| Section one:Genetic variation regulates the TSLP/TSLP receptor axis and associates with coronary artery diseaseBackgrounds:It has been reported that the TSLP/TSLP receptor axis plays an important role in cardiovascular diseases, including coronary artery diseases (CAD). However, the exact relationship between the pathway and CAD was still not clear yet. In this study, we investigated the molecular genetic mechanisms of the TSLP/TSLP receptor axis in CAD based on the Chinese Han population.Methods:A three-stage case-control association analysis study was performed with 3628 CAD cases and 3766 controls via common variants in the genes of TSLP, TSLPR and IL7R. Logistic regression analysis was used to perform the adjustment of traditional risk factors for CAD and the interaction analysis.Results:Each gene got a significant variant in the association with CAD (rs3806933T in TSLP, Padj=4.34×10-5, OR=1.18,95% CI:1.09-1.27; rs6897932T in IL7R, Padj=1.13×10-7, OR=1.31,95% CI:1.19-1.45; g.19646G>AA in TSLPR, Padj=2.04×10-6, OR=1.20,95% CI: 1.11-1.29). The interaction analysis showed that individuals with both risk alleles of rs3806933 in TSLP and rs6897932 in IL7R were more likely to suffer from CAD with OR value of 4.65 than those of other variants.Conclusion:Genetic variants in the TSLP/TSLP receptor axis could regulate the expression of their genes and contribute risk to CAD, which indicated a causal role of the axis in the development of CAD.Section two:Genetic association analyses between variants in IL27 and coronary artery diseaseBackground:Coronary artery disease (CAD) is a complex trait caused by multiple genetic factors, such as inflammatory cytokine genes. Recently, interleukin-27 (IL-27) has been determined to involve in kinds of inflammatory diseases, including CAD, but the exact function was not clear yet. In this study, we investigate genetic associations between variants in IL27 and CAD in the GeneID Chinese Han population.Methods:Case-control association analyses were performed in a total of 3,562 individuals with 1831 CAD cases and 1731 controls with tag SNPs (one promoter variant rs153109 and one missense variant rs181206) in the gene encoding IL-27. Traditional risk factors, such as age, gender, smoking, body mass index (BMI), hypertension, diabetes mellitus, Tch, TG, HDL-c and LDL-c, were studied and taken as covariates when performed the genetic association analysis. Statistical analyses were performed by Pearson chi square and logistic regression analysis using SPSS (version 17.0).Results:The traditional risk factors were significantly different between the CAD case subjects and controls (Padj<0.001). As a single variant, there was no significant association between rs153109 and rs181206 in IL27 and CAD in the GeneID Chinese Han population (rs153109C,Padj=0.552, OR=1.05,95% CI:0.90-1.21; rs181206G,Padj.387, OR=0.91, 95% CI:0.72-1.14). Under the haplotypic association analysis, we also found that the frequency distributions of the nine haplotypes composed by the two tag SNPs (rs153109 and rs181206) in IL27 were not significantly different between the cases and control subjects (Padj=0.676). In addition, when classified the total studied population into two subgroups by sex, the association analyses between rs153109 and rs181206 and CAD were still not significant (Padj>0.05 in male and female subgroups, respectively). Furthermore, we carried out the analysis between rs153109 and rs181206 and subgroup CAD, divided by the disease onset age (early-onset CAD and lately-onset CAD) or disease state (anatomical CAD and clinical CAD), and again got no significant association results (Padj>0.05 in all subgroups).Conclusion:Tag SNPs rs 153109 and rs181206 and their haplotypes in the gene encoding IL-27 were not significantly associated with CAD, which indicated that IL-27 might just be an inflammatory marker for the development of CAD in the GeneID Chinese Han population. |
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