Human Genetics

, Volume 114, Issue 5, pp 468–477

New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes

  • Peter Jagiello
  • Martin Gencik
  • Larissa Arning
  • Stefan Wieczorek
  • Erdmute Kunstmann
  • Elena Csernok
  • Wolfgang L. Gross
  • Joerg T. Epplen
Original Investigation

Abstract

Wegener’s granulomatosis (WG) is a systemic disease with complex genetic background. It is characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis, vasculitis and the presence of antineutrophil cytoplasmatic autoantibodies (C-ANCAs) in sera of patients. Here, we report on an extended association screen (EAS) with 202 microsatellite markers, representing apoptosis-related genes and further genes down-regulated in apoptotic neutrophils, using pooled DNA of 150 Northern German patients suffering from WG and 100 healthy Northern German controls. Six microsatellite allele patterns were found significantly associated with WG, three of which could be confirmed by individual genotyping. One marker remained significantly associated after multiple corrections. This marker representing the retinoid X receptor ß gene (RXRB, P=7.60×10−6, distance to gene: ~5.3 kb) is localised in the major histocompatibility complex (MHC) region between the HLA-DPB1 and DAXX genes. HLA-DPB1 typing and fine mapping of the region with additional microsatellites and single-nucleotide polymorphisms (SNPs) revealed a strong association of WG with the significantly over-represented DPB1*0401 (P=1.51×10−10, OR=3.91) allele compared with the control cohort. In addition, an extended haplotype DPB1*0401/RXRB03 was identified showing an even stronger association with WG (P=7.13×10−17, OR=6.41). These results represent the strongest association of a genomic region with WG, suggesting a major genetic contribution in the aetiology of the disease. Thus, our data demonstrate that EAS may be a valuable alternative approach for determining genetic predisposition factors in multifactorial diseases.

Keywords

Wegener’s granulomatosis Apoptosis HLA Microsatellite 

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Peter Jagiello
    • 1
  • Martin Gencik
    • 2
  • Larissa Arning
    • 1
  • Stefan Wieczorek
    • 1
  • Erdmute Kunstmann
    • 1
  • Elena Csernok
    • 3
  • Wolfgang L. Gross
    • 3
  • Joerg T. Epplen
    • 1
  1. 1.Department of Human GeneticsRuhr UniversityBochumGermany
  2. 2.Department for Med. BiologyUniversity of ViennaViennaAustria
  3. 3.Department of RheumatologyUniversity Hospital Luebeck and RheumaklinikBad BramstedtGermany

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