Jagiello Peter, Gencik Martin, Arning Larissa, Wieczorek Stefan, Kunstmann Erdmute, Csernok Elena, Gross Wolfgang L, Epplen Joerg T
Department of Human Genetics, Ruhr University, Universitätstrasse 150, 44801 Bochum, Germany.
Hum Genet. 2004 Apr;114(5):468-77. doi: 10.1007/s00439-004-1092-z. Epub 2004 Feb 14.
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 DPB10401 ( P=1.51x10(-10), OR=3.91) allele compared with the control cohort. In addition, an extended haplotype DPB10401/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.
韦格纳肉芽肿病（WG）是一种具有复杂遗传背景的全身性疾病。其特征为上、下呼吸道的坏死性肉芽肿性炎症、肾小球肾炎、血管炎以及患者血清中存在抗中性粒细胞胞浆自身抗体（C-ANCA）。在此，我们报告了一项扩展关联筛查（EAS），使用150名患有WG的德国北部患者和100名健康的德国北部对照者的混合DNA，对202个微卫星标记进行检测，这些标记代表凋亡相关基因以及在凋亡中性粒细胞中进一步下调的基因。发现六种微卫星等位基因模式与WG显著相关，其中三种可通过个体基因分型得到证实。经过多重校正后，一个标记仍保持显著相关性。这个代表视黄酸X受体β基因（RXRB，P = 7.60×10⁻⁶，与基因的距离：约5.3 kb）的标记位于主要组织相容性复合体（MHC）区域，在HLA-DPB1和DAXX基因之间。HLA-DPB1分型以及使用额外的微卫星和单核苷酸多态性（SNP）对该区域进行精细定位显示，与对照队列相比，WG与显著过度表达的DPB10401（P = 1.51×10⁻¹⁰，OR = 3.91）等位基因强烈相关。此外，还鉴定出一个扩展单倍型DPB10401/RXRB03，其与WG的关联更强（P = 7.13×10⁻¹⁷，OR = 6.41）。这些结果代表了一个基因组区域与WG的最强关联，表明该疾病病因中存在主要的遗传贡献。因此，我们的数据表明，扩展关联筛查可能是确定多因素疾病遗传易感性因素的一种有价值的替代方法。
