酒精依赖和肌萎缩侧索硬化因果关系的孟德尔随机化分析
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摘要
目的采用孟德尔随机化方法探索饮酒行为和肌萎缩侧索硬化发病风险的因果关系。方法利用大样本全基因组关联研究数据,确定与酒精依赖密切相关的遗传位点作为工具变量,通过逆方差加权法、MR-Egger回归法等两样本孟德尔随机化方法,以比值比(OR值)作为结局指标对因果关系进行评价。结果本研究共纳入476例男性酒精依赖患者和1358例男性对照,IVW方法估计的OR值为1.12(95%可信区间:1.02-1.24,P=0.021),MR-Egger回归结果表明遗传多效性不会对结果造成偏倚(截距=-0.036,P=0.755)。结论本研究采用两样本孟德尔随机化的方法,表明在男性中严重的酒精依赖会增加肌萎缩侧索硬化的风险。
Objective To explore the causal relationship between alcohol dependence and the risk of amyotrophic lateral sclerosis using the Mendelian randomization(MR)analysis.Methods Genetic variants which are closely related to alcohol dependence in large sample GWAS were employed as instrumental variables;two-sample MR methods including IVW and MR-Egger regression was carried out to estimate the causal effect and to evaluate the possible pleotropic effects of instruments.Results A total of 476 male patients with alcohol dependence and 1,358 male controls were included in this study.The odd ratio between alcohol dependence and ALS was estimated to be 1.12(95%CI:1.02-1.24,P=0.021),and the MR-Egger regression results suggested that the genetic pleiotropy was unlikely to bias our results(the intercept=-0.036,P=0.755).Conclusion The results of the two-sample MR analysis provides the evidence that severe alcohol dependence can increase the risk of ALS.
Objective To explore the causal relationship between alcohol dependence and the risk of amyotrophic lateral sclerosis using the Mendelian randomization(MR)analysis.Methods Genetic variants which are closely related to alcohol dependence in large sample GWAS were employed as instrumental variables;two-sample MR methods including IVW and MR-Egger regression was carried out to estimate the causal effect and to evaluate the possible pleotropic effects of instruments.Results A total of 476 male patients with alcohol dependence and 1,358 male controls were included in this study.The odd ratio between alcohol dependence and ALS was estimated to be 1.12(95%CI:1.02-1.24,P=0.021),and the MR-Egger regression results suggested that the genetic pleiotropy was unlikely to bias our results(the intercept=-0.036,P=0.755).Conclusion The results of the two-sample MR analysis provides the evidence that severe alcohol dependence can increase the risk of ALS.
引文
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[29] Bowden J,Smith GD,Burgess S.Mendelian randomization with invalid instruments:effect estimation and bias detection through Egger regression.International Journal of Epidemiology,2015,44(2):512-525.
[30] Noyce AJ,Kia DA,Hemani G,et al.Estimating the causal influence of body mass index on risk of Parkinson disease:A Mendelian randomisation study.Plos Medicine,2017,14(6):e1002314.
[31] Miguel-Hidalgo JJ,Overholser JC,Meltzer HY,et al.Reduced Glial and Neuronal Packing Density in the Orbitofrontal Cortex in Alcohol Dependence and Its Relationship with Suicide and Duration of Alcohol Dependence.Alcoholism Clinical & Experimental Research,2006,30(11):1845-1855.
[32] Yoshii Y,Otomo A,Pan L,et al.Loss of glial fibrillary acidic protein marginally accelerates disease progression in a SOD1(H46R)transgenic mouse model of ALS.Neuroscience Research,2011,70(3):321-329.
[33] Sircar R,Sircar D.Repeated ethanol treatment in adolescent rats alters cortical NMDA receptor.Alcohol,2006,39(1):51.
[2] Mitchell JD,Borasio GD.Amyotrophic lateral sclerosis.Lancet.Lancet,2007,369(9578):2031-2041.
[3] Kiernan MC,Vucic S,Cheah BC,et al.Amyotrophic lateral sclerosis.Lancet.Lancet,2011,377(9769):942-955.
[4] Miller RG,Mitchell JD,Lyon M,et al.Riluzole for amyotrophic lateral sclerosis(ALS)/motor neuron disease(MND).Cochrane Database of Systematic Reviews,2000,4(2):CD001447.
[5] Cheah BC,Vucic S,Krishnan AV,et al.Riluzole,neuroprotection and amyotrophic lateral sclerosis.Current Medicinal Chemistry,2010,17(18):1942.
[6] Li HF,Wu ZY.Genotype-phenotype correlations of amyotrophic lateral sclerosis.Translational Neurodegeneration,2016,5(1):3.
[7] Rosen DR,Siddique T,Patterson D,et al.Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature,1993,364(6435):362.
[8] Armon C.Smoking may be considered an established risk factor for sporadic ALS.Neurology,2010,73(20):1693-1698.
[9] Wang H,éilis J.O′Reilly,Weisskopf MG,et al.Smoking and Risk of Amyotrophic Lateral Sclerosis:A Pooled Analysis of 5 Prospective Cohorts.Archives of Neurology,2011,68(2):207-213.
[10] De Jong SW,Huisman MHB,Sutedja NA,et al.Smoking,Alcohol Consumption,and the Risk of Amyotrophic Lateral Sclerosis:A Population-based Study.American Journal of Epidemiology,2012,176(3):233-239.
[11] Ji J,Sundquist J,Sundquist K.Association of alcohol use disorders with amyotrophic lateral sclerosis:a Swedish national cohort study.European Journal of Neurology,2016,23(2):270-275.
[12] Bozzoni V,Pansarasa O,Diamanti L,et al.Amyotrophic lateral sclerosis and environmental factors.Functional Neurology,2016,31(1):7-19.
[13] Zhu Z,Zheng Z,Zhang F,et al.Causal associations between risk factors and common diseases inferred from GWAS summary data.Nature Communications,2018,9(1).
[14] Katan MB.Apolipoprotein E isoforms,serum cholesterol,and cancer.Lancet,1986,1(8479):507-508.
[15] Lawlor DA,Harbord RM,Sterne JAC,et al.Mendelian randomization:using genes as instruments for making causal inferences in epidemiology.Statistics in Medicine,2008,27(8):1133-1163.
[16] 王莉娜,张卓峰.孟德尔随机化法在因果推断中的应用.中华流行病学杂志,2017,38(4):547-552.
[17] Greenland S.An introduction to instrumental variables for epidemiologists.International Journal of Epidemiology,2000,29(4):722-729.
[18] Burgess S,Scott RA,Timpson NJ,et al.Using published data in Mendelian randomization:a blueprint for efficient identification of causal risk factors.European Journal of Epidemiology,2015,30(7):543-552.
[19] Huisman MHB,Seelen M,Doormaal PTCV,et al.Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis.Jama Neurol,2015,72(10):1155-1162.
[20] E M,Yu S,Dou J,et al.Association between alcohol consumption and amyotrophic lateral sclerosis:a meta-analysis of five observational studies.Neurological Sciences,2016,37(8):1203-1208.
[21] Okamoto K,Kihira T,Kondo T,et al.Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis:A Case-Control Study in Japan.Annals of Epidemiology,2009,19(6):359-364.
[22] Kamel F,Umbach DM,Munsat TL,et al.Association of Cigarette Smoking with Amyotrophic Lateral Sclerosis.Neuroepidemiology,1999,18(4):194-202.
[23] Wang MD,Little J,Gomes J,et al.Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis.Neurotoxicology,2016,61:101-130.
[24] Pierce BL,Burgess S.Efficient Design for Mendelian Randomization Studies:Subsample and 2-Sample Instrumental Variable Estimators.American Journal of Epidemiology,2013,178(7):1177-1184.
[25] Treutlein J,Cichon S,Ridinger M,et al.Genome-wide association study of alcohol dependence.Archives of General Psychiatry,2009,773-784.
[26] Burgess S,Butterworth A,Thompson SG.Mendelian randomization analysis with multiple genetic variants using summarized data.Genetic Epidemiology,2013,37(7):658-665.
[27] Benyamin B,He J,Zhao Q,et al.Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis.Nature Communications,2017,8(1):611.
[28] 郑辉烈,王忠旭,王增珍.Meta分析中发表偏倚的Begg′s检验、Egger′s检验及Macaskill′s检验的SAS程序实现.中国循证医学杂志,2009,9(8):910-916.
[29] Bowden J,Smith GD,Burgess S.Mendelian randomization with invalid instruments:effect estimation and bias detection through Egger regression.International Journal of Epidemiology,2015,44(2):512-525.
[30] Noyce AJ,Kia DA,Hemani G,et al.Estimating the causal influence of body mass index on risk of Parkinson disease:A Mendelian randomisation study.Plos Medicine,2017,14(6):e1002314.
[31] Miguel-Hidalgo JJ,Overholser JC,Meltzer HY,et al.Reduced Glial and Neuronal Packing Density in the Orbitofrontal Cortex in Alcohol Dependence and Its Relationship with Suicide and Duration of Alcohol Dependence.Alcoholism Clinical & Experimental Research,2006,30(11):1845-1855.
[32] Yoshii Y,Otomo A,Pan L,et al.Loss of glial fibrillary acidic protein marginally accelerates disease progression in a SOD1(H46R)transgenic mouse model of ALS.Neuroscience Research,2011,70(3):321-329.
[33] Sircar R,Sircar D.Repeated ethanol treatment in adolescent rats alters cortical NMDA receptor.Alcohol,2006,39(1):51.