Genetic susceptibility to gastrointestinal complex diseases and pharmacogenomics

The aim of our study is to provide new molecular diagnostic markers and molecular targets for novel drugs design for better prevention and treatment of complex gastrointestinal diseases. We will study both major forms of inflammatory bowel diseases (IBD), ulcerative colitis and Crohn disease, IBD-associated neoplasia (IBDNs) and colorectal cancer (CRC). We will focus on identification of novel single nucleotide polymorphisms (SNPs) associated with higher risk for complex gastrointestinal diseases and different individual response to treatment. We will describe new genes and molecular pathways involved in pathogenesis and treatment response. We will develop new bioinformatic and statistical genetic tools for best candidate gene selection. We will develop new approach for identification of functional SNPs in regulatory cis-acting regions based on allele specific expression in lymphoblastoid cell lines from CEPH families and segregation analysis. The database with genes showing most significant allele specific expression will be used for our disease association study and will be avaiable on the internet to scientific community for other disease association studies. We will also describe molecular alterations, including somatic mutations, methylation status and global gene expression profile in adenomas from IBDN patients, tumors from CRC patients and biopsies from IBD patients during standard treatment with corticosteroids and immunosuppresives and treatment with monoclonal antibody inhibitor against TNF alfa (Inflaximab). We will provide molecular markers for IBDN patients with increased risk for CRC development. We will correlate genetic data with CRC patients prognosis and survival. We will functionally characterize genes and proteins most significantly associated with disease. We will establish a comprehensive follow-up patients database and bioinformatic tools for finding statistical correlations between molecular genetic and clinicopathological data included in the database. We will conduct case-control study of patients with gastrointestinal complex diseases and matching healthy individuals using candidate gene, genome-wide haplotype and linkage disequilibrium association aproaches. We will use Taqman method for high-throughput genotyping. Candidate genes genotyped will include drug metabolizing enzymes (phase 1 and phase 2), drug transporters and genes potentially involved in pathogenesis selected in our study using bioinformatics and gene expression approaches. We will use oligo-microarrays, quantitative real time PCR (Taqman) and imunohistochemistry for expression profiling.