日本人群中 TERT 和 DSP 变异与显微镜下多血管炎和髓过氧化物酶-抗中性粒细胞胞质抗体阳性血管炎的关联：一项遗传关联研究。
Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study.
机构信息
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.
School of Medical Sciences, University of Tsukuba, Tsukuba, Japan.
出版信息
Arthritis Res Ther. 2020 Oct 16;22(1):246. doi: 10.1186/s13075-020-02347-0.
BACKGROUND
Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD.
METHODS
Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test.
RESULTS
When the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10, P = 0.0023, odds ratio [OR] 1.38; DSP P = 6.9 × 10, P = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10, P = 0.0015, OR 1.33; DSP P = 0.0011, P = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD.
CONCLUSIONS
Unexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.
背景
间质性肺病（ILD）是抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）的一种严重并发症，预后不良。日本的 AAV 相关 ILD（AAV-ILD）患病率明显高于欧洲。最近，我们报道了最强的特发性肺纤维化（IPF）易感变体 MUC5B 变体 rs35705950 在 AAV-ILD 患者中显著增加，但在无 ILD 的 AAV 患者中没有增加；然而，由于日本人群中的等位基因频率较低，MUC5B 变体本身不能解释日本 AAV-ILD 的高患病率。在这项研究中，我们研究了 TERT 和 DSP 基因中的其他 IPF 易感等位基因是否与 AAV 亚群和 AAV-ILD 的易感性相关。
方法
分析了 544 例日本 AAV 患者和 5558 例对照。在 AAV 患者中，432 例为髓过氧化物酶（MPO）-ANCA（MPO-AAV）阳性。根据 CT 或高分辨率 CT，176 例 MPO-AAV 患者阳性，216 例阴性。采用 TaqMan SNP 基因分型检测 TERT 和 DSP 变体的基因型，并通过卡方检验检测其相关性。
结果
当比较 AAV 亚群和健康对照组中 IPF 风险等位基因 TERT rs2736100A 和 DSP rs2076295G 的频率时，这两种等位基因在显微镜下多血管炎（MPA）（TERT P=2.3×10，P=0.0023，优势比[OR]1.38；DSP P=6.9×10，P=0.0069，OR 1.32）和 MPO-AAV（TERT P=1.5×10，P=0.0015，OR 1.33；DSP P=0.0011，P=0.011，OR 1.26）中均显著增加。另一方面，在比较 MPO-AAV 患者有无 ILD 时，等位基因频率无显著相关性。
结论
出乎意料的是，TERT 和 DSP IPF 风险等位基因与 MPA 和 MPO-AAV 相关，无论 ILD 是否存在。这些发现表明 TERT 和 DSP 可能是 MPA/MPO-AAV 的新易感基因，并且一些易感基因可能在 IPF 和 MPA/MPO-AAV 之间共享。
Zotero 插件