HLA Associations Reveal Genetic Heterogeneity in Psoriatic Arthritis and in the Psoriasis Phenotype
HLA Associations Reveal Genetic Heterogeneity in Psoriatic Arthritis and in the Psoriasis Phenotype
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DOI：
10.1002/art.33415
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发表时间：
2012-04-01
影响因子：
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通讯作者：
FitzGerald, Oliver
中科院分区：
文献类型：
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作者：
Winchester, Robert;Minevich, Gregory;FitzGerald, Oliver
Objective.将在风湿科就诊的受试者中严格确定的银屑病关节炎病例与在皮肤科就诊的受试者中的银屑病病例进行比较，其中排除了具有肌肉骨骼特征的受试者，以说明1）主要组织相容性复合体（MHC）对银屑病关节炎易感性的贡献与银屑病相似的程度，以及2）MHC基因是否决定银屑病关节炎表型中的数量性状。通过基于序列的HLA分型研究了从相对同质人群中招募的单独发现和验证的患者亚组，比较了HLA-B和HLA-C等位基因和单倍型的频率。在银屑病关节炎患者中，C*06：02的频率低于银屑病患者（28.7% vs 57.5%; P = 9.9 x 10（-12））。含有B*27：05或B*39：01的三种单倍型在银屑病关节炎患者中的频率显著增加，但在银屑病患者中没有增加。结构相关的B*39：06等位基因的频率没有增加。B*27与皮肤和肌肉骨骼疾病之间的间隔为0.98年（P = 2.05 x 10（-6）），而C*06的间隔为10.14年。初步证据表明，B*38：01和B*08可能与银屑病关节炎易感性有关，并且编码P2口袋的同种异型结合与B*27和B*39分子编码的侧链电荷相反的侧链可能发挥保护作用。结论。这些发现表明银屑病表型是由两种MHC效应模式引起的。第一个涉及经典的银屑病易感基因C*06，它赋予更多的渗透性皮肤病与较不普遍和更多的时间依赖性的肌肉骨骼表型发展。第二种模式似乎是由HLA-B等位基因介导的，特别是B*27，包括时间上更一致的肌肉骨骼受累，在发病率上几乎等同于皮肤病。
Objective. Rigorously ascertained cases of psoriatic arthritis in subjects presenting to a rheumatology unit were compared with cases of psoriasis in subjects presenting to a dermatology unit, where subjects with musculoskeletal features were excluded, to address 1) the extent to which the contribution of the major histocompatibility complex (MHC) to psoriatic arthritis susceptibility resembles that in psoriasis, and 2) whether MHC genes determine quantitative traits within the psoriatic arthritis phenotype.Methods. Separate discovery and validation sub-cohorts of patients recruited from a relatively homogeneous population were studied by sequence-based HLA typing, in which frequencies of the HLA-B and HLA-C alleles and haplotypes were compared.Results. In patients with psoriatic arthritis, the frequency of C*06:02 was lower than that in patients with psoriasis (28.7% versus 57.5%; P = 9.9 x 10(-12)). Three haplotypes containing B*27:05 or B*39:01 were significantly increased in frequency in patients with psoriatic arthritis, but not in those with psoriasis. The structurally related B*39:06 allele was not increased in frequency. B*27 was associated with an interval of 0.98 years between skin and musculoskeletal disease (P = 2.05 x 10(-6)), compared with an interval of 10.14 years for C*06. Preliminary evidence suggested that B*38:01 and B*08 may be associated with psoriatic arthritis susceptibility, and that allotypes encoding P2 pockets that bind side chains opposite in charge from those encoded by the B*27 and B*39 molecules may exert a protective role.Conclusion. These findings suggest that the psoriasis phenotype results from two patterns of MHC effect. The first involves the classic psoriasis susceptibility gene C*06, which confers more penetrant skin disease with less prevalent and more time-dependent musculoskeletal phenotype development. The second pattern appears to be mediated by HLA-B alleles, notably B*27, and includes temporally more coincident musculoskeletal involvement that is nearly equivalent in penetrance to that of the skin disease.