Centre de Recherche Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada.
Am J Cardiol. 2011 Nov 1;108(9):1305-10. doi: 10.1016/j.amjcard.2011.06.050. Epub 2011 Aug 18.
Only a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis (AS). The goal of this study was to validate genes previously associated with AS. Seven genes were assessed: APOB, APOE, CTGF, IL10, PTH, TGFB1, and VDR. Each gene was tested for a comprehensive set of single-nucleotide polymorphisms (SNPs). SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement, and allele frequencies were compared to 3,294 controls. A missense mutation in the APOB gene was significantly associated with AS (rs1042031, E4181K, p = 0.00001). A second SNP located 5.6 kilobases downstream of the APOB stop codon was also associated with the disease (rs6725189, p = 0.000013). Six SNPs surrounding the IL10 locus were strongly associated with AS (0.02 > p > 6.2 × 10⁻¹¹). The most compelling association for IL10 was found with a promoter polymorphism (rs1800872) well known to regulate the production of the encoded anti-inflammatory cytokine. The frequency of the low-producing allele was greater in cases compared to controls (30% vs 20%, p = 6.2 × 10⁻¹¹). SNPs in PTH, TGFB1, and VDR had nominal p values <0.05 but did not resist Bonferroni correction. In conclusion, this study suggests that subjects carrying specific polymorphisms in the IL10 and APOB genes are at higher risk for developing AS.
仅有少数研究试图阐明钙化性主动脉瓣狭窄（AS）的遗传结构。本研究的目的是验证先前与 AS 相关的基因。评估了七个基因：APOB、APOE、CTGF、IL10、PTH、TGFB1 和 VDR。每个基因都测试了一套全面的单核苷酸多态性（SNP）。在 457 名接受主动脉瓣置换手术的患者中对 SNPs 进行了基因分型，并将等位基因频率与 3294 名对照进行了比较。APOB 基因中的错义突变与 AS 显著相关（rs1042031，E4181K，p = 0.00001）。APOB 终止密码子下游 5.6 千碱基处的第二个 SNP 也与该疾病相关（rs6725189，p = 0.000013）。围绕 IL10 基因座的六个 SNP 与 AS 强烈相关（0.02 > p > 6.2 × 10⁻¹¹）。IL10 最引人注目的关联是发现与启动子多态性（rs1800872）有关，该多态性已知可调节编码抗炎细胞因子的产生。与对照组相比，病例中低产生等位基因的频率更高（30%对 20%，p = 6.2 × 10⁻¹¹）。PTH、TGFB1 和 VDR 的 SNP 具有名义 p 值 <0.05，但未通过 Bonferroni 校正。总之，本研究表明，IL10 和 APOB 基因携带特定多态性的受试者发生 AS 的风险更高。
