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.
Replication of previous findings in an independent cohort is the gold standard in genetic association studies. The goal of this study was to replicate genes previously associated with aortic valve stenosis (AS). Seven genes were considered: APOB, APOE, CTGF, IL10, PTH, TGFB1, and VDR. A comprehensive set of single-nucleotide polymorphisms (SNPs) from the published research covering the common genetic variants of each gene were genotyped in a group of 457 patients with severe AS. Allele frequencies of patients were compared to a publically available control group of the same genetic ancestry.
Methods
Blood samples were collected from 457 patients with severe AS who underwent aortic valve replacement. All patients were recruited at Institut Universitaire de Cardiologie et de Pneumologie de Québec (Quebec City, Quebec, Canada) and were French Canadians, known as a homogenous population of European ancestry. The primary indication of surgery was the presence of severe tricuspid nonrheumatic AS. Two hundred thirty-one patients (50.5%) also underwent concomitant coronary artery bypass grafting. Patients with previous cardiac surgery, greater than mild aortic regurgitation, or concomitant disease on other valves were excluded. Several anthropometric indexes were measured before surgery. Waist circumference was obtained using a measuring tape directly on the skin with the subject standing. Measurements were taken at the end of expiration at the level midway between the lower rib margin and the iliac crest. Body surface area was obtained using the formula of Dubois and Dubois. Body mass index was calculated as weight divided by the square of height. All patients underwent comprehensive Doppler echocardiographic examinations before surgery. Aortic valve area was calculated using the continuity equation, and the mean transvalvular gradient was calculated using the Bernoulli equation. Type 2 diabetes was abstracted from medical charts for patients with established diagnoses currently receiving oral hypoglycemic medication or insulin. Table 1 lists the characteristics of these patients. All patients provided written informed consent for the realization of genetic studies, and the study was approved by the local ethics committee.
| Variable | Men (n = 259 [57%]) | Women (n = 198 [43%]) |
|---|---|---|
| Age (years) | 70.7 ± 9.0 | 73.9 ± 7.9 |
| Weight (kg) | 78.5 ± 13.5 | 68.6 ± 14.8 |
| Waist circumference (cm) (n = 395) | 102.4 ± 12.0 | 98.5 ± 14.7 |
| Body surface area (m 2 ) | 1.9 ± 0.2 | 1.7 ± 0.2 |
| Body mass index (kg/m 2 ) | 27.7 ± 4.3 | 28.7 ± 6.1 |
| Mean transvalvular gradient (mm Hg) (n = 364) | 40.8 ± 16.5 | 42.6 ± 16.3 |
| Peak systolic gradient (mm Hg) (n = 360) | 67.4 ± 25.5 | 70.3 ± 25.1 |
| Aortic valve area (cm 2 ) (n = 449) | 0.82 ± 0.24 | 0.68 ± 0.20 |
| Indexed aortic valve area (cm 2 /m 2 ) (n = 449) | 0.44 ± 0.13 | 0.41 ± 0.12 |
| Mild aortic valve regurgitation | 178 (68.7%) | 130 (65.7%) |
| Left ventricular hypertrophy ⁎ | 71 (38.6%) | 50 (37.0%) |
| Coronary artery disease † | 162 (62.5%) | 82 (41.4%) |
| Hypercholesterolemia ‡ | 211 (81.5%) | 152 (76.8%) |
| Hypertension § | 172 (66.4%) | 150 (75.8%) |
| Diabetes mellitus | 68 (26.3%) | 63 (31.8%) |
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