Epistasis between two HLA antigens defines a subset of individuals at a very high risk for ankylosing spondylitis
Epistasis between two HLA antigens defines a subset of individuals at a very high risk for ankylosing spondylitis
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DOI：
10.1136/annrheumdis-2012-201774
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发表时间：
2013-06-01
影响因子：
27.4
通讯作者：
Toes, Rene E. M.
中科院分区：
文献类型：
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作者：
van Gaalen, Floris A.;Verduijn, Willem;Toes, Rene E. M.
目的脊柱关节炎（SpA）的易感性在很大程度上由遗传决定。为了理解日益复杂的遗传关联，一种方法是研究上位性或遗传相互作用。已经报道了HLA抗原和SpA（包括HLA-B27）之间的几种关联。在这项研究中，我们探讨了常见的HLA I类危险抗原之间的上位性强直性脊柱炎（AS），最典型的SpA.Methods在154例AS和5584对照组，HLA I类抗原进行了分析与AS。生物学相互作用进行了分析，通过调查的危险因素结合的影响是否偏离additivity.Results除了与HLA-B27的关联，我们发现HLA-B60和AS之间的关联（OR 1.8; 95%CI 1.2至2.8）。这在荟萃分析中得到证实（OR 2.2; CI 1.8 - 2.8）。虽然18.2%的AS患者同时具有HLA-B27和HLA-B60，但仅在0.4%的对照组中发现了这种组合。使用不含HLA-B27和HLA-B60的AS患者作为参考，HLA-B27-/HLA-B60+患者的疾病相对风险（RR）为1.2（95%CI 0.3至4.1）。对于HLA-B27+/HLA-B60-，RR为69（95% CI 40至111），但在HLA-B27+/HLA-B60+患者中增加至342（95% CI 147至708）。对于交互作用，由于交互作用的相对超额风险为251，归因比例为0.8，协同指数为4.7。结论HLA-B60和HLA-B27在AS易感性中存在较强的上位性交互作用。因此，具有HLA-B27+/HLA-B60+基因型的个体处于非常高的发展AS的风险中。
Objectives Susceptibility to spondyloarthritis (SpA) is largely genetically determined. To understand increasingly complex genetic associations, one approach is to study epistasis or genetic interactions. Several associations between HLA antigens and SpA including HLA-B27 have been reported. In this study, we investigated epistasis between common HLA class I risk antigens in ankylosing spondylitis (AS), the most typical form of SpA.Methods In 154 patients with AS and 5584 controls, HLA class I antigens were analysed for association with AS. Biological interaction was analysed by investigating whether the effects of the risk factors combined departed from additivity.Results Apart from the association with HLA-B27, we found an association between HLA-B60 and AS (OR 1.8; 95% CI 1.2 to 2.8). This was confirmed in a meta-analysis (OR 2.2; CI 1.8 to 2.8). While 18.2% of AS patients had both HLA-B27 and HLA-B60, this combination was found in only 0.4% of controls. Using AS patients without HLA-B27 and HLA-B60 as a reference, the relative risk (RR) for disease in HLA-B27-/HLA-B60+ patients was 1.2 (95% CI 0.3 to 4.1). For HLA-B27+/HLA-B60- the RR was 69 (95% CI 40 to 111) but increased to 342 (95% CI 147 to 708) in HLA-B27+/HLA-B60+ patients. For the interaction, the relative excess risk due to interaction was 251, the attributable proportion was 0.8 and the synergy index was 4.7. The interaction was confirmed in an independent cohort.Conclusions There is a strong epistatic interaction between HLA-B60 and HLA-B27 in AS susceptibility. As a result, individuals with the HLA-B27+/HLA-B60+ genotype are at a very high risk of developing AS.