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

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 beta gene (RXRB, P=7.60x10(-6), distance to gene: approximately 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=1.51x10(-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=7.13x10(-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.

Arterial Distensibility in Chronic Inflammatory Rheumatic Disorders

“…WG is a rare disease, affecting only 1 in every 30.000-50.000 people, that often begins with inflammation of the upper airways or lungs and may progress to an inflammation of blood vessels throughout the body [47][48][49][50][51]. There is a strong and specific association of WG with presence of antineutrophil cytoplasmic antibodies (ANCA) to a defined target antigen, proteinase 3 (PR3-ANCA), which is present within primary azurophil granules of neutrophils and lysozymes of monocytes [48].…”

Novel association of the CD226 (DNAM-1) Gly307Ser polymorphism in Wegener's granulomatosis and confirmation for multiple sclerosis in German patients

“…A major genomic risk locus for WG has been identified on chromosome 6p21.3 including the HLA-DPB1 gene. 6,7,8 Another HLA locus, HLA-DR, has also been linked to WG susceptibility. 9,10 Other genetic risk factors for WG comprise a polymorphism in PTPN22, 11 which has been identified as a risk factor in different (auto)-immune disorders, and variations in the a1-antitrypsin gene.…”

Wegener’s granulomatosis

“…Igazolták, hogy a retinoid X receptor beta gén (RXRB), amely a major hisztokompatibilitási komplex (MHC) területén helyezkedik el, szoros összefüggést mutat a WG-vel. A DPB1*0401 allél jelentősen túlreprezentált WG-ben szenvedő betegeken [18].…”