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Genetischer Hintergrund der Vaskulitiden

The genetics of vasculitides

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Zusammenfassung

Genetische Assoziationsstudien haben auf dem Gebiet der chronischen Entzündungs- und Autoimmunerkrankungen wesentliche Erkenntnisse für die zugrundeliegende Pathophysiologie erbracht. So sind genetische Risikofaktoren identifiziert worden, welche die Suszeptibilität für bestimmte Erkrankungen (oft mehrere) erhöhen, ohne notwendigerweise direkt in die Pathogenese oder pathogenetischen Abläufe involviert zu sein. Für die Autoimmunvaskulitiden konnten erste Risikogene bzw. -polymorphismen identifiziert werden. Einen limitierenden Faktor stellt die oft geringe Anzahl an Probanden dar. Ferner sind ethnische Unterschiede bei der Analyse ein Problem. Nur wenige der detektierten Risikogene bzw. -polymorphismen wurden daher an einer großen Kohorte und/oder auch verlässlich repliziert, z. B. PTPN22*620 W für Wegener-Granulomatose (WG) und mikroskopische Polyangiitis (MPA), die Alpha-1-Antitrypsin-Defizienz sowie das HLA-DPPB*0401 für die WG oder der HLA-DRB3/DRB4 für das Churg-Strauss-Syndrom. Genomweite Assoziationsstudien (GWAS) bieten die Möglichkeit, das gesamte Genom auf genetische Risikofaktoren zu screenen, erfordern aber die Untersuchung noch größerer Kohorten zum Erreichen statistisch signifikanter Ergebnisse. Ergebnisse aus GWAS zu M. Behçet und dem Kawasaki-Syndrom konnten neue, bisher nicht durch den Kandidatengen-Ansatz identifizierte Polymorphismen identifizieren, deren pathophysiologische Bedeutung teilweise aber (noch) völlig unklar ist und die einer Replikation bedürfen.

Abstract

Genetic association studies have been of great value in the past by contributing to the understanding of pathophysiological mechanisms of chronic inflammatory and autoimmune diseases. Many genetic risk factors have been identified which confer susceptibility for one or several (autoimmune) disease(s). Using a candidate-gene approach, the first genetic risk factors and polymorphisms of vasculitides have been identified. Due to the rarity of autoimmune vasculitides often only small sample numbers have been generated and analysed, leading to inconsistent results. Furthermore, differences in ethnic background may complicate analysis. Only few of the detected risk factors have been reliably replicated in larger cohorts, such as the association of the PTPN22*620W allele with WG and MPA, the deficiency allele Pi*Z of the alpha1 antitrypsin gene and the HLA-DPB*04041 allele with WG and the HLA-DRB3/DRB4 with CSS. Genome-wide association studies (GWAS) offer the advantage of screening the whole genome for risk factors rather than relying on disease models postulated by the investigator; however, they require even larger sample sizes. Initial results from GWA studies are available for Behçet’s disease and Kawasaki syndrome, which identified new genetic associations but require replication, especially since some of the identified risk factors could not be linked to pathophysiological pathways to date.

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Authors and Affiliations

  1. Poliklinik für Rheumatologie, Vaskulitiszentrum, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Rheumatologie und Klinische Immunologie, Klinikum Bad Bramstedt , Oskar-Alexander-Str. 26, 24576, Bad Bramstedt, Deutschland

    J.U. Holle & W.L. Gross

  2. Abteilung für Humangenetik, Ruhr-Universität, Bochum, Deutschland

    S. Wieczorek & J.T. Epplen

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  1. J.U. Holle
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  2. S. Wieczorek
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  3. J.T. Epplen
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  4. W.L. Gross
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Correspondence to J.U. Holle.

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Holle, J., Wieczorek, S., Epplen, J. et al. Genetischer Hintergrund der Vaskulitiden. Z. Rheumatol. 70, 198–204 (2011). https://doi.org/10.1007/s00393-010-0692-3

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  • DOI: https://doi.org/10.1007/s00393-010-0692-3

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