Association Study Between Lipid Metabolism-related Genes And 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 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 lipid metabolism -related gene. In the present study we have focused on identification of the candidate genes of LPL and PON1.The case group include 705 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. 5 SNPs were chosen on the LPL and PON1 gene including rs326 and rs328 present in the LPL locus,rs2299262,rs854552,rs 662 in the PON1 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 Allelic frequencies of rs326 at LPL locus showed significant difference between arteriosclerotic thrombotic cerebral infarction and control groups. Odds radio (OR) is 1.64(X~2=3.597, P=0.047 ,OR=1.64,95%CI=1.12-1.84). Incidence of arteriosclerotic thrombotic cerebral infarction in people with G allet is 1.64 times of that in people with C allet.2 Allelic frequencies of rs328 at LPL locus showed significant difference between arteriosclerotic thrombotic cerebral infarction and control groups. Odds radio (OR) is 1.47(X~2=4.83, P=0.034,OR=1.47,95%CI=1.03-2.13). Incidence of arteriosclerotic thrombotic cerebral infarction in people with G allet is 1.47 times of that in people with C allet.3 haplotype of rs326(G)-rs328(G) showed significant difference between case and control groups(X~2=8.325,P=0.00391).4 SNP of rs328 was associated with glucose metabolism,and the blood glucose level of G allet was significant higher than that of C allet.5 haplotype rs326-rs328 showed significant difference between case and control groups(X~2=10.1566,P=0.0172).6 rs229262 on PON1 gene and rs328 on LPL gene had synergy on ischemic stroke (X~2=6.26,df=2,P=0.043).The study of three tag SNPs of PON1 gene showed no association with cerebral infarction.Taken together, the present study demonstrated that (1) LPL gene might play an important role in the developing of cerebral infarction. The G allete associated with increased risk of cerebral thrombosis infarction. (2)LPL gene was concerned with glucose metabolism. SNP of rs328 increased blood glucose level. (3)haplotype containing rs326(G)-rs328(G)may carry disease-consistant variant for cerebral infarction.(4) haplotype of rs326-rs328 associated with cerebral infarction.(5) rs229262 on PON1 gene and rs328 on LPL gene had synergy on ischemic stroke.(6) SNPs of PON1 gene was not associated with cerebral infarction.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.