Ducharme Valérie, Guauque-Olarte Sandra, Gaudreault Nathalie, Pibarot Philippe, Mathieu Patrick, Bossé Yohan
Centre de recherche Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec, Canada.
J Heart Valve Dis. 2013 Mar;22(2):142-9.
Calcific aortic valve stenosis (AS) affects 2-5% of the population aged > 65 years. Functional DNA variants at the NOTCH1 locus result in bicuspid aortic valve (BAV) and severe valve calcification. The contribution of these variants to AS in the population with tricuspid aortic valve (TAV) remains to be determined.
Fourteen genetic variants surrounding the NOTCH1 gene were genotyped, including rare mutations previously reported, and common polymorphisms. The study involved 457 French Canadian patients with severe tricuspid AS. Genotyping was carried out using the Illumina BeadXpress platform. Allele frequencies of common single nucleotide polymorphisms (SNPs) for patients with AS were compared to a shared control group of European ancestry (n = 3,294). In total, 88 ancestry-informative markers were used to correct for population stratification.
The mutation R1107X, previously associated with AS and BAV, was identified in a relatively young patient (aged 58 years). The mutations R1279H and V2285I were detected in 18 and 14 heterozygotes, respectively. A common polymorphism (rs13290979) located in intron 2 was significantly associated with AS (p = 0.003), which remained significant after correction for multiple testing. However, this association was no longer significant after accounting for population stratification (p = 0.088).
In this study, rare functional variants were found in the NOTCH1 gene in a French Canadian population of patients with severe tricuspid AS. This also suggests, for the first time, the presence of a common polymorphism in this gene conferring susceptibility to AS.
钙化性主动脉瓣狭窄（AS）影响2%至5%的65岁以上人群。NOTCH1基因座的功能性DNA变异会导致二叶式主动脉瓣（BAV）和严重的瓣膜钙化。这些变异对三尖瓣主动脉瓣（TAV）人群中AS的影响尚待确定。
对NOTCH1基因周围的14个遗传变异进行基因分型，包括先前报道的罕见突变和常见多态性。该研究纳入了457名法裔加拿大严重三尖瓣AS患者。使用Illumina BeadXpress平台进行基因分型。将AS患者常见单核苷酸多态性（SNP）的等位基因频率与欧洲血统的共享对照组（n = 3294）进行比较。总共使用88个祖先信息标记来校正人群分层。
在一名相对年轻的患者（58岁）中发现了先前与AS和BAV相关的R1107X突变。分别在18名和14名杂合子中检测到R1279H和V2285I突变。位于内含子2中的一个常见多态性（rs13290979）与AS显著相关（p = 0.003），在多重检验校正后仍具有显著性。然而，在考虑人群分层后，这种关联不再显著（p = 0.088）。
在这项研究中，在法裔加拿大严重三尖瓣AS患者群体的NOTCH1基因中发现了罕见的功能性变异。这也首次表明该基因中存在一种常见多态性，赋予了对AS的易感性。
