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Genome-wide analysis yields new loci associating with aortic valve stenosis.

ABSTRACT: Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR)?=?1.20, P?=?1.2?×?10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR?=?1.15, P?=?1.8?×?10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR?=?1.28, P?=?6.6?×?10-10) and aortic root diameter (P?=?1.30?×?10-8), and rs1830321 associates with BAV (OR?=?1.12, P?=?5.3?×?10-3) and coronary artery disease (OR?=?1.05, P?=?9.3?×?10-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.

SUBMITTER: Helgadottir A

PROVIDER: S-EPMC5840367 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Genome-wide analysis yields new loci associating with aortic valve stenosis.

Helgadottir Anna A Thorleifsson Gudmar G Gretarsdottir Solveig S Stefansson Olafur A OA Tragante Vinicius V Thorolfsdottir Rosa B RB Jonsdottir Ingileif I Bjornsson Thorsteinn T Steinthorsdottir Valgerdur V Verweij Niek N Nielsen Jonas B JB Zhou Wei W Folkersen Lasse L Martinsson Andreas A Heydarpour Mahyar M Prakash Siddharth S Oskarsson Gylfi G Gudbjartsson Tomas T Geirsson Arnar A Olafsson Isleifur I Sigurdsson Emil L EL Almgren Peter P Melander Olle O Franco-Cereceda Anders A Hamsten Anders A Fritsche Lars L Lin Maoxuan M Yang Bo B Hornsby Whitney W Guo Dongchuan D Brummett Chad M CM Abecasis Gonçalo G Mathis Michael M Milewicz Dianna D Body Simon C SC Eriksson Per P Willer Cristen J CJ Hveem Kristian K Newton-Cheh Christopher C Smith J Gustav JG Danielsen Ragnar R Thorgeirsson Gudmundur G Thorsteinsdottir Unnur U Gudbjartsson Daniel F DF Holm Hilma H Stefansson Kari K

Nature communications 20180307 1

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10<sup>-22</sup>) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 ...[more]

PMID: 29511194

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Project description:BackgroundAortic valve stenosis is the most common type of valvular heart disease in the USA and Europe. Aortic valve stenosis is considered similar to atherosclerotic disease. Some studies have evaluated statins for aortic valve stenosis.ObjectivesTo evaluate the effectiveness and safety of statins in aortic valve stenosis.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS - IBECS, Web of Science and CINAHL Plus. These databases were searched from their inception to 24 November 2015. We also searched trials in registers for ongoing trials. We used no language restrictions.Selection criteriaRandomised controlled clinical trials (RCTs) comparing statins alone or in association with other systemic drugs to reduce cholesterol levels versus placebo or usual care.Data collection and analysisPrimary outcomes were severity of aortic valve stenosis (evaluated by echocardiographic criteria: mean pressure gradient, valve area and aortic jet velocity), freedom from valve replacement and death from cardiovascular cause. Secondary outcomes were hospitalisation for any reason, overall mortality, adverse events and patient quality of life.Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. The GRADE methodology was employed to assess the quality of result findings and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 to create a 'Summary of findings' table.Main resultsWe included four RCTs with 2360 participants comparing statins (1185 participants) with placebo (1175 participants). We found low-quality evidence for our primary outcome of severity of aortic valve stenosis, evaluated by mean pressure gradient (mean difference (MD) -0.54, 95% confidence interval (CI) -1.88 to 0.80; participants = 1935; studies = 2), valve area (MD -0.07, 95% CI -0.28 to 0.14; participants = 127; studies = 2), and aortic jet velocity (MD -0.06, 95% CI -0.26 to 0.14; participants = 155; study = 1). Moderate-quality evidence showed no effect on freedom from valve replacement with statins (risk ratio (RR) 0.93, 95% CI 0.81 to 1.06; participants = 2360; studies = 4), and no effect on muscle pain as an adverse event (RR 0.91, 95% CI 0.75 to 1.09; participants = 2204; studies = 3; moderate-quality evidence). Low- and very low-quality evidence showed uncertainty around the effect of statins on death from cardiovascular cause (RR 0.80, 95% CI 0.56 to 1.15; participants = 2297; studies = 3; low-quality evidence) and hospitalisation for any reason (RR 0.84, 95% CI 0.39 to 1.84; participants = 155; study = 1; very low-quality evidence). None of the four included studies reported on overall mortality and patient quality of life.Authors' conclusionsResult findings showed uncertainty surrounding the effect of statins for aortic valve stenosis.The quality of evidence from the reported outcomes ranged from moderate to very low. These results give support to European and USA guidelines (2012 and 2014, respectively) that so far there is no clinical treatment option for aortic valve stenosis.

Project description:BackgroundStudies assessing outcomes of transcatheter aortic valve replacement (TAVR) in patients with severe aortic valve stenosis (AS) with hemodynamic subtypes have demonstrated mixed results with respect to outcomes and periprocedural complications. This study aimed to assess the outcomes of TAVR in patients across various hemodynamic subtypes of severe AS.MethodsPubMed, Embase, and Cochrane databases were searched through September 2023 to identify all observational studies comparing outcomes of TAVR in patients with paradoxical low flow low gradient (pLFLG), classic LFLG, and high gradient AS (HGAS). The primary outcome was major adverse cardiovascular events (MACE). The secondary outcomes were components of MACE (mortality, myocardial infarction [MI], stroke). A bivariate, influential, and frequentist network meta-analysis model was used to obtain the net odds ratio (OR) with a 95% CI.ResultsA total of 21 studies comprising 17,298 (8742 experimental and 8556 HGAS) patients were included in the quantitative analysis. TAVR was associated with a significant reduction in the mean aortic gradient, and an increase in the mean aortic valve area irrespective of the AS type. Compared with HGAS, TAVR in classic LFLG had a significantly higher (OR, 1.68; 95% CI, 1.04-2.72), while pLFLG (OR, 0.98; 95% CI, 0.72-1.35) had a statistically similar incidence of MACE at a median follow-up of 1-year. TAVR in LFLG also had a significantly higher need for surgery (OR, 3.57; 95% CI, 1.24-10.32), and a greater risk of periprocedural (OR, 2.00; 95% CI, 1.17-3.41), 1-month (OR, 1.69; 95% CI, 1.08-2.64), and 12-month (OR, 1.41; 95% CI, 1.05-1.88) mortality compared with HGAS. The incidence of MI, major bleeding, vascular complications, paravalvular leak, pacemaker implantation, and rehospitalizations was not significantly different between all other types of AS (HGAS vs LFLG, pLFLG).ConclusionsTAVR is an effective strategy in severe AS irrespective of the hemodynamic subtypes. Relatively, pLFLG did not have significantly different risk of periprocedural complications compared with HGAS, while classical LFLG AS had higher risk of MACE, primarily driven by the greater mortality risk.

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Genome-wide analysis yields new loci associating with aortic valve stenosis.

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Genome-wide analysis yields new loci associating with aortic valve stenosis.

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