Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Yu Chen Hao, Dina Christian, Small Aeron M, Shaffer Christian M, Levinson Rebecca T, Helgadóttir Anna, Capoulade Romain, Munter Hans Markus, Martinsson Andreas, Cairns Benjamin J, Trudsø Linea C, Hoekstra Mary, Burr Hannah A, Marsh Thomas W, Damrauer Scott M, Dufresne Line, Le Scouarnec Solena, Messika-Zeitoun David, Ranatunga Dilrini K, Whitmer Rachel A, Bonnefond Amélie, Sveinbjornsson Garðar, Daníelsen Ragnar, Arnar David O, Thorgeirsson Gudmundur, Thorsteinsdottir Unnur, Gudbjartsson Daníel F, Hólm Hilma, Ghouse Jonas, Olesen Morten Salling, Christensen Alex H, Mikkelsen Susan, Jacobsen Rikke Louise, Dowsett Joseph, Pedersen Ole Birger Vesterager, Erikstrup Christian, Ostrowski Sisse R, Regeneron Genetics Center, O'Donnell Christopher J, Budoff Matthew J, Gudnason Vilmundur, Post Wendy S, Rotter Jerome I, Lathrop Mark, Bundgaard Henning, Johansson Bengt, Ljungberg Johan, Näslund Ulf, Le Tourneau Thierry, Smith J Gustav, Wells Quinn S, Söderberg Stefan, Stefánsson Kári, Schott Jean-Jacques, Rader Daniel J, Clarke Robert, Engert James C, Thanassoulis George
Аннотация
METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.
CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.