D'Cruz Leon G, McEleney Kevin G, Tan Kyle B C, Shukla Priyank, Gardiner Philip V, Connolly Patricia, Conway Caroline, Cobice Diego, Gibson David S
Northern Ireland Centre for Stratified Medicine (NICSM), Biomedical Sciences Research Institute, Ulster University, C-TRIC Building, Londonderry BT47 6SB, UK.
Respiratory Medicine Department and Clinical Trials Unit, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK.
J Pers Med. 2020 Sep 26;10(4):149. doi: 10.3390/jpm10040149.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that causes loss of joint function and significantly reduces quality of life. Plasma metabolite concentrations of disease-modifying anti-rheumatic drugs (DMARDs) can influence treatment efficacy and toxicity. This study explored the relationship between DMARD-metabolising gene variants and plasma metabolite levels in RA patients. DMARD metabolite concentrations were determined by tandem mass-spectrometry in plasma samples from 100 RA patients with actively flaring disease collected at two intervals. Taqman probes were used to discriminate single-nucleotide polymorphism (SNP) genotypes in cohort genomic DNA: rs246240 (), rs1476413 (), rs2231142 (), rs3740065 (), rs4149081 (), rs4846051 (), rs10280623 (), rs16853826 (), rs17421511 () and rs717620 (). Mean plasma concentrations of methotrexate (MTX) and MTX-7-OH metabolites were higher ( < 0.05) at baseline in rs4149081 GA genotype patients. Patients with rs1476413 SNP TT or CT alleles have significantly higher ( < 0.001) plasma poly-glutamate metabolites at both study time points and correspondingly elevated disease activity scores. Patients with the rs17421511 SNP AA allele reported significantly lower pain scores ( < 0.05) at both study intervals. Genotyping strategies could help prioritise treatments to RA patients most likely to gain clinical benefit whilst minimizing toxicity.
类风湿关节炎（RA）是一种慢性全身性自身免疫性疾病，可导致关节功能丧失并显著降低生活质量。改善病情抗风湿药（DMARDs）的血浆代谢物浓度会影响治疗效果和毒性。本研究探讨了RA患者中DMARD代谢基因变异与血浆代谢物水平之间的关系。通过串联质谱法测定了100例处于疾病活动期的RA患者在两个时间点采集的血浆样本中DMARD代谢物浓度。使用Taqman探针区分队列基因组DNA中的单核苷酸多态性（SNP）基因型：rs246240（）、rs1476413（）、rs2231142（）、rs3740065（）、rs4149081（）、rs4846051（）、rs10280623（）、rs16853826（）、rs17421511（）和rs717620（）。rs4149081 GA基因型患者在基线时甲氨蝶呤（MTX）和MTX - 7 - OH代谢物的平均血浆浓度较高（P < 0.05）。在两个研究时间点，rs1476413 SNP TT或CT等位基因的患者血浆多聚谷氨酸代谢物显著更高（P < 0.001），且疾病活动评分相应升高。rs17421511 SNP AA等位基因的患者在两个研究间隔期的疼痛评分均显著较低（P < 0.05）。基因分型策略有助于为最有可能获得临床益处同时将毒性降至最低的RA患者优先选择治疗方案。
