Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India.
Department of Paediatrics, Post Graduate Institute of Medical Education & Research, Chandigarh, India.
J Hum Genet. 2024 Jan;69(1):13-18. doi: 10.1038/s10038-023-01198-2. Epub 2023 Oct 17.
We performed genetic association study for genes encoding angiogenic and angiostatic proteins in patients with Takayasu arteritis (TAK). A total of 96 SNPs involving 60 genes were studied. Genotyping was performed in Fluidigm 96.96 Dynamic Array chip. All statistical analysis for SNP evaluation was performed using PLINK software. Initial analyses revealed five SNPs from three genes [IL-18 (encodes Interleukin-18), FGF2 (encodes Fibroblast Growth Factor-2), and ANGPT1 (encodes Angiopoietin-1)] as significantly different between controls and cases (uncorrected p < 0.05). After permutation-based analysis, two tag SNPs on the promoter region of IL-18 (rs187238 and rs1946518) and one 3'UTR tag SNP (rs1476217) of FGF2 were significantly associated with susceptibility to TAK, with p and OR (95% CI) of 0.0006 and 1.64 (1.25-2.17), 0.03 and 1.28 (1.02-1.64) & 0.016 and 1.33 (1.05-1.67), respectively; while, the two tag SNPs of ANGPT1 gene (rs6469101 and rs16875900) showed a trend (p = 0.055 & p = 0.051, respectively after permutation based correction). There is robust linkage disequilibrium between the two tag SNPs of IL-18 gene as validated by 1000 genome data of South Asian population; the eQTL effects of these tag SNPs of IL-18 and FGF2 genes on adjacent genes further suggest that these tag SNPs act as genetic risks for development of TAK in South Asians, with possible functional implications towards future biomarker development. Genotype phenotype study by genetic model-based analysis also revealed associations between genotype subsets and clinical features like fever, visual loss, left subclavian and coronary artery involvement in our TAK patients.
我们对 Takayasu 动脉炎（TAK）患者的血管生成和血管抑制蛋白编码基因进行了遗传关联研究。共研究了涉及 60 个基因的 96 个 SNP。基因分型在 Fluidigm 96.96 动态芯片上进行。所有 SNP 评估的统计分析均使用 PLINK 软件进行。初步分析显示，三个基因[白细胞介素 18（编码白细胞介素 18）、成纤维细胞生长因子 2（编码成纤维细胞生长因子 2）和血管生成素 1（编码血管生成素 1）]中的五个 SNP 在对照组和病例组之间存在显著差异（未校正 p < 0.05）。经过基于置换的分析，IL-18 启动子区域的两个标签 SNP（rs187238 和 rs1946518）和 FGF2 的一个 3'UTR 标签 SNP（rs1476217）与 TAK 的易感性显著相关，p 值和比值比（95%CI）分别为 0.0006 和 1.64（1.25-2.17）、0.03 和 1.28（1.02-1.64）和 0.016 和 1.33（1.05-1.67）；而 ANGPT1 基因的两个标签 SNP（rs6469101 和 rs16875900）显示出趋势（置换后分别为 p = 0.055 和 p = 0.051）。南亚人群 1000 基因组数据验证了 IL-18 基因的两个标签 SNP 之间存在稳健的连锁不平衡；这些 IL-18 和 FGF2 基因标签 SNP 对邻近基因的 eQTL 效应进一步表明，这些标签 SNP 作为南亚人 TAK 发病的遗传风险因素，可能对未来的生物标志物开发具有功能意义。基于遗传模型的分析进行的基因型表型研究还揭示了我们的 TAK 患者的基因型亚组与发热、视力丧失、左锁骨下动脉和冠状动脉受累等临床特征之间的关联。
