotide polymorphisms (SNPs) focusing on eight different immune-related diseases (including UC and CD). This application concerns a separate, local project in the UMCG (in addition to the large immunochip project being conducted by the International IBD Genetics Consortium in Caucasian patients). The immunochip will include high-density SNPs to cover all known immune-related loci (approx. 150), for fine-mapping as well as rare variants from the 1000 Genome project, and variants identified by re-sequencing efforts. The genotyping has been performed and the data will soon be available for further analyses once quality control has been performed. We should be able to identify whether the loci and signals discovered by meta-analyses of GWAS in Caucasian patients are involved in the Indo-European and Indian populations. 3) Can the different haplotype structures seen between ethnicities help in identifying the causal genes in associated loci? One of the major challenges in genetic research into complex diseases like IBD is identifying the causal variant in associated risk loci, many of which contain multiple genes. Fine-mapping of associated regions is often severely hampered due to linkage disequilibrium (LD) in the regions. Cross-ethnicity fine-mapping can be of great help because of the different LD structures between ethnicities. This can narrow down the associated regions and point to causal variants. The knowledge gained from such fine-mapping will be important for future re-sequencing efforts and functional studies, and it is therefore one of the main focuses of our proposal.