title: Replication of genetic association studies in aortic stenosis in adults.
abstract: 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.
authors.affiliation: Centre de Recherche Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.forename: Valérie
authors.initials: V
authors.lastname: Ducharme
authors.forename: Maxime
authors.initials: M
authors.lastname: Lamontagne
authors.forename: Sandra
authors.initials: S
authors.lastname: Guauque-Olarte
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000235:genetics*; D001055:Apolipoproteins B / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D055513:Connective Tissue Growth Factor / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010281:Parathyroid Hormone / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics; D012720:Severity of Illness Index; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; C526317:CCN2 protein, human; C470125:PTH protein, human; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D055513:Connective Tissue Growth Factor