| Background Atrial fibrillation(AF)is a very common arrhythmia clinically.The number of patients with atrial fibrillation is increasing year by year.Although the understanding and treatment of atrial fibrillation have made a great progress,it is still one of the main causes of stroke,heart failure,myocardial infarction,sudden death and other cardiovascular diseases in the world.At present,many factors have been confirmed to be risk factors for ischemic stroke in patients with atrial fibrillation,such as age,gender,smoking,drinking,cardiovascular disease,diabetes,internal carotid artery stenosis,etc.,but these risk factors cannot explain all the causes of the disease.In recent years,some studies have proved that certain single nucleotide polymorphisms and the gene-gene interactions related with atrial fibrillation and/or stroke may affect the risk of cerebrovascular events in patients with atrial fibrillation.However,reports on gene-gene interactions in patients with atrial fibrillation are relatively rare.Therefore,further exploration of gene-gene interactions is beneficial to the risk assessment system of stroke in patients with intact atrial fibrillation,as well as early warning and prevention of strokes in patients with atrial fibrillation.Purpose To analyze the genetic polymorphisms of MTHFR,MTRR,PITX2,ZFHX3 in the population of Dalian,China,and to further evaluate the gene-gene interactions between selected test sites,and explore their relationship with atrial fibrillation with stroke.Finally,to find a better assessment of the risk of stroke events in patients with atrial fibrillation.Methods A case-control design was used.In the Department of Cardiology and Neurology in the Second Affiliated Hospital of Dalian Medical University,95 patients with atrial fibrillation were continuously recruited among the hospitalized patients in the ward.They were divided into atrial fibrillation with ischemic stroke group(n=54)and atrial fibrillation without ischemic stroke group as control(n= 41).All patients have conventional electrocardiogram or Holter electrocardiogram as the diagnosis basis of atrial fibrillation.Patients with ischemic stroke meet the WHO diagnostic criteria.Head CT and MRI clearly have infarcted lesions.Clinical data,medical history and 2-3 ml of peripheral venous blood of enrolled cases were collected.Real-time fluorescence quantitative PCR(RT-PCR)was used to detect PITX2 rs2200733,MTRR rs1801394,ZFHX3 rs2106261,MTHFR rs1801133 polymorphic site nucleotide sequence polymorphisms(SNP)and determine the genotype.The gene frequency and genotype frequency of each SNP were analyzed by RxC contingency table chi-square test or Fisher exact probability test respectively.For stroke and atrial fibrillation risk factors,binary logistic regression analysis was used to adjust the impact of the risk factors on gene frequency,so as to further evaluate the association between each candidate SNPs and stroke events in patients with atrial fibrillation.The generalized multi-factor dimensionality reduction method(GMDR)was used to conduct cross-checking to evaluate the interaction strength of the four sites,select statistically significant models,and then compare the cross-validation consistency and other indicators between the models,and determine the most Good interaction model.Results Compared with the atrial fibrillation control group,patients in the atrial fibrillation with stroke group were older(78.67±9.92 vs 68.41±11.66 years old,p=0.000),white blood cell levels(9.28±4.02×109/L vs 6.48±1.90×109/L,p=0.000),CK-MB levels(2.63±5.59 U/L vs 1.09±0.99 U/L,p=0.017),and BNP(565.03±814.04pg/ml vs 258.64±279.80 pg/ml,p=0.024)were significantly higher than that of the control group,and there was no statistical difference between the two groups of statistics on the history of hypertension,diabetes,coronary heart disease and other risk factors affecting stroke.All four genes comply with Hardy-Weinberg equilibrium law.Multivariate binary logistic regression analysis was used to adjust for confounding factors such as age,white blood cells,CK-MB,BNP and other factors.It was found that the CT type of rs1801133 locus of MTHFR gene was associated with ischemic stroke events in patients with atrial fibrillation [P=0.011,OR=12.594,95% CI(1.771-89.556)].The atrial fibrillation with stroke group was further divided into two subgroups,cardiogenic stroke subgroups and other types of stroke subgroups.Finally,it was found that MTHFR rs1801133-CT was statistically significant in both the cardiogenic stroke group and the other type of stroke group,compared with the atrial fibrillation control group.GMDR was used to construct an interaction model of 4 gene loci,and it was found that the combination of the 4 loci analyzed was not statistically significant.Conclusion MTHFR rs1801133-CT is associated with ischemic stroke in patients with atrial fibrillation.Compared with wild CC,it significantly increases the risk of ischemic stroke in patients with atrial fibrillation.Further subgroup analysis suggests that the ischemic strokes may originate from cardiogenic stroke or other types of stroke.However,our study did not find that interactions among PITX2 rs2200733,MTRR rs1801394,ZFHX3 rs2106261 and MTHFR rs1801133 are related to the occurrence of ischemic stroke in atrial fibrillation patient. |
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