Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, 41013, Spain.
Department of Internal Medicine, Hospital Clínico San Cecilio, Granada, 18003, Spain.
Sci Rep. 2017 Aug 16;7(1):8453. doi: 10.1038/s41598-017-09164-7.
Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.
白塞病（BD）是一种免疫介导的系统性疾病，与 HLA Ⅰ类和其他基因有明确的关联。BD 与许多自身炎症性疾病（AIDs）有临床重叠。本研究旨在通过下一代测序（NGS）方法在 355 名 BD 患者中研究参与 AIDs 的七个基因（CECR1、MEFV、MVK、NLRP3、NOD2、PSTPIP1 和 TNFRSF1A）中的罕见变异的作用。为了检查每个基因的全局关联，使用了 4 种测试：SKAT、CollapseBt、C(α) 和加权 KBAC。参考数据库：1000 基因组计划第三阶段、Infevers、HGMD 和 ClinVar，算法：PolyPhen2 和 SIFT 用于收集发现的 62 个变异的信息。所有基因都使用 SKAT 结果关联，但只有 3 个（MVK、NOD2 和 PSTPIP1）与 C(α) 和加权 KBAC 关联。当考虑所有基因时，40 个变异与临床数据库中的 AIDs 相关，25 个变异至少被一种算法预测为致病性。仅包括 MVK、NOD2 和 PSTPIP1，BD 中与 AIDs 相关的发现变异为 20 个，预测为致病性的为 12 个。最大的贡献对应于 NOD2。本研究支持 AIDs 相关基因中的罕见变异在 BD 发病机制中的影响。
