二甲双胍治疗系统性红斑狼疮疗效与SLC47A1基因多态性的相关性研究  

Association between metformin therapeutic efficacy and SLC47A1 polymorphism in systemic lupus erythematosus

作　　者：耿时凯 孙芳芳[1] 王海婷[1] 王慧静 陈芳芳 张乐[2] 吕良敬[3] 万伟国 叶霜[1] Geng Shikai;Sun Fangfang;Wang Haiting;Wang Huijing;Chen Fangfang;Zhang Le;Lyu Liangjing;Wan Weiguo;Ye Shuang(Department of Rheumatology,RenJi Hospital South Campus,School of Medicine,Shanghai Jiaotong Univer-sity,Shanghai 201112,China;Department of Pharmacy,RenJi Hospital South Campus,School of Medicine,Shanghai Jiaotong University,Shanghai 201112,China;Department of Rheumatology,Ren Ji Hospital West Campus,School of Medicine,Shanghai Jiao tong University,Shanghai,China;Department of Rheumatology,Hua Shan Hospital,Fudan University,Shanghai,China)

机构地区：[1]上海交通大学医学院附属仁济医院南院风湿科,201112 [2]上海交通大学医学院附属仁济医院南院药剂科,201112 [3]上海交通大学医学院附属仁济医院西院风湿科,200001 [4]复旦大学附属华山医院北院风湿科,200040

出　　处：《中华风湿病学杂志》2020年第9期590-596,共7页Chinese Journal of Rheumatology

基　　金：国家重点研发计划(2016YFC0903902);上海申康医院发展中心三年行动计划(16CRl-013A)。

摘　　要：目的探索二甲双胍治疗SLE疗效及安全性与SLC47A1 rs2289669位点基因多态性的相关性。方法盲态纳入二甲双胍治疗SLE的多中心、随机、双盲、安慰剂对照临床研究中完成试验并自愿捐献外周静脉血样本的受试者,检测SLC47A1基因多态性位点突变情况。分析记录随访12个月内二甲双胍组和安慰剂组受试者SLE疾病活动情况及不良事件发生情况,分析疗效/安全性和不同基因型的相关性。分别使用t检验、χ^2检验对计量资料和计数资料进行统计分析。结果2016年5月24日至2017年12月13日,共盲态纳入二甲双胍组受试者31例,安慰剂组35例。纳入的受试者基线期临床表现(SELENA)-SLEDAI及治疗方案差异无统计学意义。经检测,受试者SLC47A1 rs2289669基因分型(AA型、GA型、GG型)在二甲双胍组与安慰剂组分布频率差异无统计学意义。二甲双胍组中,出现疾病复发的受试者较未复发的受试者具有更低频率的A等位基因[25%(4/16)与61%(28/46),χ^2=6.116,P=0.0198];AA型患者疾病复发率低于GG型[0(0/8)与57%(4/7),χ^2=6.234,P=0.0125]。二甲双胍组受试者感染发生率较安慰剂组更低[38%(12/31)与69%(24/35),χ^2=5.913,P=0.0150],但二甲双胍组中不同基因型受试者感染发生率差异无统计学意义,AA型受试者较GG型受试者呈现感染发生率降低的趋势[38%(3/8)与72%(5/7),χ^2=1.727,P=0.1888]。结论二甲双胍具有良好安全性,可能降低SLE疾病复发风险。二甲双胍治疗SLE的疗效与SLC47A1基因多态性具有相关性,AA基因型患者使用二甲双胍较GG型及GA型可在降低疾病复发率方面得到更优获益。Objective To evaluate the association between the efficacy and safety of metformin and the influence of variants in SLC47A1 rs2289669 G>A polymorphism in the treatment of systemic lupus erythematosus(SLE).Methods A multicenter,randomized,double-blind,placebo-controlled trial was conducted.Patients were consented at enrollment for blood donation for genotyping,and their peripheral blood were used to detect the distribution frequency of SLC47A1 mutations.The major or mild/moderate flares defined by modified safety lupus erythematosus national assessment(SELENA)-systemic lupus erythematosus disease activity index(SLEDAI)Flare Index(SFI)and adverse events were recorded at 12 months of follow-up.The correlation between efficacy/safety and genotype was analyzed.Student's t test andχ^2 test was used to assess the continuous variables and categorical variables.Results Between May 24,2016,and Dec 13,2017,a total of 31 patients in the metformin group and 35 in the placebo group were detected.There were no statistical significant differences in the clinical manifestations,SELENA-SLEDAI scores,and therapy of the participants at baseline.There was no significant difference in the frequency of AA genotype,GA genotype,and GG genotype of SLC47A1 rs2289669 distribution between the metformin group and the placebo group.In the metformin group,patients who flared had a lower frequency of A alleles than those non-flared[25%(4/16)vs 61%(28/46),χ^2=6.116,P=0.0198];the flare rate was significantly lower in patients with AA genotype than in GG genotype[0%(0/8)vs 57%(4/7),χ^2=6.234,P=0.0125].The infection rate was lower in the metformin group than that in the placebo group[38%(12/31)vs 69%(24/35),χ^2=5.913,P=0.0150],but there was no significant difference among different genotypes in the metformin group.Compared to GG geno-type,AA genotype showed a trend of decrease in infection rate[38%(3/8)vs 72%(5/7),χ^2=1.727,P=0.1888].Conclusion Metformin has a favorable safety profile and may reduce the frequency of flares in SLE patients with

关 键 词：SLC47A1 二甲双胍 红斑狼疮 系统性 多态性 单核苷酸 治疗结果 

分 类 号：R593.241[医药卫生—内科学]