Division of Allergy, Immunology and Rheumatology, Department of Medical Research, Taichung Veterans General Hospital, 407 Taichung, Taiwan.
Faculty of Medicine, National Yang Ming University, 112 Taipei, Taiwan.
J Immunol Res. 2020 Feb 14;2020:8640719. doi: 10.1155/2020/8640719. eCollection 2020.
Adult-onset Still's disease (AOSD) is a rare and inflammatory disorder characterized by spiking fever, rash, arthritis, and multisystemic involvement. HLA has been shown to be associated with AOSD; however, it could not explain the innate immunity and autoinflammatory characteristics of AOSD. To assess the genetic susceptibility of AOSD, we conducted a genome-wide association study (GWAS) on a cohort of 70 AOSD cases and 688 controls following a replication study of 36 cases and 200 controls and meta-analysis. The plasma concentrations of associated gene product were determined. The GWAS, replication, and combined sample analysis confirmed that SNP rs11102024 on 5'-upstream of encoding macrophage colony-stimulating factor (M-CSF) was associated with AOSD ( = 1.20 × 10, OR (95% CI): 3.28 (2.25~4.79)). Plasma levels of M-CSF increased in AOSD patients ( = 82, median: 9.31 pg/mL), particularly in the cases with activity score ≥ 6 ( = 42, 10.94 pg/mL), compared to the healthy donors ( = 68, 5.31 pg/mL) ( < 0.0001). Patients carrying rs11102024TT genotype had higher M-CSF levels (median: 20.28 pg/mL) than those with AA genotype (6.82 pg/mL) ( < 0.0001) or AT genotype (11.61 pg/mL) ( = 0.027). Patients with systemic pattern outcome were associated with elevated M-CSF and frequently observed in TT carriers. Our data suggest that genetic variants near are associated with AOSD and the rs11102024 T allele links to higher M-CSF levels and systemic outcome. These results provide a promising initiative for the early intervention and therapeutic target of AOSD. Further investigation is needed to have better understandings and the clinical implementation of genetic variants nearby in AOSD.
成人斯蒂尔病（AOSD）是一种罕见的炎症性疾病，其特征为高热、皮疹、关节炎和多系统受累。HLA 已被证明与 AOSD 相关；然而，它不能解释 AOSD 的固有免疫和自身炎症特征。为了评估 AOSD 的遗传易感性，我们对 70 例 AOSD 病例和 688 例对照进行了全基因组关联研究（GWAS），随后对 36 例病例和 200 例对照进行了复制研究和荟萃分析。测定了相关基因产物的血浆浓度。GWAS、复制和合并样本分析证实，编码巨噬细胞集落刺激因子（M-CSF）的 5'上游的 SNP rs11102024 与 AOSD 相关（ = 1.20×10，OR（95%CI）：3.28（2.25~4.79））。AOSD 患者的 M-CSF 血浆水平升高（ = 82，中位数：9.31 pg/mL），特别是在活动评分≥6 的病例中（ = 42，10.94 pg/mL），与健康供体相比（ = 68，5.31 pg/mL）（ < 0.0001）。携带 rs11102024TT 基因型的患者的 M-CSF 水平（中位数：20.28 pg/mL）高于 AA 基因型（6.82 pg/mL）（ < 0.0001）或 AT 基因型（11.61 pg/mL）（ = 0.027）。全身型结局的患者与升高的 M-CSF 相关，并且经常在 TT 携带者中观察到。我们的数据表明， 附近的遗传变异与 AOSD 相关，rs11102024T 等位基因与更高的 M-CSF 水平和全身结局相关。这些结果为 AOSD 的早期干预和治疗靶点提供了有希望的契机。需要进一步的研究来更好地了解和在 AOSD 中实施附近遗传变异的临床应用。
