Rossman Milton D, Thompson Bruce, Frederick Margaret, Maliarik Mary, Iannuzzi Michael C, Rybicki Benjamin A, Pandey Janardan P, Newman Lee S, Magira Eleni, Beznik-Cizman Bojana, Monos Dimitri
Pulmonary, Allergy and Critical Care Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Am J Hum Genet. 2003 Oct;73(4):720-35. doi: 10.1086/378097. Epub 2003 Aug 20.
Sarcoidosis is a granulomatous disorder of unknown etiology, associated with an accumulation of CD4+ T cells and a TH1 immune response. Since previous studies of HLA associations with sarcoidosis were limited by serologic or low-resolution molecular identification, we performed high-resolution typing for the HLA-DPB1, HLA-DQB1, HLA-DRB1, and HLA-DRB3 loci and the presence of the DRB4 or DRB5 locus, to define HLA class II associations with sarcoidosis. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled biopsy-confirmed cases (736 total) from 10 centers in the United States. Seven hundred six (706) controls were case matched for age, race, sex, and geographic area. We studied the first 474 ACCESS patients and case-matched controls. The HLA-DRB1 alleles were differentially distributed between cases and controls (P<.0001). The HLA-DRB11101 allele was associated (P<.01) with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% in whites. HLA-DRB1-F(47) was the amino acid residue most associated with sarcoidosis and independently associated with sarcoidosis in whites. The HLA-DPB1 locus also contributed to susceptibility for sarcoidosis and, in contrast to chronic beryllium disease, a non-E(69)-containing allele, HLA-DPB10101, conveyed most of the risk. Although significant differences were observed in the distribution of HLA class II alleles between blacks and whites, only HLA-DRB11501 was differentially associated with sarcoidosis (P<.003). In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis (DRB10401 for eye in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites). These studies confirm a genetic predisposition for sarcoidosis and present evidence for the allelic variation at the HLA-DRB1 locus as a major contributor.
结节病是一种病因不明的肉芽肿性疾病，与CD4 + T细胞的积聚和TH1免疫反应有关。由于先前关于HLA与结节病关联的研究受到血清学或低分辨率分子鉴定的限制，我们对HLA-DPB1、HLA-DQB1、HLA-DRB1和HLA-DRB3基因座以及DRB4或DRB5基因座的存在进行了高分辨率分型，以确定HLA II类与结节病的关联。结节病病例对照病因研究（ACCESS）纳入了来自美国10个中心经活检确诊的病例（共736例）。706名对照在年龄、种族、性别和地理区域上与病例匹配。我们研究了前474名ACCESS患者和病例匹配的对照。HLA-DRB1等位基因在病例和对照之间分布存在差异（P <.0001）。HLA-DRB11101等位基因在黑人和白人中均与结节病相关（P <.01），在黑人中的人群归因风险为16%，在白人中为9%。HLA-DRB1-F(47)是与结节病最相关的氨基酸残基，在白人中独立与结节病相关。HLA-DPB1基因座也导致了结节病易感性，与慢性铍病相反，不含E(69)的等位基因HLA-DPB10101传递了大部分风险。尽管在黑人和白人之间观察到HLA II类等位基因分布存在显著差异，但只有HLA-DRB11501与结节病存在差异关联（P <.003）。除了作为易感性标志物外，HLA II类等位基因可能是结节病不同表型的标志物（黑人与白人眼中的DRB10401、黑人骨髓中的DRB3以及白人高钙血症中的DPB1*0101）。这些研究证实了结节病的遗传易感性，并提供证据表明HLA-DRB1基因座的等位基因变异是主要因素。
