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目的 基于药物靶点孟德尔随机化的方法，探究二甲双胍药物作用靶点相关基因与慢性肾脏病风险的潜在因果关系，并在糖尿病人群中进行验证。方法 从DrugBank、ChEMBL、GTEx和eQTLGen数据库中获取二甲双胍药物靶点基因相关的遗传变异，基于UK Biobank的糖化血红蛋白数据库，通过共定位分析筛选出8个二甲双胍相关靶点基因，并获取其对应的35个单核苷酸多态性。结局数据来源于CKDGen数据库中关于慢性肾脏病、估计肾小球滤过率和尿白蛋白肌酐比的全基因组关联分析结果。主要采用逆方差加权法进行两样本孟德尔随机化分析，辅以MR-Egger回归法、加权中位数法及多种模式进行敏感性分析。为验证结果的稳健性，进一步采用MAGIC数据库进行共定位验证；并以IEU数据库中二甲双胍治疗数据作为暴露组进行三角验证。此外，采用美国国家健康与营养调查数据库的人群数据进行多因素logistic回归分析，以验证相关关系。结果 遗传模拟的二甲双胍对线粒体复合物Ⅰ基因的抑制效应通过降低糖化血红蛋白水平的途径，与慢性肾脏病发病风险增加（OR=1.70,95%CI:1.26～2.29,P<0.05）和估计肾小球滤过率降低（β=-0.03,95%CI:-0.04～-0.01,P<0.05 ）存在正向因果关联；甘油-3-磷酸脱氢酶1基因通过降低糖化血红蛋白水平的途径，与估计肾小球滤过率降低（β=-0.10,95%CI:-0.13～-0.06,P<0.05）和尿白蛋白肌肝比升高（β=0.32,95%CI:0.10～0.53,P<0.05）存在因果关联。结论 二甲双胍的药物作用靶点基因线粒体复合物Ⅰ和甘油-3-磷酸脱氢酶1可能与患者肾功能下降相关，提示临床使用二甲双胍时须关注其核心降糖机制对肾脏的潜在影响，加强肾功能监测和个体化用药指导，以提高治疗安全性。
Abstract：AIM To investigate the potential causal effects of metformin-targeted genes on the risk of chronic kidney disease(CKD) using drug-target Mendelian randomization and to validate these findings in the diabetic population. METHODS Genetic variations related to metformin-targeted genes were obtained using the DrugBank, ChEMBL, GTEx, and eQTLGen databases, and 35 single nucleotide polymorphisms(SNP) from 8 target genes were selected as genetic instruments for metformin targets using glycated hemoglobin A1c(HbA1c) data from the UK Biobank database and co-localization methods. Genome-wide association study(GWAS) summary statistics for CKD, estimated glomerular filtration rate(eGFR), and urinary albumin-to-creatinine ratio(UACR) were analyzed from the CKDGen database. Two-sample Mendelian randomization analysis used inverse variance weighting as the primary method, with MR-Egger regression, weighted median, and multiple modes as supplementary methods for sensitivity analysis. To verify the reliability of the results, MAGIC database was used for colocalization validation; the metformin treatment data from the IEU database were used as the exposure for triangulation verification. A multivariate logistic regression analysis was performed using population data from the United States National Health and Nutrition Examination Survey database to verify the correlation. RESULTS The study found that the mitochondrial complex I(MCI), a drug target of metformin, was significantly associated with an increased risk of CKD(OR = 1.70, 95%CI: 1.26-2.29, P < 0.05) and reduced eGFR(β =-0.03, 95%CI:-0.04--0.01, P < 0.05) through the pathway of lowering HbA1c levels. Additionally, the glycerol-3-phosphate dehydrogenase 1(GPD1) showed a significant association with a decrease in eGFR(β =-0.10, 95%CI:-0.13--0.06, P < 0.05) and an increase in UACR(β = 0.32, 95%CI: 0.10-0.53, P < 0.05) through the reduction of HbA1c levels. CONCLUSION The association between metformin target genes(MCI and GPD1) and declining renal function underscores the need to consider the potential renal impact of its core hypoglycemic mechanism, and to implement renal monitoring and individualizeddosing to enhance treatment safety.
[1]International Diabetes Federatio. IDF Diabetes Atlas[EB/OL].(2021-12-06)[2025-01-20]. https://www.doc88.com/p-81161548808932.html.
[2]白迎文,葛佳佳,杨婷,等.二甲双胍联合维生素D治疗多囊卵巢综合征疗效的Meta分析[J].中国临床药学杂志, 2022, 31(9):653.
[3]ZHENG J, XU M, WALKER V, et al. Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population:a Mendelian randomisation study[J].Diabetologia, 2022, 65(10):1664.
[4]KULKARNI A S, GUBBI S, BARZILAI N. Benefits of metformin in attenuating the hallmarks of aging[J]. Cell Metab, 2020,32(1):15.
[5]MADERO M, LEVIN A, AHMED S B, et al. Evaluation and management of chronic kidney disease:synopsis of the kidney disease:improving global outcomes 2024 clinical practice guideline[J]. Ann Intern Med, 2025, 178(5):705.
[6]中华医学会内分泌学分会,中国内分泌代谢病专科联盟.中国糖尿病合并慢性肾脏病临床管理共识[J].中华内分泌代谢杂志,2024, 40(6):455.
[7]中华医学会糖尿病学分会微血管并发症学组.中国糖尿病肾脏病防治指南(2021年版)[J].国际内分泌代谢杂志, 2021, 41(4):388.
[8]ZENG L, CHEN L, GAO F F, et al. The comparation of renal antisenescence effects and blood metabolites between dapagliflozin and metformin in non-diabetes environment[J]. Adv Biol, 2023,7(10):e2300199.
[9]CAI Z X, WU X T, SONG Z J, et al. Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis[J]. Cell Discov, 2023, 9(11):104.
[10]RASOOLY D, PELOSO G M. Two-sample multivariable mendelian randomization analysis using R[J]. Curr Protoc, 2021, 1(12):e335.
[11]KÖTTGEN A, PATTARO C. The CKDGen consortium:ten years of insights into the genetic basis of kidney function[J]. Kidney Int,2020, 97(2):236.
[12]WUTTKE M , LI Y , LI M , et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals[J].Nat Genet. 2019, 51(6):957.
[13]TEUMER A, LI Y, GHASEMI S, et al. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria[J]. Nat Commun, 2019, 10(1):4130.
[14]LUO S, WONG I C K, CHUI C S L, et al. Effects of putative metformin targets on phenotypic age and leukocyte telomere length:a mendelian randomisation study using data from the UK BioBank[J].Lancet Healthy Longev, 2023, 4(7):e337.
[15]PALMER T M, LAWLOR D A, HARBORD R M, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors[J]. Stat Methods Med Res, 2012, 21(3):223.
[16]Kidney Disease:Improving Global Outcomes(KDIGO)CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease[J]. Kidney Int, 2024,105(4s):S117.
[17]CARLSON N, HOMMEL K, OLESEN J B, et al. Metforminassociated risk of acute dialysis in patients with type 2 diabetes:a nationwide cohort study[J]. Diabetes Obes Metab, 2016, 18(12):1283.
[18]孔佳超,吴天凤.二甲双胍抗炎作用的研究进展[J].中国临床药学杂志, 2021, 30(2):152.
[19]YU Z Z, TU J J, OU M L, et al. A mechanistic analysis of metformin’s biphasic effects on lifespan and healthspan in C. elegans:elixir in youth, poison in elder[J]. Mech Ageing Dev, 2024, 221:111963.
[20]MADIRAJU A K, ERION D M, RAHIMI Y, et al. Metformin suppresses gluconeogenesis by in hibiting mitochondrial glycerophosphate dehydrogenase[J]. Nature, 2014, 510(7506):542.
[21]SCOTT B, DAY E A, O’BRIEN K L, et al. Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans[J]. Nat Metab, 2024, 6(4):651.
[22]TAHA M, AZHARY A, HAJHAMED N M, et al. A case report of metformin-associated lactic acidosis[J]. Clin Case Rep, 2024,12(8):e9255.
基本信息:
DOI：10.19577/j.1007-4406.2026.03.009
中图分类号:R977.15
引用信息:
[1]曾靓,王非,洪毅,等.二甲双胍药物作用靶点基因与慢性肾脏病风险因果关系研究与人群验证[J].中国临床药学杂志,2026,35(03):240-247.DOI:10.19577/j.1007-4406.2026.03.009.
基金信息:
福建省老年医院重点科研项目基金（编号SLN2025ZD01）; 福建医科大学大学生创新创业计划项目（编号JC2023103）
2026-03-25
2026-03-25