Correlation Study Between Mfn2 Gene And Susceptibility As Well As Prognosis Of Ischemic Cardiomyopathy

Objective: Evaluate the correlation between the genotype,allele,haplotype as well as plasma level of Mfn2(Mitofusion2,Mfn2)and Ischemic cardiomyopathy(ICM),on the base of results establish and validation a diagnostic and prognostic predictive model of ICM,and provide a theoretic evidence to early diagnosis and assess the prognosis of ICM.Method: 1)Section 1: In this study we recruited the participants who in hospital in cardiovascular center of first affiliated hospital of Xinjiang medical university from January,2012 to December 2015.It include1092 participants who is diagnosed with ICM and 960 participants as control group,then performed genotyping test on 12 Tag Single nucleotide polymorphism(SNP)by using Improved multiplex ligation detection reaction(i MLDR)technique,then evaluate the correlation between geneotype、allele as well as haplotype and susceptibility to ICM.2)Section 2: on the basis of section 1’s result we screened out 6 SNPs which(is deemed highly correlated with ICM)its P < 0.3 in dominant model and enrolled them into this section,as well as we tested the plasma level of Mfn2,All participants randomly divided into training group and validation group,on training group’s data we performed univariable analysis,screened out the variables which its P<0.1 and performed lasso regression analysis,and use variables screened out from the lasso regression analysis we developed a logistic regression model,than validated the model,The discrimination ability of the model was evaluated by receiver operator curve(ROC)、 and the consistency of the model was evaluated by calibration plot and hosmer-lemshow test,the clinical utility of the model evaluated by decision curve analysis(DCA).3)section 3: 1092 ICM patients in section1 and section 2 are enrolled in this section,and include the genotype of 12 Tag SNPs,plasma level of Mfn2,Demographic information、clinical information as well as the laboratory test results and treatment status.All ICM patients were followed-up in 3,6,12,24,36,48 and 60 month after diagnosed with ICM,according to the result of follow-up divided into dead group and not-dead group.all ICM patients were randomly divided training group and validation group,on training group’s data we performed univariable Cox regression analysis,to optimize the variable selection we screened out the variables with P<0.1 and incorporated into the Lasso regression analysis,then using the variables which are screened out from the Lasso regression analysis we established the multivariable Cox regression model,then validated the model,evaluated the discrimination ability of the model by ROC,evaluate the consistency by calibration plot,evaluate the clinical usefulness by DCA.Result: 1)Section 1:(1)in rs1042842,Individuals with mutant AG genotype have a 1.924 times higher risk of developing ICM compared to those with wild AA genotype[OR=2.924(2.206-3.876),P<0.001],and individuals with mutant GG genotype have a 5.486 times higher risk of developing ICM compared to those with wild AA genotype[OR=6.486(4.85-8.674),P<0.001],in dominant model,individuals with mutant genotype(AG+GG)have 3.197 times higher risk of developing ICM compared to those with wild AA genotype[OR=4.197(3.211-5.487),P<0.001],in allele analysis,individuals with mutant G allele have the 1.182 times higher risk of ICM compared to individuals with wild A allele[OR=2.483(2.182-3.825),P<0.001].(2)In rs2295281,individuals with mutant CT genotype have 1.093 times higher risk of developing ICM compared to those with wild CC genotype[OR=2.093(1.69-2.593),P<0.001],individuals with mutant TT genotype have 2.828 times higher risk of developing ICM compared to those with wild CC genotype[OR=3.828(2.966-4.941),P < 0.001],in dominant model,individuals with mutant genotype(CT+TT)have 1.548 times higher risk of developing ICM compared to those with wild CC genotype[OR=2.548(2.082-3.118),P < 0.001].In allele analysis,individuals with mutant T allele have the 0.969 times higher risk of ICM compared to individuals with wild C allele[OR=1.969(1.738-2.230),P<0.001].(3)In rs3088064,in the analysis of allele,individuals with mutant C allele have the 0.146 times higher risk of ICM compared to individuals with wild G allele[OR=1.969(1.738-2.230),P<0.001].(4)In rs4240897,in the analysis of allele,individuals with mutant A allele have the 0.133 times higher risk of ICM compared to individuals with wild G allele[OR=1.133(1.002-1.282),P=0.047].2)Section 2:(1)in univariable analysis,there are significant difference in age,gender,smoking,drinking alcohol,hypertension,diabetes,Mfn2,Body mass index(BMI),white blood cell,red blood cell,Hemoglobin,low-density cholesterol,N terminal pro B type natriuretic peptide(NT-pro BNP),ejection fraction(EF),left ventricular end diastolic diameter(LVDD)(P<0.05).(2)And we screened out the 20 variables which has the P value<0.1 incorporated into the Lasso regression analysis and screened out 8 variables,by using these 8 variables established a logistic regression model,result indicate that: age,diabetes,hemoglobin,ejection fraction,and left ventricular end diastolic diameter,plasma level of Mfn2,mutation of rs1042842 、 rs2295281 are the independent predictive factors of ICM(P<0.05).(3)the result of validation indicate that:the model has good discrimination ability both in training group and validation group(the AUC of ROC is 0.937 in training group and 0.934 in the validation group).the P value of hosmer-lemeshow(H-L)test is 0.2655 in training group and 0.3315 in validation group,indicated that the model have good consistency between observed value and predicted value both in training group and validation group.The clinical curve analysis indicated use this model in clinic,it has net benefit between rom to 1.0,have good clinical utility.3)Section 3:(1)The univariable Cox regression analysis in training set indicate that: plasma level of Mfn2,heart rate,hemoglobin,Serum sodium,Serum albumin level,left ventricular end diastolic diameter,NT-pro BNP,treating by Percutaneous coronary intervention(PCI)or Coronary artery bypass graft(CABG),mutation of rs1042842 and rs2295281 are correlated with the long-term prognosis of ICM(P<0.05);(2)to optimize the variable selection we incorporated 15 variables with P<0.1 into the Lasso regression analysis and 15 variables reduced to 9,by using these 9 variables established multivariable Cox regression model,the result indicated that: plasma level of Mfn2,heart rate,Serum sodium,treating by PCI or CABG,using of β blocker,left ventricular end diastolic diameter,mutation of rs1042842、rs2295281 and rs2236054 are the predictive factors of the long term prognosis of ICM(P<0.05).(3)then validated the model,This nomogram have good discrimination ability,the Area under curve(AUC)value of ROC in training set is 0.824(1 year),0.809(3 year)and 0.877(5year),in validation set 0.808(1year),0.767(3 year)and 0.790(5year).according to calibration plot in training set and validation set,this nomogram has good consistency between actual value and predictive value of the model.According do decision curve analysis in training set and validation set,this model have good clinical usefulness.Conclusion: 1)In 12 Tag SNPs of Mfn2 gene,the mutant genotype as well as the mutant allele of rs1042842 and rs2295281 have the correlation with high risk of ICM,in rs3088064 and rs4240897 the mutant allele have the correlation with high risk of ICM.2)In Mfn2 gene mutation of rs1042842 and rs2295281 are correlated with decrease of plasma level of Mfn2,Plasma level of Mfn2 is the protective factor of ICM.The mutation of rs1042842 and rs2295281 increase the risk of ICM by decreasing plasma level of Mfn2.3)Plasma level of Mfn2 and mutation of rs2236054 are the protective factor of the long-term prognosis of ICM,mutation of rs1042842 and rs2295281 are the risk factors of the long-term prognosis of ICM.