A Replicated, Genome-Wide Significant Association of Aortic Stenosis With a Genetic Variant for Lipoprotein(a)
2017; Lippincott Williams & Wilkins; Volume: 135; Issue: 12 Linguagem: Inglês
10.1161/circulationaha.116.026103
ISSN1524-4539
AutoresBenjamin J. Cairns, Sean Coffey, Ruth C. Travis, Bernard Prendergast, Jane Green, James C. Engert, Mark Lathrop, George Thanassoulis, Robert Clarke,
Tópico(s)Aortic Thrombus and Embolism
ResumoHomeCirculationVol. 135, No. 12A Replicated, Genome-Wide Significant Association of Aortic Stenosis With a Genetic Variant for Lipoprotein(a) Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBA Replicated, Genome-Wide Significant Association of Aortic Stenosis With a Genetic Variant for Lipoprotein(a)Meta-Analysis of Published and Novel Data Benjamin J. Cairns, PhD, Sean Coffey, PhD, MBBS, Ruth C. Travis, DPhil, Bernard Prendergast, DM, Jane Green, DPhil, James C. Engert, PhD, Mark Lathrop, PhD, George Thanassoulis, MD, MSc and Robert Clarke, MD Benjamin J. CairnsBenjamin J. Cairns From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). , Sean CoffeySean Coffey From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). , Ruth C. TravisRuth C. Travis From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). , Bernard PrendergastBernard Prendergast From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). , Jane GreenJane Green From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). , James C. EngertJames C. Engert From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). , Mark LathropMark Lathrop From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). , George ThanassoulisGeorge Thanassoulis From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). and Robert ClarkeRobert Clarke From Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (B.J.C., R.C.T., J.G.); British Heart Foundation Centre of Research Excellence, University of Oxford, United Kingdom (B.J.C.); Kolling Institute, University of Sydney, Australia (S.C.); Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (S.C.); Guy's and St Thomas' Hospitals, London, United Kingdom (B.P.); Department of Medicine, McGill University, Montreal, QC, Canada (J.C.E., G.T.); McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada (M.L.); Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, QC, Canada (G.T.); and Clinical Trial Service Unit and Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (R.C.). Originally published21 Mar 2017https://doi.org/10.1161/CIRCULATIONAHA.116.026103Circulation. 2017;135:1181–1183Trials of dedicated lipoprotein(a) (Lp(a))-lowering agents1 have refocused interest on Lp(a) as a causal risk factor for coronary artery disease (CAD), and potentially for aortic valve stenosis (AS). Elevated plasma Lp(a) concentrations have been linked to causal variants for CAD (chiefly rs10455872 and rs3798220) at the LPA locus on chromosome 6q26-27.2 The rs10455872 variant is also the sole genome-wide significant variant associated with aortic valve calcium.3 Several small studies have tentatively replicated this association, not only for aortic valve calcium, which does not necessarily cause functional impairment of the valve, but also for clinically relevant AS.3–5 However, none of these studies has definitively established that rs10455872 is associated with clinically relevant AS. We conducted a meta-analysis of associations of rs10455872 and rs3798220 variants with AS by using evidence from all published studies, together with novel data from the UK Biobank.Approximately 152 000 UK Biobank participants had rs10455872 and rs3798220 assayed using Affymetrix Axiom arrays. All participants gave written informed consent to a protocol approved by the North West Multicentre Research Ethics Committee (UK). Genotype data were available for 112 186 eligible participants after exclusions for genomic quality control, genotype missingness, sex mismatch, relatedness, and non–British Caucasian ancestry. Minor allele frequencies were 0.08 for rs10455872 (G allele) and 0.02 for rs3798220 (C allele), there was no evidence of deviations from the Hardy-Weinberg equilibrium, and the variants were independent (linkage disequilibrium r2=0.0015). We identified 535 cases of nonrheumatic AS (International Classification of Diseases, 10th Revision: I35.0 and I35.2) from hospital and death records, and matched each case to up to 20 controls, by sex, age, and recruitment center (total, 10 617 controls). Among the 535 AS cases, 259 (48%) had aortic valve replacement at or after AS diagnosis, and 263 (49%) had concomitant CAD, whereas proportionally fewer controls (1434/10 617, 14%) had any evidence of CAD. Odds ratios were estimated by logistic regression, adjusting for sex, age, center, genotyping batch, and the first 10 principal components of genotype.Searching EMBASE and MEDLINE (Ovid and PubMed) and cited reference lists, we identified published studies of LPA variants and AS: the MDCS (Malmö Diet and Cancer Study)3; combined analysis of the CCHS (Copenhagen City Heart Study) and CGPS (Copenhagen General Population Survey)4; and, separately, the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study, and the MHI (Montreal Heart Institute) Biobank.5 In the MHI Biobank, cases were ascertained by echocardiography, whereas all other studies used coded electronic health records. Published estimates were converted to per-allele relative risks (RRs) by weighted regression. Under the rare disease assumption, odds ratios were treated as relative risks. All studies reported estimates for rs10455872.3–5 Only CCHS and CGPS reported an estimate for rs3798220.4 Estimates were combined by fixed-effect meta-analysis.Results are shown in the Figure. Combining previous studies only, AS was significantly associated with rs10455872 at the genome-wide level (RR, 1.65; 95% confidence interval [CI], 1.43–1.90; P=4×10–12; I2=0% for heterogeneity). In CCHS and CGPS, AS was not associated with rs3798220. In UK Biobank, AS was associated both with rs10455872 (RR, 1.69; 95% CI, 1.39–2.05; P=1×10–7) and with rs3798220 (RR, 1.63; 95% CI, 1.11–2.38; P=1×10–2). Combined analysis of previous studies with UK Biobank gave summary RRs of 1.66 (95% CI, 1.48–1.86; P=2×10–18; I2=0%) for rs10455872 and 1.43 (95% CI, 1.04–1.99; P=3×10–2; I2=39%) for rs3798220. A random-effect model for rs3798220 gave an RR of 1.37 (95% CI, 0.87–2.16; P=2×10–1).Download figureDownload PowerPointFigure. Meta-analysis of aortic stenosis risk in relation to LPA variants rs10455872 and rs3798220. Each individual study estimate is represented as a square, with area proportional to the inverse of its variance, which is its weight in the fixed-effect meta-analysis; summary estimates are shown as diamonds. CCHS indicates Copenhagen City Heart Study; CGPS, Copenhagen General Population Survey; CI, confidence interval; EPIC, European Prospective Investigation into Cancer and Nutrition; het, heterogeneity; MDCS, Malmö Diet and Cancer Study; and MHI, Montreal Heart Institute.Plasma Lp(a) is a recognized risk factor for AS, but rs10455872 is the first genetic variant affecting Lp(a) levels to be robustly linked to the disease, with genome-wide significance in published studies and replication in the UK Biobank. The association of rs10455872 with AS was highly consistent between studies, although estimates of absolute differences in plasma Lp(a) by rs10455872 genotype have varied between about 20 and 50 mg/dL per minor allele.3–5 Together with our meta-analysis, these estimates suggest a 10% to 30% greater risk of AS per 10 mg/dL greater genetically determined Lp(a) level. However, absolute risks of AS associated with particular Lp(a) concentrations have yet to be elucidated, particularly in the context of concomitant CAD. The relative risk for AS per minor allele of rs10455872 was similar to that for CAD,2,3 consistent with an independent effect, but further studies are required to clarify the relationships between CAD and AS. AS risk may also be related to rs3798220, but there was limited statistical power for this low-frequency variant.The strong and consistent associations of rs10455872 with AS risk confirm a probable causal role of high plasma Lp(a) in clinically relevant AS, in addition to its previously reported association with aortic valve calcium. This study also provides strong support for Lp(a) as a therapeutic target for AS prevention. Novel Lp(a)-lowering agents can substantially reduce Lp(a) levels,1 and further development of these agents will be aided by better quantification of the relationships between LPA variants, plasma Lp(a) levels, and AS risk. Continued genetic discovery may reveal additional therapeutic targets to prevent or slow the progression of aortic stenosis.Benjamin J. Cairns, PhDSean Coffey, PhD, MBBSRuth C. Travis, DPhilBernard Prendergast, DMJane Green, DPhilJames C. Engert, PhDMark Lathrop, PhD*George Thanassoulis, MD, MSc*Robert Clarke, MD*AcknowledgmentsThis research has been conducted using the UK Biobank resource (Application 1153). The UK Biobank data used in this study is available to bona fide researchers on application (http://www.ukbiobank.ac.uk/register-apply). All authors contributed to the design of the study. Dr Cairns analyzed the data and wrote the first draft of the manuscript. All authors contributed to interpreting the data and to critically revising the manuscript for intellectual content.Sources of FundingThis research was supported by funding to Dr Cairns from the British Heart Foundation Center of Research Excellence, Oxford (British Heart Foundation grant number RE/13/1/30181).DisclosuresDr Thanassoulis has participated in Advisory Boards for Amgen and Ionis Pharmaceuticals and is a consultant to Ionis Pharmaceuticals. The other authors report no conflicts of interest.Footnotes*Prof Lathrop, Dr Thanassoulis, and Prof Clarke each contributed equally to this work.Circulation is available at http://circ.ahajournals.org.Correspondence to: Benjamin J. Cairns, PhD, Cancer Epidemiology Unit, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom. E-mail [email protected]References1. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke ST, Witztum JL, Stroes ES, Tsimikas S. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.Lancet. 2016; 388:2239–2253. doi: 10.1016/S0140-6736(16)31009-1.CrossrefMedlineGoogle Scholar2. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N Engl J Med. 2009; 361:2518–2528. doi: 10.1056/NEJMoa0902604.CrossrefMedlineGoogle Scholar3. Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, Kerr KF, Pechlivanis S, Budoff MJ, Harris TB, Malhotra R, O'Brien KD, Kamstrup PR, Nordestgaard BG, Tybjaerg-Hansen A, Allison MA, Aspelund T, Criqui MH, Heckbert SR, Hwang SJ, Liu Y, Sjogren M, van der Pals J, Kälsch H, Mühleisen TW, Nöthen MM, Cupples LA, Caslake M, Di Angelantonio E, Danesh J, Rotter JI, Sigurdsson S, Wong Q, Erbel R, Kathiresan S, Melander O, Gudnason V, O'Donnell CJ, Post WS; CHARGE Extracoronary Calcium Working Group. Genetic associations with valvular calcification and aortic stenosis.N Engl J Med. 2013; 368:503–512. doi: 10.1056/NEJMoa1109034.CrossrefMedlineGoogle Scholar4. Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population.J Am Coll Cardiol. 2014; 63:470–477. doi: 10.1016/j.jacc.2013.09.038.CrossrefMedlineGoogle Scholar5. Arsenault BJ, Boekholdt SM, Dubé MP, Rhéaume E, Wareham NJ, Khaw KT, Sandhu MS, Tardif JC. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort.Circ Cardiovasc Genet. 2014; 7:304–310. doi: 10.1161/CIRCGENETICS.113.000400.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Nsaibia M, Devendran A, Goubaa E, Bouitbir J, Capoulade R and Bouchareb R (2022) Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail?, Journal of Clinical Medicine, 10.3390/jcm11123331, 11:12, (3331) Kaltoft M, Sigvardsen P, Afzal S, Langsted A, Fuchs A, Kühl J, Køber L, Kamstrup P, Kofoed K and Nordestgaard B (2022) Elevated lipoprotein(a) in mitral and aortic valve calcification and disease: The Copenhagen General Population Study, Atherosclerosis, 10.1016/j.atherosclerosis.2021.11.029, 349, (166-174), Online publication date: 1-May-2022. Liu Q, Yu Y, Xi R, Li J, Lai R, Wang T, Fan Y, Zhang Z, Xu H and Ju J (2022) Association Between Lipoprotein(a) and Calcific Aortic Valve Disease: A Systematic Review and Meta-Analysis, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2022.877140, 9 Koutsogianni A, Liberopoulos E, Tellis K and Tselepis A (2021) Oxidized phospholipids and lipoprotein(a): An update, European Journal of Clinical Investigation, 10.1111/eci.13710, 52:4, Online publication date: 1-Apr-2022. Melita H, Manolis A, Manolis T and Manolis A (2022) Lipoprotein(a) and Cardiovascular Disease: A Missing Link for Premature Atherosclerotic Heart Disease and/or Residual Risk, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000001160, 79:1, (e18-e35) Zebhi B, Lazkani M and Bark D (2021) Calcific Aortic Stenosis—A Review on Acquired Mechanisms of the Disease and Treatments, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.734175, 8 Nayor M, Shen L, Hunninghake G, Kochunov P, Barr R, Bluemke D, Broeckel U, Caravan P, Cheng S, de Vries P, Hoffmann U, Kolossváry M, Li H, Luo J, McNally E, Thanassoulis G, Arnett D and Vasan R (2021) Progress and Research Priorities in Imaging Genomics for Heart and Lung Disease: Summary of an NHLBI Workshop, Circulation: Cardiovascular Imaging, 14:8, Online publication date: 1-Aug-2021. Langsted A and Nordestgaard B (2021) Genetics of Lipoprotein(a): Cardiovascular Disease and Future Therapy, Current Atherosclerosis Reports, 10.1007/s11883-021-00937-0, 23:8, Online publication date: 1-Aug-2021. Afshar M, Yazdan-Ashoori S, Engert J and Thanassoulis G (2021) Drugs for Prevention and Treatment of Aortic Stenosis: How Close Are We?, Canadian Journal of Cardiology, 10.1016/j.cjca.2021.02.017, 37:7, (1016-1026), Online publication date: 1-Jul-2021. Kamstrup P (2020) Lipoprotein(a) and Cardiovascular Disease, Clinical Chemistry, 10.1093/clinchem/hvaa247, 67:1, (154-166), Online publication date: 8-Jan-2021. Kronenberg F (2021) Lipoprotein(a) Prevention and Treatment of Atherosclerosis, 10.1007/164_2021_504, (201-232), . Thanassoulis G (2020) Preventing Aortic Stenosis by Changing the Way We Think About an Old Disease, JAMA Cardiology, 10.1001/jamacardio.2020.0722, 5:6, (627), Online publication date: 1-Jun-2020. Chen H, Cairns B, Small A, Burr H, Ambikkumar A, Martinsson A, Thériault S, Munter H, Steffen B, Zhang R, Levinson R, Shaffer C, Rong J, Sonestedt E, Dufresne L, Ljungberg J, Näslund U, Johansson B, Ranatunga D, Whitmer R, Budoff M, Nguyen A, Vasan R, Larson M, Harris W, Damrauer S, Stark K, Boekholdt S, Wareham N, Pibarot P, Arsenault B, Mathieu P, Gudnason V, O'Donnell C, Rotter J, Tsai M, Post W, Clarke R, Söderberg S, Bossé Y, Wells Q, Smith J, Rader D, Lathrop M, Engert J and Thanassoulis G (2020) Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis , JAMA Cardiology, 10.1001/jamacardio.2020.0246, 5:6, (694), Online publication date: 1-Jun-2020. Capoulade R, Torzewski M, Mayr M, Chan K, Mathieu P, Bossé Y, Dumesnil J, Tam J, Teo K, Burnap S, Schmid J, Gobel N, Franke U, Sanchez A, Witztum J, Yang X, Yeang C, Arsenault B, Després J, Pibarot P and Tsimikas S (2020) ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis, Heart, 10.1136/heartjnl-2019-315840, 106:10, (738-745), Online publication date: 1-May-2020. Zheng K, Tzolos E and Dweck M (2020) Pathophysiology of Aortic Stenosis and Future Perspectives for Medical Therapy, Cardiology Clinics, 10.1016/j.ccl.2019.09.010, 38:1, (1-12), Online publication date: 1-Feb-2020. Ma G, Wilkinson M, Reeves R, Yeang C, DeMaria A, Cotter B, Patel M, Mahmud E and Tsimikas S (2019) Lipoprotein(a) in Patients Undergoing Transcatheter Aortic Valve Replacement, Angiology, 10.1177/0003319719826461, 70:4, (332-336), Online publication date: 1-Apr-2019. Chen H, Engert J and Thanassoulis G (2019) Risk factors for valvular calcification, Current Opinion in Endocrinology, Diabetes & Obesity, 10.1097/MED.0000000000000471, 26:2, (96-102), Online publication date: 1-Apr-2019. Kronenberg F (2019) Prediction of cardiovascular risk by Lp(a) concentrations or genetic variants within the LPA gene region, Clinical Research in Cardiology Supplements, 10.1007/s11789-019-00093-5, 14:S1, (5-12), Online publication date: 1-Apr-2019. Mathieu P and Boulanger M (2019) Autotaxin and Lipoprotein Metabolism in Calcific Aortic Valve Disease, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2019.00018, 6 Tsimikas S (2019) Potential Causality and Emerging Medical Therapies for Lipoprotein(a) and Its Associated Oxidized Phospholipids in Calcific Aortic Valve Stenosis, Circulation Research, 124:3, (405-415), Online publication date: 1-Feb-2019. Trenkwalder T, Nelson C, Musameh M, Mordi I, Kessler T, Pellegrini C, Debiec R, Rheude T, Lazovic V, Zeng L, Martinsson A, Gustav Smith J, Gådin J, Franco-Cereceda A, Eriksson P, Nielsen J, Graham S, Willer C, Hveem K, Kastrati A, Braund P, Palmer C, Aracil A, Husser O, Koenig W, Schunkert H, Lang C, Hengstenberg C and Samani N (2019) Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis, International Journal of Cardiology, 10.1016/j.ijcard.2018.11.094, 276, (212-217), Online publication date: 1-Feb-2019. Vuorio A, Watts G and Kovanen P (2019) Lipoprotein(a) as a risk factor for calcific aortic valvulopathy in heterozygous familial hypercholesterolemia, Atherosclerosis, 10.1016/j.atherosclerosis.2018.11.040, 281, (25-30), Online publication date: 1-Feb-2019. Nelson C, Lai F, Nath M, Ye S, Webb T, Schunkert H and Samani N (2019) Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors, Circulation: Genomic and Precision Medicine, 12:1, Online publication date: 1-Jan-2019. Capoulade R, Yeang C, Chan K, Pibarot P and Tsimikas S (2018) Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels, JAMA Cardiology, 10.1001/jamacardio.2018.3798, 3:12, (1212), Online publication date: 1-Dec-2018. Thanassoulis G (2018) Precision Medicine for Prosthetic Valve Deterioration, Journal of the American College of Cardiology, 10.1016/j.jacc.2018.04.065, 72:3, (252-254), Online publication date: 1-Jul-2018. Gardezi S, Coffey S, Prendergast B and Myerson S (2017) Serum biomarkers in valvular heart disease, Heart, 10.1136/heartjnl-2016-310482, 104:4, (349-358), Online publication date: 1-Feb-2018. Tsimikas S, Fazio S, Ferdinand K, Ginsberg H, Koschinsky M, Marcovina S, Moriarty P, Rader D, Remaley A, Reyes-Soffer G, Santos R, Thanassoulis G, Witztum J, Danthi S, Olive M and Liu L (2018) NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis, Journal of the American College of Cardiology, 10.1016/j.jacc.2017.11.014, 71:2, (177-192), Online publication date: 1-Jan-2018. Afshar M and Thanassoulis G (2018) Genetic Disorders Involving Valve Function Encyclopedia of Cardiovascular Research and Medicine, 10.1016/B978-0-12-809657-4.99703-5, (313-326), . Thanassoulis G (2018) OBSOLETE: Genetic Disorders Involving Valve Function Reference Module in Biomedical Sciences, 10.1016/B978-0-12-801238-3.99703-4, . Mathieu P, Arsenault B, Boulanger M, Bossé Y and Koschinsky M (2017) Pathobiology of Lp(a) in calcific aortic valve disease, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2017.1367286, 15:10, (797-807), Online publication date: 3-Oct-2017. Ellis K, Boffa M, Sahebkar A, Koschinsky M and Watts G (2017) The renaissance of lipoprotein(a): Brave new world for preventive cardiology?, Progress in Lipid Research, 10.1016/j.plipres.2017.09.001, 68, (57-82), Online publication date: 1-Oct-2017. Fahed A, Shibbani K, Andary R, Arabi M, Habib R, Nguyen D, Haddad F, Moubarak E, Nemer G, Azar S and Bitar F (2017) Premature Valvular Heart Disease in Homozygous Familial Hypercholesterolemia, Cholesterol, 10.1155/2017/3685265, 2017, (1-7), Online publication date: 6-Jul-2017. March 21, 2017Vol 135, Issue 12 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.026103PMID: 28320808 Originally publishedMarch 21, 2017 Keywordsgenetic association studiesmeta-analysisaortic valve stenosislipoproteinsgeneticsPDF download Advertisement SubjectsGenetic, Association StudiesLipids and CholesterolValvular Heart Disease
Referência(s)