- 等位基因与日本人群髓过氧化物酶-抗中性粒细胞胞质抗体阳性血管炎复发风险的关联。
Association of - alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population.
机构信息
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
出版信息
Front Immunol. 2023 Mar 8;14:1119064. doi: 10.3389/fimmu.2023.1119064. eCollection 2023.
BACKGROUND
Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between and with susceptibility to, and with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of , which is in strong linkage disequilibrium with and , with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether is associated with the risk of relapse in MPO-AAV.
METHODS
First, the association of with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported and were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (P) were corrected for multiple comparisons in each analysis using the false discovery rate method.
RESULTS
The association of with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: P=5.8x10, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: P=1.1x10, OR 1.71, 95%CI 1.34-2.17). was in strong linkage disequilibrium with and , and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of (P=0.049, Q=0.42, hazard ratio [HR]:1.87), (P=0.020, Q=0.22, HR:2.11) and (P=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including carriers, showed longer relapse-free survival with nominal significance (P=0.010, Q=0.42, HR:0.31). By combining and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (P=0.0055, Q=0.033, HR:4.02).
CONCLUSION
is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.
背景
抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）的治疗中，疾病复发仍是一个主要问题。在欧洲人群中， 与蛋白酶 3-ANCA 阳性 AAV 的易感性和复发风险相关。在日本人群中，我们之前报道过 与髓过氧化物酶-ANCA 阳性 AAV（MPO-AAV）的易感性以及 与 MPO-AAV 的保护作用相关。随后，在中国人群中也报道了 与 MPO-AAV 易感性相关， 与 紧密连锁不平衡，且与 相关。然而，这些等位基因与复发风险之间的关联尚未报道。在此，我们研究了 是否与 MPO-AAV 的复发风险相关。
方法
首先，我们在 440 名日本患者和 779 名健康对照中检验了 与 MPO-AAV 和显微镜下多血管炎（MPA）易感性的关联，及其与先前报道的 和 的关系。其次，在之前报道的关于缓解诱导治疗的队列研究中，对 199 名 MPO-ANCA 阳性、PR3-ANCA 阴性的患者进行了分析，以评估 与复发风险的关联。在每个分析中，未校正的 P 值（P）使用错误发现率方法进行了多重比较校正。
结果
在日本人群中证实了 与 MPO-AAV 和 MPA 的易感性相关（MPO-AAV：P=5.8x10，比值比[OR]1.74，95%置信区间[CI]1.40-2.16，MPA：P=1.1x10，OR 1.71，95%CI 1.34-2.17）。 与 和 紧密连锁不平衡，条件逻辑回归分析无法确定因果等位基因。在对数秩检验中，与非携带者相比， 携带者（P=0.049，Q=0.42，风险比[HR]1.87）、 携带者（P=0.020，Q=0.22，HR：2.11）和 携带者（P=0.043，Q=0.48，HR：1.91）的无复发生存期较短，具有统计学意义。相反，HLA-DRβ1 第 13 位丝氨酸（HLA-DRβ1_13S）的携带者，包括 携带者，无复发生存期较长，具有统计学意义（P=0.010，Q=0.42，HR：0.31）。通过 与 HLA-DRβ1_13S 联合分析，发现复发风险最高和最低的两组之间存在显著差异（P=0.0055，Q=0.033，HR：4.02）。
结论
在日本人群中， 不仅与 MPO-AAV 的易感性相关，还与复发风险相关。
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