Human leukocyte antigen-DRB1 position 11 residues are a common protective marker for sarcoidosis
Human leukocyte antigen-DRB1 position 11 residues are a common protective marker for sarcoidosis
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DOI：
10.1165/ajrcmb.25.3.4261
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发表时间：
2001-09-01
影响因子：
6.4
通讯作者：
du Bois, RM
中科院分区：
文献类型：
--
作者：
Foley, PJ;McGrath, DS;du Bois, RM
遗传因素，特别是人类白细胞抗原（HLA）是结节病易感性的重要决定因素，结节病是一种病因不明的慢性肉芽肿性疾病。为了阐明HLA在结节病中的作用，我们确定了来自三个欧洲人群（英国、捷克和波兰）的病例对照样本中的HLA-DR和-DQ等位基因，并将这些结果与其他三个人群（意大利、日本和斯堪的纳维亚）的结果进行比较，以确定HLA-DR和/或-DQ等位基因是否作为种族依赖性或种族独立性疾病风险的修饰因子。虽然与易感性相关的等位基因的变异是明显的，但与保护相关的等位基因频率的减少在六个群体中是非常一致的。先前检测到的TAP 2位点单核苷酸多态性与结节病之间的关联被证明是由于与HLA-DR位点的连锁不平衡。编码DR 1和DR 4抗原的保护性HLA-DR等位基因被发现在位置11处共享特征性的小疏水残基，其在剩余的非保护性HLA-DR等位基因中被小亲水残基取代。该残基位置在HLA-DR复合物抗原结合沟的口袋内（命名为P6），其中它是唯一的可变氨基酸，因此决定了该口袋的肽结合偏好。在我们所研究的三个人群中，在结节病病例中观察到携带HLA-DR等位基因的频率非常显著地降低，这表明HLA-DR残基是结节病的重要保护性标记。
Genetic factors, in particular human leukocyte antigens (HLAs) are important determinants of susceptibility to sarcoidosis, a chronic granulomatous disease of undetermined etiology. To clarify the role of HLA in sarcoidosis we determined HLA-DR and -DQ alleles in case-control samples from three European populations (United Kingdom, Czech, and Polish) and compared these results with those published for three additional populations (Italian, Japanese, and Scandinavian) to determine whether the HLA-DR and/or -DQ alleles act as ethnic-dependent, or ethnic-independent modifiers of disease risk. Although variations were apparent in the alleles associated with susceptibility, reductions in the frequency of alleles associated with protection were remarkably consistent in the six populations. Previously detected associations between single-nucleotide polymorphisms at the TAP2 locus and sarcoidosis were shown to be due to linkage disequilibrium with the HLA-DR locus. The protective HLA-DR alleles, which encode the DR1 and DR4 antigens, were found to share characteristic small hydrophobic residues at position 11, which were replaced by small hydrophilic residues in the remaining, nonprotective, HLA-DR alleles. This residue position is within a pocket of the HLA-DR complex antigen binding groove (designated P6), where it is the only variable amino acid and therefore determines the peptide binding preferences of this pocket. A highly significant reduction in the frequency of individuals carrying HLA-DR alleles with a hydrophobic residue at position I I was observed in the sarcoidosis cases in the three populations we examined, This suggests this HLA-DR residue is an important protective marker in sarcoidosis.