Diseases Due to Environmental Factors

Coordinator: Prof. Dr. Stefan Schreiber

The network on environmental disorders focuses on chronic inflammatory diseases that affect human barrier organs. These diseases are asthma (lung), atopic dermatitis (skin), Crohn’s disease/ulcerative colitis (gastrointestinal mucosa), psoriasis (skin) and sarcoidosis (lung). Common themes among these complex diseases include overlaps in their pathophysiology and a (poly)genic susceptibility that has been documented by twin concordance, linkage analysis and other genetic-epidemiological characteristics. All diseases need external trigger factors to precipitate genetic susceptibility into disease manifestation. Although not yet identified, trigger factors are likely linked to the life-style of industrialized societies and may explain the rising incidence that has been observed for some of these conditions over the last decades.

The network’s scientific approach is dominated by its focus on systematic positional cloning of susceptibility genes. Therefore, the three network sites (Berlin, Kiel, Munich) are associated with sites of the national genotyping platform (SMP-DNA) and local genetic epidemiology methods centers (SMP-GEM). A large percentage (i.e. more than four million) of all SNP genotypes that have been generated during the first funding period of the NGFN (NGFN-1) was committed by the environmental diseases network. Notable among other scientific highlights are the identification of causative variants in the first disease genes for Crohn’s disease (NOD2, DLG5), the first disease gene for sarcoidosis (BTNL2) and the identification of a new locus for atopic dermatitis (chromosome 3q). Multiple association leads have been identified in the other disease areas and the remaining linkage regions, which hold the promise of discovery of several novel disease genes during NGFN-2.

The environmental disorders network has further optimized its structures: The concentration on a scientific approach that centers around positional cloning ensures a high degree of exchange in molecular tools and techniques. It has been decided to jointly explore chromosomal risk regions (mostly defined by linkage analysis) that overlap between the diseases under study. More than 16.000 index patient phenotypes are available in a central database and corresponding DNAs are exchanged throughout the network. This process required a stringent selection of the diseases and a discussion process to align molecular strategies.

The scientific progress of the network is dependent on supportive structures provided by systematic methodological platforms (SMPs) of the NGFN-2. Cutting edge bioinformatics to predict protein structures and potential interaction partners for disease genes suggested by positional cloning is of great importance. Likewise guidance by bioinformatics predictions is important to target the experimental annotation of disease-associated variants with relevant mechanisms. The network continues to support a central pathway-mapping group that has demonstrated the expertise for a fast generation of molecular tools and cell culture based model systems during NGFN-1. Some of the recent publications demonstrate the capacity of the pathway-mapping group to create new insights regarding disease mechanisms. The pathway mapping-group is linked into the systematic approach taken by the SMP-DNA to explore the phylogeny of gene variants. As genes important for barrier integrity (e.g. NOD and NALP family of genes) are of particular importance for the network, these genes will be analysed preferentially in the systematic experimental pipeline that extends from the phylogeny analysis by the SMP-DNA through the functional annotation in the SMPs RNA, Bioinformatics, Protein, and Cell.

The network on infection and inflammation addresses - among other projects -interactions between bacteria and innate immune system. As the bacterial flora on human barrier organs is a likely trigger factor to convert genetic susceptibility (e.g. by sequence variants in genes important to innate immunity) into inflammatory disease, both networks have coordinated their respective scientific interests. A series of TRANSNET projects that include the infection and inflammation network and the GBF will examine the interaction between human genetic susceptibility and bacterial genome. In addition, DNA that has been collected in the infection and inflammation network from patients with rheumatoid arthritis will be analysed using the genotyping pipeline of the environmental disorders network.

Many service activities were paid directly by the budget of the core area in NGFN-1. For NGFN-2, the clinical networks were asked to include the costs for services provided by the core area (now structured into SMPs) in their budgets. The network applies for a total funding volume of 15.8 Mill. Euro. 7.2 million Euro are used for scientific agendas within the network, whereas 8.6 Mill. Euro are for experiments carried out by the SMPs that represent the former core area of the NGFN-1.

The network has asked three small/medium size enterprises (SMEs) to participate. The intention is that the SMEs (CONARIS Research Institute AG, Scienion AG and Xantos AG, which all have previously received BIOCHANCE awards from the BMBF) gain access to potential targets defined through scientific discovery in the network. While the scientific exploration process usually stops at this point, further validation of targets increases their chance to be clinically developed by large pharmaceutical companies. In addition, the consortium has the possibility to convert selected targets into novel therapies and move these into early phases of clinical trials.

The network has clear management structures that mandate a rational approach to resource consumption. Workforce and genotyping resources have already been distributed during NGFN1 asymmetrically favouring projects that show the highest dynamics or are under intense competitive pressure, respectively. This concept is now strengthened during NGFN-2.