Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
Institute of Rheumatology, 11000 Belgrade, Serbia.
Int J Mol Sci. 2023 May 10;24(10):8538. doi: 10.3390/ijms24108538.
Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely rs1800460, rs1142345, rs1801133 and rs4149056 were tested for association with severe disease outcomes in 102 patients with SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS) model. Association was found between rs1801133 and higher risk for elevated systolic pressure in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS rank and elevated systolic pressure. Our results open a door wide for more extensive research on pharmacogenomics markers in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with SSc and help in prevention of adverse drug reactions.
系统性硬化症 (SSc) 是一种罕见的结缔组织疾病，在风湿性疾病中发病率和死亡率最高。患者之间的疾病进展高度异质，这意味着需要对治疗进行个体化。在来自塞尔维亚的 102 名接受免疫抑制剂硫唑嘌呤 (AZA) 和甲氨蝶呤 (MTX) 或其他类型药物治疗的 SSc 患者中，测试了四个药物遗传学变体(rs1800460、rs1142345、rs1801133 和 rs4149056) 与严重疾病结局的关联。使用 PCR-RFLP 和直接 Sanger 测序进行基因分型。使用 R 软件进行统计分析和多基因风险评分 (PRS) 模型的开发。除了接受 MTX 治疗的患者外，在所有患者中，rs1801133 与收缩压升高的风险增加相关，在接受其他类型药物治疗的患者中，rs1801133 与肾功能不全的风险增加相关。在接受 MTX 治疗的患者中，变体 rs4149056 可预防肾功能不全。对于接受 MTX 治疗的患者，PRS 等级和收缩压升高的趋势更高。我们的研究结果为进一步研究 SSc 患者的药物遗传学标志物打开了大门。总之，药物遗传学标志物可以预测 SSc 患者的结局，并有助于预防药物不良反应。
