The Study on the Association between TNFSF4/TNFRSF4 Gene and Cerebral Infarction
|School||Central South University|
|Keywords||atherosclerosis cerebral infarction TNFSF4 TNFRSF4 gene polymorphism TaqMan-PCR|
Research background and object:Cerebral infarction is a kind of common polygenic disease caused by genetic and environmental factors. In our country, the incidence, mortality and disabled rate of cerebral infarction is still head the list. Epidemiological survey of stroke shows that genetic factors play an important role in the pathogenesis of cerebral infarction. Some environmental factors, such as atherosclerosis, hypertension, hyperlipidemia, diabetes, heart disease, are also associated with heredity. Searching for predisposing genes of stroke is the focal point of the study for genetic mechanism of cerebral infarction.Atherosclerosis, the predominant process underlying cerebral infarction, is now considered an inflammatory disease. Activated T cells are implicated in important cellular and molecular events in atherogenesis.TNFSF4 (OX40 ligand) and TNFRSF4 (OX40) are important members of the tumor necrosis factor (TNF) and TNF receptor family and OX40L/OX40 mediated signaling is important in activation of T cells and facilitates B-T cell interaction. Further studies discover that the gene mutation of TNFSF4 results in atherosclerosis. The TNFSF4 gene is located within the region associated with atherosclerosis in mice. Mice overexpressing TNFSF4 showed Significantly larger atherosclerotic lesions compared with conthol. The TNFSF4 gene knocked out mice show resistance to atherosclerosis compared with control even though fed with high fat diet. Furthermore, clinical study showed that humans with a SNP in the TNFSF4 gene have a higher incidence of myocardial infarction.TNFRSF4 gene is located in the region of 1p34-36,which is a QTL of myocardial infarction and is near to a mouse atherosclerosis QTL(Athsql).It is suggest that the TNFRSF4 gene also underlie atherosclerosis and myocardial infarction.Although atherosclerosis is the fundamental cause of cerebral infarction, there is still few report focused on the relationship between TNFSF4/TNFRSF4 genes and cerebral infarction published overtly. In the present research, we study the relationship between TNFSF4/TNFRSF4 genes SNPs and cerebral infarction in a Chinese population, aimed to explore whether TNFSF4/TNFRSF4 genes influence the susceptivity of cerebral infarction and to offer a new direction for the screening about the high risk group of cerebral infarction.Methods:The association study methed was adopted to use in the present study. A group of patients without genetic relationship were randomly chosen as case group in Hunan Han population. Another comparative group of healthy individuals matched at age and sex were chosen as the control group. The data about case history, physical examination and blood test on blood sugar and blood lipid were recorded detailedly. By utilizing real-time fluorescent PCR method based on TaqMan probe and DNA sequencing method, this study focus on 5 SNPs of TNFSF4/TNFRSF4 genes and analyzing the association with the hereditary susceptibility of cerebral infarction. Objects examined were composed of 620 individuals of Hunan han population totally:(1) case group was composed of 324 individuals: 194 cases of male and 127 female aged between 36 years and 86 years, the mean is 59.8±11.5 years.(2) control group was made up of 194 male and 102 female, totally 296 individuals, aged between 31 and 86 years, the mean is 61.44±11.9 years.Results:1. There are large variations of 5 TNFSF4/TNFRSF4 gene SNPs between Hunan Han population and the west population in NCBI dbSNP.2. There are no significant difference of TNFSF4 genes rs3850641 A-G, rs1234313 A-＞G; rs1234314 C-＞G site polymorphisms and allele frequencies between case group and control.3. There is significant difference of TNFSF4 gene rs3861950 C-T site polymorphism and allele frequency between case group and control. The frequencies of C allele is significantly higher in case group than in control, especially in the groups doesn’t complicated by hypertension or diabetes mellitus and those without family history. Logistic regression analysis shows that the risk factor of C allele is 3.7 times higher than others (p=0.002, OR:3.706).4. There is no significant difference of TNFSF4 gene rs17568 A-G site polymorphism and allele frequency between case group and control.5. There is no significant difference of blood lipid level in 5 TNFSF4/TNFRSF4 gene SNPs between case group and control.6. There is no significant difference in haplotype(s) ofTNFSF4 gene rs3861950, rs3850641, rs1234313, rs1234314 between case group and control.Conclusions:1.There is no association between TNFSF4 gene rs3850641 A-G, rs1234313 A-G and rs1234314 C-G site polymorphism and cerebral infarction in Hunan Han population.2.TNFSF4 gene rs3861950 C-T site polymorphism is associated with cerebral infarction in Hunan Han population. C allele is considered to be one independent risk factor in Hunan Han population.3.There is no association between TNFRSF4 gene rs17568 A-G site polymorphism and cerebral infarction in Hunan Han population.4.There is no association between haplotype(s) of TNFSF4 gene rs3861950, rs3850641, rs1234313, rs1234314 and cerebral infarction in Hunan Han population.