The Relationship Between Arteriosclerosis Index And Filaggrin Gene Mutations And Ischemic Stroke

Part 1Arterial sclerosis index and the risk of ischemic stroke:a prospective cohort study Background and objectivesIn China,2 million individuals were diagnosed stroke every year and 1.7 million subjects died for stroke.Stroke is the leading cause of death and more than 20%of the deaths were due to stroke.Arterial sclerosis is the important pathologic basis in ischemic stroke.However,conventional detection approaches applied in arterial sclerosis were expensive and inconvenient,limited the evaluation of arterial function in general population.Atherogenic index of plasma(AIP)and atherosclerosis index(AI)are calculated according to the routine blood lipid test item and are good indicators for evaluating the risk of atherosclerosis in individuals.However,rare researches were performed to assess the relationship between arterial sclerosis index and ischemic stroke.Therefore,we aimed to evaluate the association between arterial sclerosis index and the risk of ischemic stroke in Chinese rural population.Methods and subjectsAll the subjects were recruited from 6 villages in Yixing city,Jiangsu province aged 35-75 years old by cluster sampling approach.The baseline investigation of epidemiological data,physical examination and blood biochemical test were conducted from May 2009 to August 2009.4081 subjects,1657 male and 2424 female,who were free of cardiovascular disease were included for follow up.The follow up were conducted in May 2014 and ended in January 2016.AIP and AI were calculated according to the blood lipids level and all individuals were divided into AIP and AI abnormal group in baseline.Besides,according the quartile group,the subjects were also divided into low,medium low,medium high and high groups.The relationship between arterial sclerosis index and incident ischemic stroke was examined by Cox proportional hazards regression model.The interaction between hypertension and arterial sclerosis index on the risk of ischemic stroke was evaluated by multiplicative interaction model.ResultsDuring the mean 5.16 years follow-up(21057.96 person-years),161 were diagnosed ischemic stroke.The incidence density was 764.56/100 thousand person-years,658.06/100 thousand person-years for female and 918.29/100 thousand person-years for male.After adjusting for age,sex,smoking history,alcohol use,body mass index,hypertension history and diabetes history,The risk of ischemic stroke was increased in AIP abnormal subjects and the hazard ratio(HR)and 95%confidence interval(CI)were 1.45 and 1.05-2.01,P=0.025.The risk of ischemic stroke was increasing across AIP medium low,medium high and high group and HRs(95%CIs)were 1.46(0.89-2.37),P=0.1;1.70(1.05-2.75),P=0.031;2.12(1.32-3.40),P=0.002;Ptrend=0.001.The association of AIP and ischemic stroke were even stronger smoking and drinking individuals.No significant association between AI abnormality and the quartile group and the incidence of ischemic stroke,however in diabetes subjects and hypertension-subjects,abnormal AI significantly increased the risk of ischemic stroke,HRs(95%CIs)were 1.85(1.08-3.18),P=0.025;3.38(1.36-8.42),P=0.009,respectively.Multiplicative interactions were found between hypertension and arterial sclerosis index,HR(95%CI)for AIP and hypertension was 1.86(1.34-2.60),P<0.001 and HR(95%CI)for AI and hypertension was 2.13(1.26-3.61),P=0.005.ConclusionsOur findings support that AIP abnormally increase is an independent risk factor of ischemic stroke.In hypertensive and diabetic population,AI abnormally elevation is significantly associated with the increased risk of ischemic stroke.Both AIP and AI have a significant interaction with hypertension.Part 2Molecular epidemiological study of FLNA and FLNB genetic variants with hypertension and ischemic stroke Background and objectivesCardiovascular disease is the leading cause of death in China,and hypertension is the major risk factor of stroke and coronary heart disease.Vascular wall elasticity and endothelial injury caused by arteriosclerosis were proved to be the primary cause of blood pressure rising and the occurrence of complications of hypertension,such as stroke.The filamins act as molecular scaffolding protein and participate in the process of cell migration,differentiation and inflammation,which are of great importance in the development of arterial blood vessels,aging and pathological arteriosclerosis.We aimed to explore the relationship between Filamin A(FLNA)and Filamin B(FLNB)polymorphisms with hypertension and ischemic stroke in Chinese Han Population.The results of the study will provide a new insight to reveal the pathogenesis of hypertension and ischemic stroke in Chinese Han population.Subjects and methodsAll the subjects aged 35-75 years old were recruited from 6 villages in Yixing city,Jiangsu province by cluster sampling approach.Hypertension subjects were referred to?Guidelines for hypertension prevention and control in China?(2005 revision),and 2012 hypertension cases and 2210 controls were included in hypertension case control study.After excluding subjects with cardiovascular disease or incomplete information,4081 individuals were finally confirmed for follow up.Tagging single nucleotide polymorphisms(tagSNP)selection were referred to the HapMap data of Chinese Han population in Beijing with minor allele frequency(MAF)?0.05 and r2 ?0.8.Finally 2 tagSNPs of FLNA and 5 tagSNPs of FLNB were confirmed for genotyping.Logistic regression was performed to analysis the relationship between selected tagSNPs with hypertension and Cox regression was applied to evaluate the association between selected tagSNPs and ischemic stroke.Haplotype analysis were according to HAPSTAT3.0 software.Generalized multi factor dimensionality reduction(GMDR)was used for gene-gene and gene-environmental interaction analysis.ResultsAfter adjusting,for age,gender,smoking history,alcohol use,fasting glucose,blood lipids and body mass index,FLNA and FLNB polymorphisms were not associated with hypertension.Subgroup analysis indicated in<55 years group and none-smoking history group,dominant model of rs2070816 in FLNA and recessive model of rs839230 in FLNB were related with increased risk of hypertension,odds ratio(95%confidence interval)were 1.31(1.013-1.566),P=0.026;1.21(1.03-1.43),P=0.021,respectively.Further adjusting hypertension history based on the factors above,FLNA and FLNB polymorphisms were not associated with incident ischemic stroke and stratified analysis revealed that dominant model of rs9822918 in FLNB was associated with decreased risk of ischemic stroke in<55 years group and drinking group;hazard ratio(95%confidence interval)were 0.19(0.037-0.95),P=0.044;0.46(0.22-0.95),P=0.037,respectively.Haplotype analysis showed that no haplotype in FLNB was observed to be with hypertension and ischemic stroke.No significantly gene-gene and gene-environmental interactions were found with hypertension by GMDR analysis.Filamin B level in plasma was significantly increased across normotensive group,hypertension group and ischemic stroke group,the mean level in each group was 3.24±4.02 ng/ml,3.74 ±5.85 ng/ml,11.97 ±13.93 ng/ml,Ptrend<0.001.Correlation analysis indicated positive correlation between Filamin B level with atherogenic index of plasma and triglyceride,the correlation coefficient was r=0.199,P<0.001 and r=0.158,P<0.001 respectively.ConclusionsThe genetic variation of FLNA and FLNB gene may be associated with hypertension and ischemic stroke and age,smoking and drinking may modify the function of FLNA and FLNB polymorphism.Increased level of Filamin B indicated that Filamin B may be a sensitive biomarker closely associated with ischemic stroke diagnosis and prognosis,and more researches are warranted.The positively correlation between Filamin B and atherogenic index of plasma and triglyceride revealed the potential role of Filamin B in blood lipid metabolism and the relevant mechanism still need to be further verified.