Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis
Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis
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DOI：
10.1086/342407
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发表时间：
2002-09-01
影响因子：
9.8
通讯作者：
Gregersen, PK
中科院分区：
文献类型：
--
作者：
Jawaheer, D;Li, WT;Gregersen, PK
类风湿关节炎(RA)是一种具有复杂遗传成分的炎症性疾病。长期以来，在许多不同的人群中观察到类风湿关节炎与人类白细胞抗原(人类白细胞抗原)复合体之间的关联，大多数研究都集中在人类白细胞抗原-DRB1“共享表位”在疾病易感性中的直接作用。我们进行了广泛的单倍型分析，使用了分布在整个人类白细胞抗原复合体中的54个标记，这些标记分布在一组469个患有类风湿关节炎的多基因家系中。结果表明，除了与DRB1等位基因的关联外，在主要组织相容性复合体中至少存在两个额外的遗传效应。其中一个位于人类白细胞抗原复合体中心部分的497kb区域内，这个区间不包括DRB1。这种遗传风险因子存在于高度保守的祖先A1-B8-DRB1*03(8.1)单倍型的一段片段上。在DRB1*0404单倍型的子集中，其他风险基因也可能存在于人类白细胞抗原I类区域。这些数据强调了在试图了解人类白细胞抗原与疾病的关联时定义单倍型的重要性，它们清楚地表明这种与类风湿关节炎的关联是复杂的，不能完全用DRB1基因座来解释。
Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.