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中华肝脏外科手术学电子杂志 ›› 2025, Vol. 14 ›› Issue (01) : 60 -67. doi: 10.3877/cma.j.issn.2095-3232.2025022

临床研究

辛伐他汀预防胆石症的孟德尔随机化研究
牛斌1, 佘林璐2, 翁康强2, 李沪2, 吴翔2, 戴英波2,()   
  1. 1.519000 珠海,中山大学附属第五医院胃肠外科
    2.519000 珠海,中山大学附属第五医院泌尿外科
  • 收稿日期:2024-11-10 出版日期:2025-02-10
  • 通信作者: 戴英波

Mendelian randomization of simvastatin in preventing cholelithiasis

Bin Niu1, Linlu She2, Kangqiang Weng2, Hu Li2, Xiang Wu2, Yingbo Dai2,()   

  1. 1.Department of Gastrointestinal Surgery, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
    2.Department of Urology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
  • Received:2024-11-10 Published:2025-02-10
  • Corresponding author: Yingbo Dai
引用本文:

牛斌, 佘林璐, 翁康强, 李沪, 吴翔, 戴英波. 辛伐他汀预防胆石症的孟德尔随机化研究[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(01): 60-67.

Bin Niu, Linlu She, Kangqiang Weng, Hu Li, Xiang Wu, Yingbo Dai. Mendelian randomization of simvastatin in preventing cholelithiasis[J/OL]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(01): 60-67.

目的

利用全基因组关联(GWAS)分析相关数据,通过孟德尔随机化(MR)研究探讨辛伐他汀对胆石症的预防作用。

方法

采用MR 研究方法,以基因工具变量探讨辛伐他汀预防胆石症的作用。以ieuopen GWAS 数据库公开发表的基因数据为参考依据,借助R 语言平台,筛选出与辛伐他汀关联有统计学意义的单核甘酸多态性(SNP)作为工具变量,通过逆方差加权分析法(IVW)、加权中位数法(WM)和MR-Egger 法分别判断辛伐他汀与胆石症的因果关联,绘制SNP 相关的辛伐他汀与胆石症风险的森林图及散点图。

结果

共筛选出36 个与辛伐他汀相关的SNP。IVW分析(OR=0.956,95%CI:0.935~0.978,P=8.57×10-5)、WM 分析(OR=0.957, 95%CI:0.926~0.983,P=1.82×10-3)、MR-Egger 回归法分析(OR=0.963,95%CI:0.922~1.007,P=1.07×10-1)均显示辛伐他汀与胆石症具有负相关因果关联。MR-Egger 回归法分析表明无多效性(截距=-6.36×10-5P=0.69)。根据散点图直线斜率判断,IVW、WM、MR-Egger 回归法分析的因果关联估计相近。辛伐他汀每增加一个标准差,胆石症的发病风险减低约4.4%。

结论

两样本MR 分析结果表明,辛伐他汀与胆石症的发病风险存在负向因果关系,辛伐他汀每增加一个标准差,胆石症发病风险会降低约4.4%。

Objective

To analyze related data by genome-wide association studies (GWAS) and evaluate preventive effect of simvastatin on cholelithiasis by Mendelian randomization (MR).

Methods

MR was adopted to evaluate the preventive effect of simvastatin on cholelithiasis with genetic variants as instrumental variables.Based on the published gene data in ieuopen GWAS database, the single nucleotide polymorphism (SNP) with significant association with simvastatin was selected as an instrumental variable using R language platform.The causal association between simvastatin and cholelithiasis was evaluated by inverse-variance weighted (IVW), weighted median (WM) and MR-Egger methods, respectively.The forest and scatter plots of simvastatin and the risk of cholelithiasis associated with SNP were delineated.

Results

A total of 36 SNPs associated with simvastatin were screened.IVW (OR=0.956, 95%CI: 0.935-0.978, P=8.57×10-5),WM (OR=0.957, 95%CI: 0.926-0.983, P=1.82×10-3) and MR-Egger regression analyses (OR=0.963,95%CI: 0.922-1.007, P=1.07×10-1) showed negative causal association between simvastatin and cholelithiasis.MR-Egger regression analysis indicated no pleiotropic effect (intercept=-6.36×10-5, P=0.69).According to the slope of the straight line in the scatter plot, the causal correlation estimates were similar among IVW, WM and MR-Egger regression methods.With every one standard deviation (SD) increase of simvastatin, the risk of cholelithiasis decreased by approximately 4.4%.

Conclusions

MR analysis of two samples demonstrates that there is a negative causal association between simvastatin and the risk of cholelithiasis.The risk of cholelithiasis will decreased by approximately 4.4% with every one SD increase of simvastatin.

表1 筛选后36 个辛伐他汀相关SNP 的染色体位点
图1 SNP 与辛伐他汀及胆石症风险的森林图 注:纵轴各组数字表示所分析的SNP,每个黑点代表辛伐他汀水平增加导致胆石症发病风险的OR,红点代表使用3 种不同的方法汇总结果,水平线段表示估计值的95%CI;SNP 为单核昔酸多态性,simvastatin 为辛伐他汀,cholelithiasis 为胆石症,MR 为孟德尔随机化
图2 SNP 与辛伐他汀及胆石症风险的关联及合并效应的散点图 注:SNP 为单核甘酸多态性,simvastatin 为辛伐他汀,cholelithiasis 为胆石症,MR 为孟德尔随机化
图3 采用留一法对SNP 与辛伐他汀及胆石症关系的MR 效应值进行敏感性分析 注:纵轴各组数字表示所剔除的SNP,每个黑点表示排除特定SNP 后辛伐他汀水平增加所导致的胆石症发病风险的OR,红点代表使用所有SNP的IVW 估算值,水平线段表示估计值的95%CI;SNP 为单核甘酸多态性,IVW 为逆加权方差法,MR 为孟德尔随机化
图4 SNP 与辛伐他汀及胆石症风险的漏斗图 注:漏斗图显示左右基本对称,说明文献偏倚不大;SNP 为单核甘酸多态性,MR 为孟德尔随机化
[1]
Lammert F, Gurusamy K, Ko CW, et al.Gallstones[J].Nat Rev Dis Primers, 2016(2):16024.
[2]
Stinton LM, Myers RP, Shaffer EA.Epidemiology of gallstones[J].Gastroenterol Clin North Am, 2010, 39(2):157-169, vii.
[3]
Tsai CJ, Leitzmann MF, Willett WC, et al.Prospective study of abdominal adiposity and gallstone disease in US men[J].Am J Clin Nutr, 2004, 80(1):38-44.
[4]
Choi K, Amarasena T, Hughes A, et al.Management of bile duct stones at cholecystectomy: an Australian single-centre experience over 2 years[J].Surg Endosc, 2021, 35(3):1247-1253.
[5]
Wirth J, Joshi AD, Song M, et al.A healthy lifestyle pattern and the risk of symptomatic gallstone disease: results from 2 prospective cohort studies[J].Am J Clin Nutr, 2020, 112(3):586-594.
[6]
Portincasa P, Moschetta A, Palasciano G.Cholesterol gallstone disease[J].Lancet, 2006, 368(9531):230-239.
[7]
European Association for the Study of the Liver (EASL).EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones[J].J Hepatol, 2016, 65(1):146-181.
[8]
Criner GJ, Connett JE, Aaron SD, et al.Simvastatin for the prevention of exacerbations in moderate-to-severe COPD[J].N Engl J Med, 2014,370(23):2201-2210.
[9]
Saunders KD, Cates JA, Abedin MZ, et al.Lovastatin inhibits gallstone formation in the cholesterol-fed prairie dog[J].Ann Surg,1991, 214(2):149-154.
[10]
Duane WC, Hunninghake DB, Freeman ML, et al.Simvastatin, a competitive inhibitor of HMG-CoA reductase, lowers cholesterol saturation index of gallbladder bile[J].Hepatology, 1988, 8(5):1147-1150.
[11]
Tazuma S, Kajiyama G, Mizuno T, et al.A combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than is ursodeoxycholic acid monotherapy[J].J Clin Gastroenterol, 1998, 26(4):287-291.
[12]
Boyko EJ.Observational research-opportunities and limitations[J].J Diabetes Complications, 2013, 27(6):642-648.
[13]
Katan MB.Apolipoprotein E isoforms, serum cholesterol, and cancer[J].Lancet, 1986, 1(8479):507-508.
[14]
Emdin CA, Khera AV, Kathiresan S.Mendelian randomization[J].JAMA, 2017, 318(19):1925-1926.
[15]
Hemani G, Zheng J, Elsworth B, et al.The MR-base platform supports systematic causal inference across the human phenome[J].Elife, 2018,7: e34408.
[16]
Li R, Huang G, Li Y, et al.Assessing the role of statin therapy in bladder cancer: evidence from a mendelian randomization study[J].Front Pharmacol, 2024, 15:1427318.
[17]
Min Y, Wei X, Liu Z, et al.Assessing the role of lipid-lowering therapy on multi-cancer prevention: a mendelian randomization study[J].Front Pharmacol, 2023, 14:1109580.
[18]
Li W, Ren A, Qin Q, et al.Causal associations between human gut microbiota and cholelithiasis: a mendelian randomization study[J].Front Cell Infect Microbiol, 2023, 13:1169119.
[19]
Burgess S, Butterworth A, Thompson SG.Mendelian randomization analysis with multiple genetic variants using summarized data[J].Genet Epidemiol, 2013, 37(7):658-665.
[20]
Bowden J, Davey Smith G, Haycock PC, et al.Consistent estimation in Mendelian randomization with some invalid instruments using a weighted Median estimator[J].Genet Epidemiol, 2016, 40(4):304-314.
[21]
Bowden J, Davey Smith G, Burgess S.Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J].Int J Epidemiol, 2015, 44(2):512-525.
[22]
Verbanck M, Chen CY, Neale B, et al.Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J].Nat Genet,2018, 50(5):693-698.
[23]
Smith GD, Ebrahim S.Mendelian randomization: prospects,potentials, and limitations[J].Int J Epidemiol, 2004, 33(1):30-42.
[24]
Burgess S, Davies NM, Thompson SG.Bias due to participant overlap in two-sample Mendelian randomization[J].Genet Epidemiol, 2016,40(7):597-608.
[25]
Smith JL, Roach PD, Wittenberg LN, et al.Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones[J].J Gastroenterol Hepatol,2000, 15(8):871-879.
[26]
Chapman BA, Burt MJ, Chisholm RJ, et al.Dissolution of gallstones with simvastatin, an HMG CoA reductase inhibitor[J].Dig Dis Sci,1998, 43(2):349-353.
[27]
Tazuma S, Takizawa I, Kunita T, et al.Effects of long-term treatment with low-dose pravastatin on biliary lipid and bile acid composition in patients with nonfamilial hyperlipoproteinemia[J].Metabolism, 1995,44(11):1410-1412.
[28]
Mazzella G, Parini P, Festi D, et al.Effect of simvastatin,ursodeoxycholic acid and simvastatin plus ursodeoxycholic acid on biliary lipid secretion and cholic acid kinetics in nonfamilial hypercholesterolemia[J].Hepatology, 1992, 15(6):1072-1078.
[29]
Mitchell JC, Logan GM, Stone BG, et al.Effects of lovastatin on biliary lipid secretion and bile acid metabolism in humans[J].J Lipid Res, 1991, 32(1):71-78.
[30]
Hoogerbrugge-vd Linden N, de Rooy FW, Jansen H, et al.Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia[J].Gut, 1990, 31(3):348-350.
[31]
Abedin MZ, Narins SC, Park EH, et al.Lovastatin alters biliary lipid composition and dissolves gallstones: a long-term study in prairie dogs[J].Dig Dis Sci, 2002, 47(10):2192-2210.
[32]
Saunders KD, Cates JA, Abedin MZ, et al.Lovastatin and gallstone dissolution: a preliminary study[J].Surgery, 1993, 113(1):28-35.
[33]
Smit JW, van Erpecum KJ, Stolk MF, et al.Successful dissolution of cholesterol gallstone during treatment with pravastatin[J].Gastroenterology, 1992, 103(3):1068-1070.
[34]
Smit JW, van Erpecum KJ, Gadella MM, et al.Does the HMG-CoA reductase inhibitor pravastatin influence nucleation of cholesterol crystals in supersaturated model bile?[J].Eur J Gastroenterol Hepatol,1996, 8(3):197-200.
[35]
Miettinen TE, Vuoristo M.The sedimentable sterols in gallstone patients before and during ursodeoxycholic acid and simvastatin treatments[J].Scand J Gastroenterol, 1998, 33(12):1297-1302.
[36]
Erichsen R, Frøslev T, Lash TL, et al.Long-term statin use and the risk of gallstone disease: a population-based case-control study[J].Am J Epidemiol, 2011, 173(2):162-170.
[37]
Wang HH, Portincasa P, de Bari O, et al.Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol[J].Eur J Clin Invest, 2013, 43(4):413-426.
[38]
Chiu HF, Chen CC, Kuo HW, et al.Statin use and the risk of gallstone disease: a population-based case-control study[J].Expert Opin Drug Saf, 2012, 11(3):369-374.
[39]
Martin D, Schmidt R, Mortensen EM, et al.Association of statin therapy and risks of cholelithiasis, biliary tract diseases, and gallbladder procedures: retrospective cohort analysis of a US population[J].Ann Pharmacother, 2016, 50(3):161-171.
[40]
Shaffer EA.Gallstone disease: epidemiology of gallbladder stone disease[J].Best Pract Res Clin Gastroenterol, 2006, 20(6):981-996.
[41]
Ahmed MH, Hamad MA, Routh C, et al.Statins as potential treatment for cholesterol gallstones: an attempt to understand the underlying mechanism of actions[J].Expert Opin Pharmacother, 2011, 12(17):2673-2681.
[42]
Han T, Lv Y, Wang S, et al.PPARγ overexpression regulates cholesterol metabolism in human L02 hepatocytes[J].J Pharmacol Sci,2019, 139(1):1-8.
[43]
Bertolotti M, Gabbi C, Anzivino C, et al.Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis[J].Eur J Clin Invest, 2006, 36(3):170-175.
[44]
Smit JW, van Erpecum KJ, Portincasa P, et al.Effects of simvastatin and cholestyramine on bile lipid composition and gall bladder motility in patients with hypercholesterolaemia[J].Gut, 1995, 37(5):654-659.
[45]
Porsch-Ozçürümez M, Hardt PD, Schnell-Kretschmer H, et al.Effects of fluvastatin on biliary lipids in subjects with an elevated cholesterol saturation index[J].Eur J Clin Pharmacol, 2001, 56(12):873-879.
[46]
Lanzarotto F, Panarotto B, Sorbara R, et al.Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid:evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans[J].Gut, 1999, 44(4):552-556.
[47]
Bodmer M, Brauchli YB, Krähenbühl S, et al.Statin use and risk of gallstone disease followed by cholecystectomy[J].JAMA, 2009,302(18):2001-2007.
[48]
Tsai CJ, Leitzmann MF, Willett WC, et al.Statin use and the risk of cholecystectomy in women[J].Gastroenterology, 2009, 136(5):1593-1600.
[49]
Pulkkinen J, Eskelinen M, Kiviniemi V, et al.Effect of statin use on outcome of symptomatic cholelithiasis: a case-control study[J].BMC Gastroenterol, 2014, 14:119.
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