Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere University Hospital, Centre for Laboratory Medicine, University of Tampere, Medical School, Finn Medi 2, FI-33521 Tampere, Finland.
Eur Heart J. 2009 Dec;30(23):2939-46. doi: 10.1093/eurheartj/ehp316. Epub 2009 Aug 17.
The interleukin 18 (IL-18) gene has a single nucleotide promoter region (-137) G-to-C polymorphism (rs187238) which leads to attenuated transcriptional activity of the gene and to lower production of pro-atherogenic IL-18. The C allele of this polymorphism is associated with a lower risk of sudden cardiac death (SCD). We examined the process by which this polymorphism alters the risk of SCD and coronary artery disease (CAD) by analysing the interactions between this polymorphism and environmental factors.
TaqMan 5' nuclease assay was used to genotype the study population of the Helsinki Sudden Death Study, comprising medicolegal autopsies of 700 men. According to adjusted logistic regression analysis, there was a significant interaction between IL-18 genotype and hypertension impacting on the risk of SCD due to coronary heart disease (CHD) (P = 0.011) and the severity of autopsy-verified CAD (P = 0.026). Among GG homozygotes, hypertension was a major risk factor for SCD due to CHD [adjusted odds ratio (OR) 3.75 with 95% CI 1.78-7.91, P < 0.001] and hypertension also associated with larger coronary atherosclerotic plaque areas (P = 0.002) and the occurrence of complicated plaques (adjusted OR 8.38 with 95% CI 2.39-29.33, P < 0.001). Among C allele carriers, hypertension was not a significant risk factor for CHD-related SCD or CAD and did not associate with the development of coronary atherosclerotic plaques. According to gene expression analysis of atherosclerotic tissue samples obtained from live patients, hypertension also interacted significantly with IL-18 genotype affecting the expression of IL-18 (P = 0.030) mRNA and interferon-gamma mRNA (P = 0.004).
Hypertension interacts with IL-18 gene promoter -137 G/C polymorphism, affecting the risk of SCD and the development of coronary atherosclerosis.
白细胞介素 18（IL-18）基因的单核苷酸启动子区域（-137）存在 G 到 C 多态性（rs187238），导致基因转录活性减弱，前动脉粥样硬化性 IL-18 产生减少。该多态性的 C 等位基因与心脏性猝死（SCD）的风险降低相关。我们通过分析该多态性与环境因素之间的相互作用，研究了该多态性改变 SCD 和冠状动脉疾病（CAD）风险的过程。
采用 TaqMan 5' 核酸酶检测法对包括法医学尸检的 700 名男性在内的赫尔辛基心脏性猝死研究的研究人群进行基因分型。根据调整后的逻辑回归分析，IL-18 基因型与高血压之间存在显著的相互作用，影响了冠心病（CHD）导致的 SCD 风险（P=0.011）和尸检证实的 CAD 的严重程度（P=0.026）。在 GG 纯合子中，高血压是 CHD 导致 SCD 的主要危险因素[调整后的比值比（OR）为 3.75，95%置信区间（CI）为 1.78-7.91，P<0.001]，高血压还与更大的冠状动脉粥样硬化斑块面积相关（P=0.002），并与复杂斑块的发生相关（调整后的 OR 为 8.38，95%CI 为 2.39-29.33，P<0.001）。在 C 等位基因携带者中，高血压不是 CHD 相关 SCD 或 CAD 的显著危险因素，与冠状动脉粥样硬化斑块的发展无关。根据从存活患者获得的动脉粥样硬化组织样本的基因表达分析，高血压还与 IL-18 基因型显著相互作用，影响 IL-18（P=0.030）和干扰素-γ（P=0.004）mRNA 的表达。
高血压与 IL-18 基因启动子-137 G/C 多态性相互作用，影响 SCD 和冠状动脉粥样硬化的发生风险。
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