79
views
0
recommends
+1 Recommend
0 collections
    8
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Genetic associations with valvular calcification and aortic stenosis.

      The New England journal of medicine

      Aged, Aortic Valve, pathology, radiography, Aortic Valve Stenosis, ethnology, genetics, Calcinosis, Female, Genome-Wide Association Study, Heart Valve Diseases, Humans, Linear Models, Lipoprotein(a), Male, Mendelian Randomization Analysis, Middle Aged, Mitral Valve, Polymorphism, Single Nucleotide, Tomography, X-Ray Computed

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

          Related collections

          Most cited references 31

          • Record: found
          • Abstract: found
          • Article: not found

          Mutations in NOTCH1 cause aortic valve disease.

          Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study.

            Calcified coronary artery plaque, measured at cardiac computed tomography (CT), is a predictor of cardiovascular disease and may play an increasing role in cardiovascular disease risk assessment. The Multi-Ethnic Study of Atherosclerosis (MESA) and the Coronary Artery Risk Development in Young Adults (CARDIA) study of the National Heart, Lung, and Blood Institute are population-based studies in which calcified coronary artery plaque was measured with electron-beam and multi-detector row CT and a standardized protocol in 6814 (MESA) and 3044 (CARDIA study) participants. The studies were approved by the appropriate institutional review board from the study site or agency, and written informed consent was obtained from each participant. Participation in the CT examination was high, image quality was good, and agreement for the presence of calcified plaque was high (kappa = 0.92, MESA; kappa = 0.77, CARDIA study). Extremely high agreement was observed between and within CT image analysts for the presence (kappa > 0.90, all) and amount (intraclass correlation coefficients, >0.99) of calcified plaque. Measurement of calcified coronary artery plaque with cardiac CT is well accepted by participants and can be implemented with consistently high-quality results with a standardized protocol and trained personnel. If predictive value of calcified coronary artery plaque for cardiovascular events proves sufficient to justify screening a segment of the population, then a standardized cardiac CT protocol is feasible and will provide reproducible results for health care providers and the public. (c) RSNA, 2005.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Age, Gene/Environment Susceptibility-Reykjavik Study: multidisciplinary applied phenomics.

              In anticipation of the sequencing of the human genome and description of the human proteome, the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) was initiated in 2002. AGES-Reykjavik was designed to examine risk factors, including genetic susceptibility and gene/environment interaction, in relation to disease and disability in old age. The study is multidisciplinary, providing detailed phenotypes related to the cardiovascular, neurocognitive (including sensory), and musculoskeletal systems, and to body composition and metabolic regulation. Relevant quantitative traits, subclinical indicators of disease, and medical diagnoses are identified by using biomarkers, imaging, and other physiologic indicators. The AGES-Reykjavik sample is drawn from an established population-based cohort, the Reykjavik Study. This cohort of men and women born between 1907 and 1935 has been followed in Iceland since 1967 by the Icelandic Heart Association. The AGES-Reykjavik cohort, with cardiovascular risk factor assessments earlier in life and detailed late-life phenotypes of quantitative traits, will create a comprehensive study of aging nested in a relatively genetically homogeneous older population. This approach should facilitate identification of genetic factors that contribute to healthy aging as well as the chronic conditions common in old age.
                Bookmark

                Author and article information

                Journal
                3766627
                23388002
                10.1056/NEJMoa1109034

                Comments

                Comment on this article