A Population-based Study Of The Inflammatory Reaction Passageway Gene Polymorphism For Stroke In A Chinese Population

Cerebral stroke was a common cerebral vascular disease(CVD)with high disease insidence, high morbidity and mortality.It was the third cause of death to continue cardiac disease and cancer for human. Genetics research indicated that most stroke was polygenic disease, and the occurrence of stroke was concerned with individial hereditary susceptibility, and interaction between heredity and environmental factor. So far, the genetics onset foundation was indefinite, but the association analysis of candidate genes would provide new clues to genetics invasion of stroke. Association study was also called correlation study based on population, which aim was to choose SNP in the vicinity of candidate gene. And through case-control study, it could provide a hypothesis if mixed factors was excluded. SNPs were molecular polymorphisms of single nucleotide substitution, insertion,or depletion. The density and quantity of SNPs was very great, so it was a real genetic marker.The present study had focused on inflammatory passageway genes as candidate susceptibility genes. Through case-control study, our research explored genetic association of PPARγ, NOS2A, PTGS2 and PLA2R1 genes and their synergy on stroke.The present study had chosen Chinese Han descent from Changchun region of Jilin province. A total of 756 cases of Chinese Han descent, consisting of 531 males and 225 females with stroke, and 404 unrelated healthy individals were recruited in this study. The case group was chosen from the patients who were in hospital from the neurological department, the first Hospital of Jilin University from 2005 to 2006. All patients were definitely diagnosed as stroke,and were confirmed by computed tomography and magnetic resonance imaging. The case group was divided into two subgroups,cerebral hemorrhage and ischemic stroke. And the ischemic stroke was further divided into two subgroups, including the lacunar infarction and the arteriosclerotic thrombotic cerebral infarction.And the controls were healthy individals, and their ages were matched with patients.Our study adopted SNPs as genetic markers and choosed seven SNPs based on inflammatory reaction passageway genes. PCR-based RFLP method was utilized to detect genotype, and the result expressed heterozygosis degree of rs1699337 and rs2297512 was lower than ten percent so that the two situs were not chosen as genetic markers.The Hardy-Weinberg(H-W) equilirium was tested for genotypic distributions of SNPs by using the chisquare goodness-of-fit test. The grouped data were tested by chisquare software, and the measurement data were tested by SPSS15.0 software. It was considered as significant difference if double p value was less than 0.05. And binomial logistic regression was used to judge traditional risk factors of stroke. And it was used to calculate respective odds ratio and 95% confidence interval. The linkage disequilibrium analysis of UNPHASED program was used to analyze two situs in the same gene. And the conditioning on allele analysis together with conditioning on genotype analysis were used to analyze synergy of all the five SNPs of PPARγ, NOS2A, PTGS2 and PLA2R1 genes. The followings were major results obtained in this study.1. Analysis for case-controlSNP of rs1875796 was associated with ischemic stroke in females. There was a significant difference in frequency of allele and genotype between the female ischemic stroke group and the female control group, especially in arteriosclerotic thrombotic cerebral infarction group. The frequcncy of allele C in female ischemic stroke group was greater than that in female control group. Logistic regrssion showed SNP of rs1875796 CC+CT genotype was an independent risk factor for ischemic stroke in female. There was no significant difference in frequency of allele and genotype between the ischemic stroke group and the control group in other four SNPs, and there was no significant difference in frequency of allele and genotype between the hemorrhagic stroke group and the control group in all the five SNPs.2. Analysis for quantitative traitSNP of rs2203053 was associated with LDL-c metabolism, and the LDL-c level of CC+CT genotype was significant higher than that of TT genotype.3. Analysis for clinical subgroupThere was a significant difference in frequency of genotype and allele between abnormality of glycometabolism group and normality of glycometabolism group in females(P=0.015 and P=0.002). The distribution of genotype and allele for rs28944190 had a significant difference between coronary artery disease crowd and without coronary artery disease crowd(P=0.009 and P=0.045), especially in males(P=0.001 and P=0.007). There was a significant difference in frequency of allele between hypertension crowd and without hypertension crowd in females(P=0.037).4. The synergy on ischemic stroke of gene and gene unificationConditioning on allele and conditioning on genotype showed all the five SNPs had no synergy on ischemic stroke. Linkage disequilibrium analysis showed SNP of rs2203053 and rs4665135 were not in the same LD region.To sum up, the present study demonstrated that(1) PPARγgene was related with ischemic stroke in female, especially arteriosclerotic thrombotic cerebral infarction subtype, and allele C was an independent risk factor for ischemic stroke in females. (2)PPARγgene was correlated with abnormality of glycometabolism in female, and allele C increased females risk in trouble with abnormality of glycometabolism. (3)PPARγgene may be conjunct genetics passageway between ischemic stroke and abnormality of glycometabolism. (4)NOS2A gene was correlated with coronary artery disease, especially males. And allele C increased males risk in trouble with coronary artery disease. (5)PTGS2 gene was correlated with hypertension in females, and allele A increased females risk in trouble with hypertension. (6)PLA2R1 gene was concerned with LDL-c metabolism, and SNP of rs2203053 increased LDL-c level. (7)All the five SNPs unification was not correlated with ischemic stroke . These findings are very important for elucidating the genetic mechanisms of stroke, and also for the individualized treatment of aiming at etiopathogenesis directly, potential economic retums and social effects.