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RA I Genetic and Phenotypic Architecture of Inflammatory Barrier Diseases

Summary

RA I (successor of the former RA A) will continue identifiying the genetic and phenotypic architecture of complex inflammatory barrier diseases. Additional inflammatory diseases (CHD, obesity, stroke, SLE) where clinical expertise and patient samples exist have now been included. The 2nd FP will shift the focus from genome-wide association studies (GWAS) to state-of-the-art sequencing approaches that capture the entire DNA variation in a given sample. Applying the novel technology first to samples of deeply characterized extreme phenotypes and then to prospective population-representative cohorts, the resultion of the phenotypic/genetic relationship will be increased. Translation into systematic pharmacogenomic studies will become more important. Challenges especially exist at the computational and data management level since the amount of data generated in this RA will clearly overstrain the current IT infrastructure at all locations (see CL IX). The RA will also foster the development of novel analytical tools, databases and storage solutions in collaboration with CL IX to make the different large-scale data sets usable for clinical research and diagnostics.

Contribution to the Scientific Agenda

The RA will conduct a comprehensive investigation of the genetic architecture of chronic inflammatory barrier diseases and promote discovery and annotation of genetic causations with overarching importance for chronic inflammation. Collaborative projects with other RAs and CLs include: (1) extraction of genetic variant spectra at known risk loci for inflammatory barrier diseases by genotyping and targeted resequencing, (2) development of new analysis algorithms, e.g. for gender-specific and gene x environment interactions, (3) integration of genetic data and other “–omics” data as extended molecular phenotypes, (4) investigation of whole-genome/exome sequencing data for assessing complete genetic risk profiles and (5) providing the genetic basis for rederivation of disease phenotypes in RA VI.

Figure: Important existing and planned infrastructures of RA I in the 2nd FP: existing infrastructure (grey shading), planned infrastructure (turquoise), positions that need to be established in the 2nd FP (green hexagons), and new re-search foci (yellow boxes). CD/Crohn‘s disease, UC/ulcerative colitis, PSOR/psoriasis, AD/atopic dermatitis, PER/periodontitis, SARC/sarcoidosis,RA/ SLE/rheumatoid arthritis/systemic lupus erythematosus, CHD/ coronary artery disease. In addition to the adult cohorts, pediatric cases (early onset) of different inflammatory diseases are collected for all disease entities via the children’s hospitals. The phar-macogenomic cohorts are a bridge to the translational RA establishing whole-genome/-exome sequencing as a routine method that can be applied to thousands of samples; data will be prepared in an intuitive webinterface and large Ger-man control reference exome/genome data sets need to be created.

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