Association Between Single Nucleotide Polymorphisms In Chromosome9p21and Cerebral Infarction In Han Chinese

Background and objectivesSingle nucleotide polymorphisms in chromosome9p21were reported to be associated with coronary artery disease, cardial infarction and other diseases, such as tumor, diabetes mellitus, and so on. Given that ischemic stroke and coronary artery disease or cardial infarction shared common several aspects of pathogenesis, the association study of9p21SNPs and ischemic cerebral diseases warrants further investigations. The association between9p21SNPs and coronary artery disease or cardial infarction has been confirmed by many studies, however, the findings of relationship between9p21and ischemic cerebral diseases were inconsistent. Therefore, the relationship between9p21SNPs and ischemic cerebral diseases is a primary target of stroke research.In this study, we investigated the association of9p21SNPs and cerebral infarction and subtype cerebral infarction in Chinese Han people. In additon, whether the association was involved in conventional risk factors for ischemic cerebrovascular diseases was also investigated. The relationship of cerebral infarction and haplotypes constructed by the studied SNPs were also analyzed. MethodsThe study was case-control design. The patients who admitted in the department of Neurology, Jinling Hospital during July2009and June2010were recruited. The control came from medical physical center.Eight SNPs (rs10757274, rs10757278, rs2383206, rs2383207, rs1004638, rs1333049, rs3731245and rs1537378) were genotyped in this study. These SNPs were identified association with ischemic cerebral diseases but the findings were inconsistent. Taqman SNP genotyping Assays was used. Clinical data including sex, age, body mass index (BMI), history of hypertension, diabetes mellitus, hyperlipemia, smoking, abused alcohol and atrial fibrillation were collected. All genotyped SNPs were performed Hardy Weinberg equilibrium test. The frequency of genotypes and alleles were analyzed by chisq square test between control and case groups. Univariate logistic regression model in different genetic models (dominant, recessive and additive models) were used for analyzing the association of SNPs and cerebral infarction. Then, multivariate logistic regression models were constructed for adjusting age, sex, body mass index, history of hypertension, diabetes mellitus, hyperlipemia, smoking, abused alcohol and atrial fibrillation. To prevent false discovery rate from multiple comparison, Q value was used for correcting p value. Q<0.05was considered as statistic significant difference.The history of hypertension and diabetes mellitus were the main risk factors for ischemic cerebral diseases. And the association of9p21SNPs and cerebral infarction might be influenced by sex. Stratafied analysis by hypertension, diabetes mellitus and sex were performed for the association of SNPs and cerebral infarction.Pathogenesis was different in all kinds of subtype cerebral infarction. They were also influenced by different genetic factors. The association study of subtype cerebral infarction classed by TOAST (Trial of Org10172in Acute Stroke Treatment) classification and SNPs was performed.Haplotype blocks were constructed by Haploview software. The frequency and score test of haplotypes were performed with Haplo.stats software package. Univariate and mutivariate linear regression models were used to analyze the association of haplotypes and cerebral infarction.Results In this study,769cerebral infarction cases and682control subjects were enrolled. All examed SNPs in both were conformed to Hardy Weinberg equilibrium. Three SNPs (rs2383207, rs3731245and rsl537378) were associated with cerebral infarction after adjusting for traditional risk factors in multiple logistic regression models and by Q value for multiple comparisons. The association stratafied by hypertension was not found in the hypertension groups among the three SNPs (rs2383207, rs3731245and rsl537378). In the non-hypertension group, rs2383207and rs1537378were associated with cerebral infarction (p<0.0167). SNPs rs2383207(OR=1.558;95%CI:1.108-2.191) and rs1537378(OR=1.642,95%CI:1.099-2.455) were significant in recessive model after adjusting the potential confounders of age, sex, body mass index, the history of diatetes mellitus, hyperlipemia, smoking, abused alcohol and atrial fibrilation, and rsl537378was also significant in additive model (OR=1.603,95%:1.115-2.299). Rs3731245was associated with cerebral infarction with diabetes mellitus in recessive model (OR=2.009,95%CI:1.203-3.355). The association of rs2383207and rsl537378with cerebral infarction were significant different in male in doninant model, and rs1537378in female in recessive model (p=0.011, OR=1.763,95%CI:1.141-2.724). And rs1537378was associated with large atherosclerotic cerebral infarction. No signifcance was found between the three SNPs and small arterial cerebral infarction. Haplotypes GTAAAGAG、ACAATAAG and ACAAAGAG were associated with cerebral infarction(p<0.00125). The last one was a risk factor (p=1.550e-06, OR=1.840,95%CI:1.355-2.499), but the others were protective factors.ConclusionsChromosome9p21SNPs is associated significantly with cerebral infarction in Han Chinese, but the mechanisms may be different in different sub-population. The influced factors for the association were warrant to be confirmed with larger sample size. And the detailed mechanisms warrants to be clarified in the future study.