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Major Histocompatibility Complex HLA Region Largely Explains the Genetic Variance Exercised on Neutrophil Membrane Proteinase 3 Expression

Sibylle von Vietinghoff^*, Andreas Busjahn, Constanze Schönemann, Gero Massenkeil, Björn Otto^*, Friedrich C. Luft^* and Ralph Kettritz^*

Medical Faculty of the Charité, ^* Department of Nephrology and Hypertension, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Max Delbrück Center for Molecular Medicine Campus Buch; Institute of Transfusion Medicine, Campus Virchow Klinikum; Department of Hematology and Oncology, Campus Virchow Klinikum; and HealthTwiSt, Berlin, Germany

Address correspondence to: Dr. Sibylle von Vietinghoff, Wiltbergstrasse 50, 13125 Berlin, Germany. Phone: +49-30-9417-2246; Fax:+49-30-9417-2206; E-mail: sibylle.vietinghoff{at}charite.de

Received for publication May 24, 2006. Accepted for publication August 17, 2006.

ANCA-associated vasculitides, a common cause of rapidly progressive glomerulonephritis, are influenced by genetic variance. Neutrophil membrane expression of the ANCA antigen proteinase 3 (PR3) is pathogenically important. A subset of membrane PR3–positive neutrophils can be distinguished from a membrane-negative subset in any given subject. The percentage of membrane PR3–positive neutrophils is genetically determined. In this study, 17 pairs of HLA-matched siblings were typed for their percentage of membrane PR3–positive neutrophils. The HLA-matched siblings showed a high concordance (r = 0.67, P < 0.05), similar to that seen in monozygotic twins. For testing of whether the HLA system influences membrane PR3 percentage, membrane PR3 typing and HLA typing of 51 unrelated patients with Wegener’s granulomatosis and 49 normal control subjects was performed. Using two independent statistical methods, a group of 34 HLA antigens was found to predict a large fraction of the membrane PR3 phenotype in patients and control subjects. Certain major histocompatibility HLA antigens have been implicated to conflicting degrees in ANCA-associated vasculitides. However, in earlier studies, the contribution of the HLA system to the genetic variance of the disease was unclear. In this cohort, found was an association of Wegener’s granulomatosis with the same group of HLA antigens that predicted for membrane PR3 percentage and a similar correlation with clinical parameters at initial presentation. The disease status in 80% of the patients and 82% of the control subjects could be predicted correctly on the basis of HLA typing by discriminate function analysis (P < 0.001). After removal of the predicted individual from the sample, this association remained significant (64 and 63% correct prediction; P < 0.001). The data suggest that a complex interaction of the entire HLA system is responsible for the genetic influence on membrane PR3 percentage and Wegener’s granulomatosis.

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				S. von Vietinghoff, G. Tunnemann, C. Eulenberg, M. Wellner, M. Cristina Cardoso, F. C. Luft, and R. Kettritz NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils Blood, May 15, 2007; 109(10): 4487 - 4493. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673