Vainas Tryfon, Stassen Frank R M, Bruggeman Cathrien A, Welten Rob J Th J, van den Akker Luc H J M, Kitslaar Peter J E H M, Peña Amado S, Morré Servaas A
Department of Surgery, Maastricht University Hospital, Maastricht, The Netherlands.
J Vasc Surg. 2006 Aug;44(2):326-32. doi: 10.1016/j.jvs.2006.04.035.
Genes involved in the regulation of immune responses, such as Toll-like receptor 4 (TLR4) and CD14, show genetic variations with potential functional implications. Because atherosclerosis is an inflammatory process apparently modulated by chronic infections, we studied the effect of single nucleotide polymorphisms (SNPs) in TLR4 and CD14 on the extent of clinically relevant atherosclerosis in patients with peripheral arterial disease (PAD).
Using an in-house-developed polymerase chain reaction-based restriction length polymorphism assay, we determined the genotype, allele frequency, and carrier traits of the TLR4 +896 A>G and the CD14 -260 C>T SNPs in 607 white Dutch patients with PAD. The extent of clinically relevant atherosclerosis was determined on the basis of the number of vascular territories involved, ie, coronary, cerebral, aortic, and peripheral.
A total of 55% of the patients had PAD only. Approximately one third of the patients had two and 11% had three vascular territories affected by clinically relevant atherosclerosis. The TLR4 +866 G allele frequency was 11%, and the CD14 -260 T allele frequency was approximately 74%. Among PAD patients, TLR4 +896 G allele carriership was univariantly associated with extensive (more than two vascular territories affected) atherosclerotic disease (odds ratio, 2.22; P = .020; chi(2) test), whereas CD14 -260 C>T carriership/homozygosity was not. Trend analysis showed that the TLR4 +866 G allele frequency increased with the number of vascular territories affected by clinically relevant atherosclerosis (P trend, .0074). In a multivariate logistic regression analysis including cardiovascular risk factors and TLR4 and CD14 SNPs, only the interaction variable "TLR4 +896 G allele carriership/CD14 -260 TT genotype" survived as an independent predictor of extensive atherosclerotic disease (P = .031; odds ratio, 4.2; 95% confidence interval, 1.1-15.4).
The carrier trait TLR4 G allele/CD14 TT genotype, rather than each SNP individually, is associated with the extent of clinically relevant atherosclerotic disease. Considering the importance of immune responses in atherogenesis and the genetic variation of immune regulatory genes, our data provide an explanation for interindividual differences in susceptibility to atherosclerosis and demonstrate the need to take a wider approach in analyzing relevant carrier traits instead of individual polymorphisms in relation to atherosclerosis.
参与免疫反应调节的基因，如Toll样受体4（TLR4）和CD14，存在具有潜在功能影响的基因变异。由于动脉粥样硬化是一个明显受慢性感染调节的炎症过程，我们研究了TLR4和CD14中的单核苷酸多态性（SNP）对周围动脉疾病（PAD）患者临床相关动脉粥样硬化程度的影响。
我们使用内部开发的基于聚合酶链反应的限制性片段长度多态性分析方法，确定了607名荷兰白人PAD患者中TLR4 +896 A>G和CD14 -260 C>T SNP的基因型、等位基因频率和携带者特征。根据涉及的血管区域数量，即冠状动脉、脑动脉、主动脉和外周动脉，确定临床相关动脉粥样硬化的程度。
共有55%的患者仅患有PAD。约三分之一的患者有两个血管区域受累，11%的患者有三个血管区域受临床相关动脉粥样硬化影响。TLR4 +866 G等位基因频率为11%，CD14 -260 T等位基因频率约为74%。在PAD患者中，TLR4 +896 G等位基因携带者单变量分析与广泛（超过两个血管区域受累）动脉粥样硬化疾病相关（优势比，2.22；P = 0.020；卡方检验），而CD14 -260 C>T携带者/纯合子则无此关联。趋势分析表明，TLR4 +866 G等位基因频率随着临床相关动脉粥样硬化受累血管区域数量的增加而升高（P趋势，0.0074）。在包括心血管危险因素以及TLR4和CD14 SNP的多变量逻辑回归分析中，只有交互变量“TLR4 +896 G等位基因携带者/CD14 -260 TT基因型”作为广泛动脉粥样硬化疾病的独立预测因子保留下来（P = 0.031；优势比，4.2；95%置信区间，1.1 - 15.4）。
携带者特征TLR4 G等位基因/CD14 TT基因型，而非单独的每个SNP，与临床相关动脉粥样硬化疾病的程度相关。考虑到免疫反应在动脉粥样硬化发生中的重要性以及免疫调节基因的遗传变异，我们的数据为个体对动脉粥样硬化易感性的差异提供了解释，并表明在分析与动脉粥样硬化相关的相关携带者特征而非个体多态性时需要采用更广泛的方法。
