广东汉族类风湿关节炎患者肿瘤坏死因子α启动子区单核苷酸多态性与肿瘤坏死因子α拮抗剂疗效的关系

Influence of tumor necrosis factor-alpha promoter single nucleotide polymorphisms on clinical response to tumor necrosis factor blocker treatment in patients with rheumatoid arthritis from Guangdong Han population

目的探讨广东汉族类风湿关节炎(RA)患者肿瘤坏死因子α(TNF-α)基因启动子区单核苷酸多态性(SNPs)与TNF-α拮抗剂疗效的关系。方法以100例健康志愿者为对照组,以54倒RA患者为RA组。RA组中24列接受英夫利西单抗3 mg·kg^(-1),分别于wk 0、2、6给药;30例接受阿达木单抗40 mg或80 mg,每2 wk皮下注射1次,疗程12 wk,所有患者继续服用原剂量的甲氯蝶呤(MTX)。记录治疗前和治疗后wk 10(英夫利西单抗)或wk 12(阿达木单抗)的相关临床指标,疾病的活动度用28关节计数的疾病活动评分(DAS28)进行评价,DAS28的变化作为主要临床疗效指标。对TNF-α启动子区约1 300 bp的片段进行直接基因测序,分析RA患者TNF-α基因的基因型与TNF-α拮抗剂临床疗效之间的关系。结果与对照组相比,RA组SNPs位点rs1799724(-857C/T)等位基因T频率较高,差异有显著意义(P<0.05),而rs 1799964(-1031C/T)和rs 1800630(-863A/C)位点在RA组和对照组之间的基因型频率分布未发现显著差异。RA组中,rs 1799724(-857C/T)携带T等位基因的患者较携带C等位基因的患者在接受TNF-α抑制剂治疗后DAS28改善更显著(P<0.05)。结论在广东汉族人群中,TNFα的启动子区的rs 1799724.(-857C/T)可能是RA的一种遗传易感标记;携带-857T的RA患者对TNF-α拮抗剂临床治疗效果优于携带-857C者。

AIM To investigate the influence of single nucleotide necrosis factor alpha （TNF-α） promoter on clinical responses to TNF b polymorphisms （SNPs） in tumor locker treatment in patients with rheumatoid arthritis （RA） from Guangdong Han population. METHODS One hundred health volunteers were used as control group. Fifty-four active RA patients refractory to methotrexate （MTX） treatment were included in this study. Twenty-four of them received 3 infusions of infliximab （3 mg·kg^-1） at wk 0, wk 2, and wk 6, and 30 of them received adalimumab 40 or 80 mg subcutaneously every other week for 12 wk treatment. All patients continued to take stable background dose of MTX. Patient＇s clinical and laboratory parameters were assessed before and after the treatment at wk 10 for infliximab sub-group or at wk 12 for adalimumab sub-group. Disease activity of patient was assessed by the 28-joint Disease Activity Score （DAS28）, and the primary efficacy index is the reduction of DAS28. SNPs were genotyped within tumor necrosis factor-lymphotoxin-alpha （TNF-LTA） promoter about 1 300 bp. The influence of SNPs in TNF-cx promoter on clinical responses to TNF blocker treatment in patients with RA were analysed. RESULTS Compared with normal controls, the frequency of -857T allele were significantly higher in RA patients （P 〈 0.05） , while the genotype frequency distribution of rs1799964 （-1031C/T） and rs1800630 （-863A/C） in RA patients did not differ from that in normal controls. The RA patients who were -857T allele carriers （genotypes T/T ＋ C/T） got greater reduction on the DAS28 after TNF blocker treatment than the RA patients who were -857C allele carriers （genotypes C/C）. COCLUSION The SNPs of rs1799724 （-857C/I＇） may be one of the susceptibility genotype of RA in Guangdong Han population. RA patients with the T allele of -857C/T SNP respond better to TNF blocker treatment than homozygotes with the C allele.