Background and aim of the study: 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.

Methods: 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.

Results: 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).

Conclusion: 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.