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STUDY GROUP ON GENETICS IN RA
Evaluation of genetic influences on the susceptibility to, and clinical course of, rheumatoid arthritis has been substantially hampered by the large number of patients needed for statistical evaluation owing to the high variability of the polymorphic areas in the genome and the many resulting markers. In large multicentre studies, twins and families are collected for genome wide screens that require DNA samples from thousands of patients and their progeny pedigree ancestors. Patient recruitment in such multicentre genetic studies is often limited to a singular time point at study inclusion, while the clinical course of the disease can either not be documented or has to be reconstructed retrospectively by chart review. For the longitudinal analysis of treatment effects and of the progression of erosive disease, prospective patient recruitment would be necessary, which requires large logistic efforts and long observation periods before conclusive results could be expected. Consequently, the focus of the existing multicentre studies is often the identification of disease susceptibility markers, while predictors of differential clinical outcome are characterised less accurately.
On the other hand, numerous clinical studies have been performed prospectively in different centres in Europe, with controlled treatment options and detailed documentation of the radiographic progression of joint destruction. In those studies the primary aim was not a comparison with unaffected siblings or other family members for identification of genetic factors influencing disease susceptibility, but the dissection of parameters influencing the structural damage and functional disability resulting from the divers clinical courses of the disease.
The drawback of such single centre studies is clearly their limited cohort size. In particular, the recruitment of patients with the most severe clinical courses, which include those with high systemic activity, extra-articular manifestations of the disease and major organ vasculitis, is often limited to only a small number of patients because they are found infrequently even in tertiary referral centres. Yet the identification of patients at risk from life threatening manifestations of the disease, with the help of distinct genetic markers, would be of great importance for treatment decisions early in the course of the disease.
To create a platform for cooperation between centres involved in clinical research on genetic influences on the disease course of RA, representatives of a number of those centres met in Leipzig last year and suggested setting up a “Study Group on Genetics in RA” under the umbrella of the EULAR Standing Committee on Investigative Rheumatology, which was approved by ESCIR in Stockholm in June 2002.
The aim of the Study Group on Genetics in RA is, therefore, to find a means of combining patient cohorts collected in different European centres in order to increase the statistical validity of genetic analysis. One of the suggested possibilities is the exchange of DNA samples from the banks established in the different centres for analysis of specific markers. In addition, technological efforts in those centres during the establishment of new techniques can be synergised by offering those typing methods for the analysis of DNA samples collected in other centres.
Over the past year, a first attempt at collaboration has been made by exchanging DNA samples from a well characterised and repeatedly published patient cohort in Leipzig with other centres. In a research project with the group of R Kinne (Department of Experimental Rheumatology, University of Jena, Germany), germline mutations of c-fos and c-jun are analysed, while a continuing collaboration with the group of PD Wassmuth (Institute for Transplantation, Diagnostics and Cell Therapeutics, University of Düsseldorf) focuses on cytokine polymorphisms. In addition, immunogenetic typing for a cohort of patients with RA collected by G Keysser (Department of Medicine, University of Halle, Germany) has been performed by the group in Leipzig.
A new impulse for the assessment of genetic markers might also come from new technology that can be automated, allowing larger numbers of samples to be analysed in short periods of time. One example is a new typing facility that has been installed by the group of P Ahnert in Leipzig, which uses an automated single base extension method for the determination of multiple polymorphisms at “one shot” to analyse the influence of single gene variants and, more importantly, patterns of gene variants
The Study Group on Genetics in RA invites all interested groups to discuss future directions.