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Homozygosity for DNASE2 single-nucleotide polymorphisms in the 5’ regulatory region is associated with rheumatoid arthritis
  1. Manuela Rossol (manuela.rossol{at}medizin.uni-leipzig.de)
  1. University of Leipzig, Department of Internal Medicine II, Division of Rheumatology, Germany
    1. Matthias Pierer (matthias.pierer{at}medizin.uni-leipzig.de)
    1. University of Leipzig, Department of Internal Medicine II, Division of Rheumatology, Germany
      1. Sybille Arnold (sybille.arnold{at}medizin.uni-leipzig.de)
      1. University of Leipzig, Department of Internal Medicine II, Division of Rheumatology, Germany
        1. Gernot Keyszer (gernot.keyszer{at}medizin.uni-halle.de)
        1. University of Halle (Saale), Germany
          1. Harald Burkhardt (harald.burkhardt{at}kgu.de)
          1. Johann Wolfgang Goethe University Frankfurt am Main, Germany
            1. Christoph Baerwald (christoph.baerwald{at}medizin.uni-leipzig.de)
            1. University of Leipzig, Department of Internal Medicine II, Division of Rheumatology, Germany
              1. Ulf Wagner (ulf.wagner{at}medizin.uni-leipzig.de)
              1. University of Leipzig, Department of Internal Medicine II, Division of Rheumatology, Germany

                Abstract

                Objectives: To analyze the distribution of single nucleotide polymorphisms (SNP’s) in the 5’ regulatory region of the DNASE2 gene, in patients with rheumatoid arthritis (RA) and healthy controls.

                Methods: A total of 906 RA patients and 878 healthy controls were genotyped. All subjects were of German Caucasian origin. Genotyping was performed by real-time polymerase chain reaction technology, using a TaqMan 5’-allele discrimination assay.

                Results: In the initial analysis of unrelated case-control samples, three DNASE2 SNP alleles in the 5’-regulatory region were significantly more frequent in RA patients compared to healthy controls. The strongest association was found for the -1066 G allele (33.5% vs. 27.2%, p = 0.007, odds ratio 1.34). Homozygosity for this allele (genotype GG) resulted in an additional increase in disease susceptibility (12.5% vs. 6.2%, odds ratio 2.17). The association was replicated in a second case–control series of 483 RA patients from two German multi-center studies and 474 controls. The association of DNASE2 -1066 GG homozygosity with RA was limited to rheumatoid factor positive disease, but was not influenced by the presence of anti-CCP or antinuclear antibodies. Similarly, the presence or absence of the HLA DRB1 shared epitope or the RA associated PTPN22 allele had no influence on this association.

                Conclusions: The association of SNP’s in the 5’ regulatory region of the DNA degrading enzyme DNASE2 with RA implies a role for this enzyme in the pathogenesis of this autoimmune disease.

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