脑梗死相关基因的遗传学研究
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摘要
脑梗死是由多个基因和环境因素共同作用导致的一类极其复杂的疾病。遗传因素在脑梗死的病理生理方面起着十分重要的作用,但是并非经典的孟德尔单基因遗传疾病,引起脑梗死的致病基因迄今仍不明确。近年来,对脑梗死候选基因的研究成为脑梗死遗传机制研究的重点。动脉粥样硬化是脑梗死发生的重要病理生理基础,其发生与脂代谢、炎症反应、血管内皮细胞受损和平滑肌细胞增生等有关。为了从分子水平探讨脑梗死的发病机制,寻找脑梗死的致病基因,我们从动脉粥样硬化与脑梗死发病的直接相关性考虑,确定了与脑梗死发病的相关候选基因。本研究以中国北方汉族脑梗死患者为研究对象,采用候选基因和病例对照的方法,应用生物信息学技术及聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术研究了与动脉粥样硬化相关的COX-2、PLA2R1及eNOS基因SNPs与脑梗死的关系,并探讨了多个易感基因的之间的协同作用和基因与危险因素之间的协同作用。研究结果发现了COX-2 SNP是动脉粥样硬化性脑梗死的独立危险因素,并且发现了COX-2、PLA2R1及eNOS基因位点之间的联合作用,及COX-2基因与糖尿病在脑梗死的发病过程中有着一定协同作用。
Cerebral infarction is a common cerebrovascular disease with high morbidity and mortality. It is the most frequent course of adult-onset disability and the cost of related care is among the fastest-growing expenses for medical care.Cerebral infarction is a kind of multiple genetic disease.While the cause for cerebral infarction remains unknown, several lines of evidence from family, twin and epidemiology suggest that genetic factors are likely to play an essential role in the developing of cerebral infarction and influence susceptibility to cerebral infarction. These data have demonstrated that cerebral infarction is not a simple Mendelian disease but looks like a complex disease involving several genes with each susceptible gene having only a modest individual effect. It has been known that cerebral infarction is a complicated disease caused by several genes and enviroment factor.Although the virulence gene is not clear, it is an useful strategy to determine potential candidate genes of cerebral infarction for understanding and prevention of cerebral infarction. In recent years, SNPs have been used as new DNA markers in mapping of disease-related genes in humans. There is no doubt that SNPs will play a key role in identifying of disease-related genes, investigating the mechanism of the genome-environment interaction and gene-gene interaction.
In recent years, it has been known that lipid metabolism,inflammation reaction , damage of vascular endothelial cell and SM cell proliferation play a key role in atherosclerosis. Artherosclerosis is the main patho-physiological foundation of cerebral infarction. More and more attention has been paid to the atherosclerosis-related gene. In the present study we have focused on identification of the candidate genes of PLA2R1 COX-2 and eNOS.
The case group include 276 individuals, chosen from the patients who were in neurological department, the first Hospital of Jilin University during Oct. 2005 to June 2006. Clinical diagnosed as ischemic stroke and confirmed by CT or MRI.By using bioinformatics methods 4 SNPs were chosen on the PLA2R1 COX-2 and eNOS gene including rs2203053 and rs4665135 present in the PLA2R1 locus,rs689466 in the COX-2 locus,rs1800780 in the eNOS locus. SNPs were genotyped using PCR-based RFLP analysis. Genotyping data were put into the SPSS database. The Hardy-Weinberg (H-W) equilibrium was tested for genotype frequency distributions of SNPs using the goodness of fit test. To elucidate relation between each SNP and cerebral infarction,we analyse genotypic and allelic frequency of each SNP in controls and cerebral infartion group.In addition, cerebral infarction patients were sub-grouped of arteriosclerotic thrombotic cerebral infarction and lacunar infarct and the genetic association between SNPs and clinical subgroups was then analyzed. linkage disequilibrium ,combined effects of four SNPs and associations of clinical subgroup were tested by UNPHASED programs .
The details of major results obtained in this study is as follows:
1 The H-W equilibrium
The goodness of fit test showed that genotype frequency distributions of all subjects were not deviated from the H-W equilibrium, thus these samples were suitable for the genetic analysis.
2 allelic and genotypic frequency for each SNP in case and control group
Allelic frequencies of rs689466 at COX-2 locus showed significant difference between case and control groups. Odds radio (OR) of A/A to G/G and A/G is 1.553(X2=4.732,df=1, 95%CI=1.043～2.313, P=0.03). rs689466 at COX-2 locus has significant correlation with ischemic stroke. Logistic regression analysis showed that incidence of ischemic stroke in people with A/A genotype is 1.701 times of that in people with CC+TT genotype.There was no significant difference for the frequencies of alleles and genotype of rs2203053 and rs4665135 at PLA2R1 locus,rs1800780 at eNOS locus between case and control groups.
3 Analysis for different cerebral infarction
There was significant difference for the frequencies of alleles and genotype of rs689466 at COX-2 locus between arteriosclerotic thrombotic cerebral infarction and control groups. OR of A/A to G/G and A/G is 1.68(X2=5.377,df=1, 95%CI=1.082～2.609, P=0.02). Logistic regression analysis showed that incidence of ischemic stroke in people with A/A is 2.092 times of that in people without the mutation. rs689466 at COX-2 locus has significant correlation with thrombotic cerebral infarction.Although OR of A/A to G/G and A/G is 1.358(X2=1.342,df=1, 95%CI=0.808～2.283, P=0.247), Logistic regression analysis showed that A/A genotype is not a indepent risk factor for lacunar infarct. The results showed that rs2203053 were not associated with cerebral infarction.
4 LD between paired SNPs
The estimated LD showed that rs2203053 and rs4665185 were not in the same LD block with SHEsis programs D′<0.05.
5 Analysis for combined effects of multiple locus using conditional test:
The conditional test was used to test the combined effect of distint loci on the disease by conditioning on allele(COA)or by conditioning on genotype( COG ) .The COA test showed a disease association for the rs4665135-rs689466-rs1800780 combination. The COG test also showed an association for the above locus combinations.In arteriosclerotic thrombotic cerebral infarction group COG test showed an association for rs4665135-rs689466-rs1800780 combinations. In lacunar infarct group COG test showed an association for rs4665135-rs689466-rs1800780 and rs4665135-rs1800780 combinations.
6 Analysis for clinical subgroups:
We found that A allele of COX-2 in cerebral infarction with diabetes is higher than in cerebral infarction without diabetes(p<0.05). Taken together, the present study demonstrated that COX-2 might play an important role in the developing of cerebral infarction. rs689466 A/G allele at COX-2 locus may be associated with cerebral infarction. There is synergistic effect between COX-2 and diabetes in the developing of cerebral infarction. There is combined effect of rs4665135-rs689466 -rs1800780 in the cerebral infartion group.And there is combined effect of rs4665135-rs1800780 in the lacunar infarction group.These findings are very important for elucidating the molecular genetic mechanisms of cerebral infarction, and also for genetic diagnosis, developing new drugs and prediction of cerebral infarction.
Cerebral infarction is a common cerebrovascular disease with high morbidity and mortality. It is the most frequent course of adult-onset disability and the cost of related care is among the fastest-growing expenses for medical care.Cerebral infarction is a kind of multiple genetic disease.While the cause for cerebral infarction remains unknown, several lines of evidence from family, twin and epidemiology suggest that genetic factors are likely to play an essential role in the developing of cerebral infarction and influence susceptibility to cerebral infarction. These data have demonstrated that cerebral infarction is not a simple Mendelian disease but looks like a complex disease involving several genes with each susceptible gene having only a modest individual effect. It has been known that cerebral infarction is a complicated disease caused by several genes and enviroment factor.Although the virulence gene is not clear, it is an useful strategy to determine potential candidate genes of cerebral infarction for understanding and prevention of cerebral infarction. In recent years, SNPs have been used as new DNA markers in mapping of disease-related genes in humans. There is no doubt that SNPs will play a key role in identifying of disease-related genes, investigating the mechanism of the genome-environment interaction and gene-gene interaction.
In recent years, it has been known that lipid metabolism,inflammation reaction , damage of vascular endothelial cell and SM cell proliferation play a key role in atherosclerosis. Artherosclerosis is the main patho-physiological foundation of cerebral infarction. More and more attention has been paid to the atherosclerosis-related gene. In the present study we have focused on identification of the candidate genes of PLA2R1 COX-2 and eNOS.
The case group include 276 individuals, chosen from the patients who were in neurological department, the first Hospital of Jilin University during Oct. 2005 to June 2006. Clinical diagnosed as ischemic stroke and confirmed by CT or MRI.By using bioinformatics methods 4 SNPs were chosen on the PLA2R1 COX-2 and eNOS gene including rs2203053 and rs4665135 present in the PLA2R1 locus,rs689466 in the COX-2 locus,rs1800780 in the eNOS locus. SNPs were genotyped using PCR-based RFLP analysis. Genotyping data were put into the SPSS database. The Hardy-Weinberg (H-W) equilibrium was tested for genotype frequency distributions of SNPs using the goodness of fit test. To elucidate relation between each SNP and cerebral infarction,we analyse genotypic and allelic frequency of each SNP in controls and cerebral infartion group.In addition, cerebral infarction patients were sub-grouped of arteriosclerotic thrombotic cerebral infarction and lacunar infarct and the genetic association between SNPs and clinical subgroups was then analyzed. linkage disequilibrium ,combined effects of four SNPs and associations of clinical subgroup were tested by UNPHASED programs .
The details of major results obtained in this study is as follows:
1 The H-W equilibrium
The goodness of fit test showed that genotype frequency distributions of all subjects were not deviated from the H-W equilibrium, thus these samples were suitable for the genetic analysis.
2 allelic and genotypic frequency for each SNP in case and control group
Allelic frequencies of rs689466 at COX-2 locus showed significant difference between case and control groups. Odds radio (OR) of A/A to G/G and A/G is 1.553(X2=4.732,df=1, 95%CI=1.043～2.313, P=0.03). rs689466 at COX-2 locus has significant correlation with ischemic stroke. Logistic regression analysis showed that incidence of ischemic stroke in people with A/A genotype is 1.701 times of that in people with CC+TT genotype.There was no significant difference for the frequencies of alleles and genotype of rs2203053 and rs4665135 at PLA2R1 locus,rs1800780 at eNOS locus between case and control groups.
3 Analysis for different cerebral infarction
There was significant difference for the frequencies of alleles and genotype of rs689466 at COX-2 locus between arteriosclerotic thrombotic cerebral infarction and control groups. OR of A/A to G/G and A/G is 1.68(X2=5.377,df=1, 95%CI=1.082～2.609, P=0.02). Logistic regression analysis showed that incidence of ischemic stroke in people with A/A is 2.092 times of that in people without the mutation. rs689466 at COX-2 locus has significant correlation with thrombotic cerebral infarction.Although OR of A/A to G/G and A/G is 1.358(X2=1.342,df=1, 95%CI=0.808～2.283, P=0.247), Logistic regression analysis showed that A/A genotype is not a indepent risk factor for lacunar infarct. The results showed that rs2203053 were not associated with cerebral infarction.
4 LD between paired SNPs
The estimated LD showed that rs2203053 and rs4665185 were not in the same LD block with SHEsis programs D′<0.05.
5 Analysis for combined effects of multiple locus using conditional test:
The conditional test was used to test the combined effect of distint loci on the disease by conditioning on allele(COA)or by conditioning on genotype( COG ) .The COA test showed a disease association for the rs4665135-rs689466-rs1800780 combination. The COG test also showed an association for the above locus combinations.In arteriosclerotic thrombotic cerebral infarction group COG test showed an association for rs4665135-rs689466-rs1800780 combinations. In lacunar infarct group COG test showed an association for rs4665135-rs689466-rs1800780 and rs4665135-rs1800780 combinations.
6 Analysis for clinical subgroups:
We found that A allele of COX-2 in cerebral infarction with diabetes is higher than in cerebral infarction without diabetes(p<0.05). Taken together, the present study demonstrated that COX-2 might play an important role in the developing of cerebral infarction. rs689466 A/G allele at COX-2 locus may be associated with cerebral infarction. There is synergistic effect between COX-2 and diabetes in the developing of cerebral infarction. There is combined effect of rs4665135-rs689466 -rs1800780 in the cerebral infartion group.And there is combined effect of rs4665135-rs1800780 in the lacunar infarction group.These findings are very important for elucidating the molecular genetic mechanisms of cerebral infarction, and also for genetic diagnosis, developing new drugs and prediction of cerebral infarction.
引文
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