Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis.
Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis.
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DOI：
10.1172/jci117900
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发表时间：
1995-05
期刊：
影响因子：
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通讯作者：
C. Weyand;Timothy G. McCarthy;J. Goronzy
中科院分区：
文献类型：
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作者：
C. Weyand;Timothy G. McCarthy;J. Goronzy
RA是一组异质性疾病，其特征在于临床表现、病程和可能对治疗干预的反应的变化。我们已经解决了这个问题，是否遗传和潜在的病因更同质亚组的RA患者可以定义的基础上表达的RA连锁序列基序的HLA-DRB 1基因的第三高变区。根据临床表现和病程分类的患者的遗传比较表明，轻度疾病患者与进展为严重和破坏性疾病的患者在遗传上不同。具体而言，类风湿因子（RF）阴性患者优先表达RA连锁的HLA-DRB 1等位基因与精氨酸取代的位置71，而等位基因与赖氨酸取代的位置71积累在RF+患者。RF-患者根据临床标志物（糜烂性疾病发作时间和是否需要积极治疗）进一步细分。临床异质性与遗传异质性相关。早期糜烂性疾病患者和需要积极治疗的患者的HLA-DRB 1 *04+型频率较高。晚期糜烂性/非糜烂性疾病或良性病程可通过非侵袭性治疗控制的患者优先表达HLA-DRB 1 *01或缺乏RA连锁单倍型。这些数据表明RA的异质性反映了遗传差异。疾病相关序列基序内的序列变异以及候选遗传元件周围的多态性影响RA的模式、病程和治疗反应。HLA-DRB 1基因第71位氨基酸具有独特的作用，对其的了解可能为疾病的病因学研究提供重要线索。
RA is a heterogeneous group of disorders characterized by variations in clinical manifestations, disease course, and probably response to therapeutic interventions. We have addressed the question whether genetically and potentially etiologically more homogeneous subgroups of RA patients can be defined based upon the expression of the RA-linked sequence motif in the third hypervariable region of the HLA-DRB1 gene. Genetic comparison of patients classified upon clinical manifestation and disease course demonstrated that patients with mild disease were genetically distinct from those progressing to severe and destructive disease. Specifically, rheumatoid factor (RF) negative patients preferentially expressed RA-linked HLA-DRB1 alleles with an arginine substitution in position 71, whereas the alleles with a lysine substitution in position 71 accumulated in RF+ patients. RF- patients were further subdivided based on clinical markers (time of onset of erosive disease and requirement for aggressive therapy). Clinical heterogeneity correlated with genetic heterogeneity. Patients with early erosive disease and patients requiring aggressive therapy frequently typed HLA-DRB1*04+. Patients with late erosive/nonerosive disease or a benign disease course manageable with nonaggressive treatment preferentially expressed HLA-DRB1*01 or lacked an RA-linked haplotype. These data indicate that the heterogeneity of RA reflects genetic differences. Sequence variations within the disease-linked sequence motif, as well as polymorphisms surrounding the candidate genetic element, affect pattern, course, and treatment response of RA. Amino acid position 71 in the HLA-DRB1 gene has a unique role, the understanding of which may provide important clues to disease etiology.