Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria de Granada ibs.GRANADA.
Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, PTS Granada, Granada.
Rheumatology (Oxford). 2022 Mar 2;61(3):1204-1210. doi: 10.1093/rheumatology/keab443.
Combining of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (KD) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between them.
A total of 1190 vasculitis patients and 11 302 healthy controls were analysed. First, in the discovery phase, genome-wide data of 405 KD patients and 6252 controls and 215 IgAV patients and 1324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3726 controls). Polymorphisms with P-values ≤5 × 10-8 in the global IgAV-KD meta-analysis were considered as shared genetic risk loci.
A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (P = 8.06 × 10-10). Additionally, when IgAV was individually analysed, a strong association between rs3743841 and this vasculitis was also evident [P = 1.25 × 10-7; odds ratio = 1.47 (95% CI 1.27, 1.69)]. In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes.
We identified a new risk locus with pleiotropic effects on the two childhood vasculitides analysed. This locus represents the strongest non-HLA signal described for IgAV to date.
将不同病理的基因组数据组合为单一表型已成为一种有用的策略，可用于鉴定免疫介导性疾病之间共享的遗传风险基因座。我们的研究旨在通过对它们之间的遗传重叠进行首次全面的大规模分析，增加对川崎病（KD）和 IgA 血管炎（IgAV）遗传贡献的认识。
共分析了 1190 例血管炎患者和 11302 例健康对照者。首先，在发现阶段，使用逆方差荟萃分析将 405 例 KD 患者和 6252 例对照者、215 例 IgAV 患者和 1324 例对照者的全基因组数据进行了组合，这些患者和对照者均为欧洲血统。其次，选择前 10-8 个关联多态性在另外的独立队列中进行复制（570 例病例和 3726 例对照者）。在全球 IgAV-KD 荟萃分析中，P 值≤5×10-8 的多态性被认为是共享的遗传风险基因座。
位于 NAGPA 基因内含子中的遗传变异 rs3743841 在跨疾病荟萃分析中达到全基因组显著水平（P=8.06×10-10）。此外，当单独分析 IgAV 时，rs3743841 与这种血管炎之间也存在强烈的关联[P=1.25×10-7；优势比=1.47（95%可信区间 1.27，1.69）]。基于基因座的功能注释表明，该多态性作为一种调节变体，调节 NAGPA 和 SEC14L5 基因的表达水平。
我们在分析的两种儿童血管炎中发现了一个具有多效性作用的新风险基因座。该基因座是迄今为止描述 IgAV 的最强非 HLA 信号。
