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249 results on '"White, H.D."'

1. Alirocumab and Cardiovascular Outcomes in Patients With Previous Myocardial Infarction: Prespecified Subanalysis From ODYSSEY OUTCOMES

Author

Chiang, C.E., Schwartz, G.G., Elbez, Y., Szarek, M., Bhatt, D.L., Bittner, V.A., Diaz, R., Erglis, A., Goodman, S.G., Hagstrom, E., Jukema, J.W., Liberopoulos, E., Loy, M., Pordy, R., White, H.D., Simon, T., Steg, P.G., and ODYSSEY OUTCOMES Investigators

Subjects
Male, Kardiologi, Treatment Outcome, Myocardial Infarction, Humans, Cardiac and Cardiovascular Systems, Female, Acute Coronary Syndrome, Proprotein Convertase 9, Antibodies, Monoclonal, Humanized, Cardiology and Cardiovascular Medicine
Abstract

Background: After acute coronary syndrome (ACS), patients with a previous myocardial infarction (MI) may be at particularly high risk for major adverse cardiovascular events (MACE) and death. We studied the effects of the PCSK9 inhibitor alirocumab in patients with recent ACS according to previous history of MI..Methods: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, beginning 1 to 12 months after ACS with median 2.8-year follow-up. The primary MACE outcome comprised death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, and hospitalization for unstable angina. Of 18,924 patients, 3633 (19.2%) had previous MI. Results: Patients with previous MI were older, more likely male, with more cardiovascular risk factors and previous events. With placebo, 4-year risks of MACE and death were higher among those with vs without previous MI (20.5% vs 8.9%, P < 0.001; 7.4% vs 3.4%, P < 0.001, respectively). Alirocumab reduced the risk of events regardless of the presence or absence of a history of MI (MACE, adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI], 0.78-1.05 vs 0.82, 0.73-0.92; P-interaction = 0.34; death, aHR 0.84; 95% CI, 0.64-1.08 vs 0.87, 0.72-1.05; P-interaction = 0.81). Estimated absolute risk reductions with alirocumab were numerically greater with vs without previous MI (MACE, 1.91% vs 1.42%; death, 1.35% vs 0.41%). Conclusions: A previous history of MI places patients with recent ACS at high risk for recurrent MACE and death. Alirocumab reduced the relative risks of these events consistently in patients with or without previous MI but with numerically greater absolute benefit in the former subgroup. (ODYSSEY OUTCOMES: NCT01663402)

Published
2022

2. Relation of red blood cell distribution width to risk of major adverse cardiovascular events, death, and effect of alirocumab after acute coronary syndromes

Author

Moriarty, P.M., Steg, P.G., McGinniss, J., Zeiher, A.M., White, H.D., Manvelian, G., Pordy, R., Loy, M., Jukema, J.W., Harrington, R.A., Gray, J.V., Gorby, L.K., Goodman, S.G., Diaz, R., Bittner, V.A., Bhatt, D.L., Szarek, M., Schwartz, G.G., and ODYSSEY OUTCOMES Investigators

Subjects
Erythrocytes, Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Cholesterol, LDL, major adverse cardiovascular events, Treatment Outcome, Risk Factors, Internal Medicine, Humans, acute coronary syndromes, Acute Coronary Syndrome, red blood cell distribution width, Cardiology and Cardiovascular Medicine, Alirocumab
Abstract

Elevated red blood cell distribution width (RDW) is associated with increased risk for major adverse cardiovascular events (MACE) and death in patients with cardiovascular disease. The ODYSSEY OUT-COMES trial compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins despite optimized statin treatment. This post hoc analysis determined whether RDW independently predicts risk of MACE and death in patients after recent ACS, whether RDW influences MACE reduction with alirocumab, and whether alirocumab treatment affects RDW. Associations of baseline RDW with risk of MACE and death were analyzed in the placebo group in adjusted proportional hazards models. Interactions of RDW and treatment on the risk of MACE and death were evaluated. An increasing quartile of RDW was associated with characteristics that predicted risk of MACE and death including age, hypertension, diabetes, atherosclerotic conditions and events, revascularizations, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. After ad-justing for baseline characteristics associated with the risk of MACE or death, baseline RDW remained independently associated with the risk of MACE and death in the placebo group (hazard ratios [95% confidence intervals] 1.08 [1.02-1.15] and 1.13 [1.03-1.24] per 1% increase of RDW, respectively, both p < 0.001). There was no interaction of RDW and treatment on MACE or death, nor did alirocumab affect RDW. RDW was associated with an increased risk of MACE and death, independent of established risk factors.(c) 2022 National Lipid Association. Published by Elsevier Inc.This is an open access article under the CC BY-NC-ND license( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Published
2022

4. Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial

Author

Tardif, J.C., Pfeffer, M.A., Kouz, S., Koenig, W., Maggioni, A.P., McMurray, J.J.V., Mooser, V., Waters, D.D., Gregoire, J.C., L'Allier, P.L., Jukema, J.W., White, H.D., Heinonen, T., Black, D.M., Laghrissi-Thode, F., Levesque, S., Guertin, M.C., Dube, M.P., and Investigators, D.G.

Subjects
Myocardial infarction, Adenylate cyclase type 9 (ADCY9), Precision medicine, CETP, Genetics, Cardiology and Cardiovascular Medicine, Atherosclerosis
Abstract

Aims In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. Methods and results dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1–3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75–1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65–0.96) for myocardial infarction, 0.92 (95% CI 0.64–1.33) for stroke, 1.21 (95% CI 0.91–1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60–9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70–0.98). Conclusion Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. Clinical Trial Registration Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939

Published
2022

5. Achievement of ESC/EAS LDL-C treatment goals after an acute coronary syndrome with statin and alirocumab

Author

Landmesser, U., McGinniss, J., Steg, P.G., Bhatt, D.L., Bittner, V.A., Diaz, R., Dilic, M., Goodman, S.G., Jukema, J.W., Loy, M., Pecin, I., Pordy, R., Poulsen, S.H., Szarek, M., White, H.D., Schwartz, G.G., and ODYSSEY OUTCOMES Investigators

Subjects
Epidemiology, EZETIMIBE, Cholesterol, LDL, Guidelines, Ezetimibe, THERAPY, Treatment Outcome, Double-Blind Method, DENSITY-LIPOPROTEIN CHOLESTEROL, LDL cholesterol, Humans, lipids (amino acids, peptides, and proteins), Acute coronary syndrome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, Goals, Alirocumab
Abstract

Aims European guidelines set low-density lipoprotein cholesterol (LDL-C) treatment goals Methods and results The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18 924 patients with recent ACS and hyperlipidaemia despite high-intensity or maximum-tolerated statin therapy. This subanalysis comprised 17 589 patients with LDL-C ≥1.4 mmol/L at baseline who did not receive ezetimibe treatment. High-intensity statin treatment was used in 88.8%. Median (interquartile range) baseline LDL-C was 2.3 (1.9−2.7) mmol/L. With alirocumab, 94.6% of patients achieved LDL-C Conclusion Among patients with recent ACS and LDL-C ≥1.4 mmol/L despite optimized statin therapy, the addition of alirocumab allowed 94.6% to achieve the 2019 European guideline LDL-C goal

Published
2022

6. Metabolic risk factors and effect of alirocumab on cardiovascular events after acute coronary syndrome: a post-hoc analysis of the ODYSSEY OUTCOMES randomised controlled trial

Author

Ostadal, P., Steg, P.G., Poulouin, Y., Bhatt, D.L., Bittner, V.A., Chua, T., Diaz, R., Goodman, S.G., Huo, Y., Jukema, J.W., Karpov, Y., Pordy, R., Scemama, M., Szarek, M., White, H.D., Schwartz, G.G., and ODYSSEY OUTCOMES Investigators

Subjects
Male, Endocrinology, Diabetes and Metabolism, PCSK9 Inhibitors, Antibodies, Monoclonal, Humanized, Brain Ischemia, Stroke, Endocrinology, Treatment Outcome, Double-Blind Method, Risk Factors, Internal Medicine, Humans, Female, Acute Coronary Syndrome
Abstract

Background Many patients with acute coronary syndrome have concurrent metabolic risk factors that affect risk of major adverse cardiovascular events (MACE). We aimed to assess the effects of the PCSK9 inhibitor alirocumab compared with placebo on MACE according to baseline metabolic risk factors.Methods We performed a post-hoc analysis of the ODYSSEY OUTCOMES trial, which was a multicentre, doubleblind, randomised controlled trial done in 1315 hospitals and outpatient clinics in 57 countries. Patients aged 40 years or older with recent acute coronary syndrome (ie, in the past 1-12 months) and elevated concentrations of atherogenic lipoproteins, despite high-intensity or maximum-tolerated statin treatment, were eligible for enrolment. Between Nov 2, 2012, and Feb 9,2017, patients were randomly assigned (1:1) to 75 mg alirocumab by subcutaneous injection every 2 weeks or matching placebo, beginning 1-12 months after acute coronary syndrome and were followed up for a median of 2.8 years (IQR 2.3-3.4). Patients and investigators were masked to group assignment and treatment dose adjustment. The primary outcome was a composite of death from coronary artery disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. Analysis of MACE according to an ordinal number of metabolic risk factors was done post hoc. Metabolic risk factors were defined as blood pressure of at least 130/85 mm Hg or treatment with antihypertensive medication, triglyceride concentration of at least 150 mg/dL, HDL cholesterol concentration less than 40 mg/dL for men and 50 mg/dL women, fasting plasma glucose concentration of at least 100 mg/dL or treatment with glucose-lowering medication, and BMI of at least 30 kg/m(2). Risk of MACE and effect of alirocumab were assessed according to the number of metabolic risk factors. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.Findings Of 18 924 patients, 3882 (41%) of 9462 in the alirocumab group and 3859 (41%) of 9462 in the placebo group had three or more metabolic risk factors. In the placebo group, MACE incidence increased monotonically with each metabolic risk factor from 7.8% (no risk factors) to 19.6% (five risk factors; HR 1.18,95% CI 1.13-1.24 per metabolic risk factor). Alirocumab decreased relative risk of MACE consistently across categories defined by the number of metabolic risk factors (p(interaction)=0.77) but absolute risk reduction (aRR) increased with the number of metabolic risk factors (no risk factors aRR 0.7%, -1.81 to 3.29 vs five risk factors aRR 3.9%, -1.45 to 9.25; p(interaction )

Published
2022

7. Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab

Author

Hagström, E., Steg, P.G., Szarek, M., Bhatt, D.L., Bittner, V.A., Danchin, N., Diaz, R., Goodman, S.G., Harrington, R.A., Jukema, J.W., Liberopoulos, E., Marx, N., McGinniss, J., Manvelian, G., Pordy, R., Scemama, M., White, H.D., Suryapranata, H., Zeiher, A.M., Schwartz, G.G., Hagström, E., Steg, P.G., Szarek, M., Bhatt, D.L., Bittner, V.A., Danchin, N., Diaz, R., Goodman, S.G., Harrington, R.A., Jukema, J.W., Liberopoulos, E., Marx, N., McGinniss, J., Manvelian, G., Pordy, R., Scemama, M., White, H.D., Suryapranata, H., Zeiher, A.M., and Schwartz, G.G.

Abstract

Contains fulltext : 283504.pdf (Publisher’s version ) (Open Access), BACKGROUND: Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain. METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score-matched models. RESULTS: Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; P(trend)<0.0001) and after adjustment for low-density lipoprotein cholesterol (P(trend)=0.035). Higher baseline apoB stratum was associated with greater relative (P(trend)<0.0001) and absolute reduction in MACE with alirocumab versus placebo. In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB s

Published
2022

8. Alirocumab after acute coronary syndrome in patients with a history of heart failure

Author

White, H.D., Schwartz, G.G., Szarek, M., Bhatt, D.L., Bittner, V.A., Chiang, C.E., Diaz, R., Goodman, S.G., Jukema, J.W., Loy, M., Pagidipati, N., Pordy, R., Ristic, A.D., Zeiher, A.M., Wojdyla, D.M., Steg, P.G., and ODYSSEY OUTCOMES Investigators

Subjects
Treatment Outcome, Anticholesteremic Agents, ODYSSEY OUTCOMES, Humans, Heart failure, MACE, Acute Coronary Syndrome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertase 9, Acute coronary syndromes, Cardiology and Cardiovascular Medicine, Antibodies, Monoclonal, Humanized, Alirocumab
Abstract

Aims: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. Methods and results: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (P-interaction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF. Conclusion: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS. Key Question Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis of the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), we evaluated major adverse cardiovascular events (MACE) in patients with or without a history of HF assigned to treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. Key Finding Alirocumab reduced low-density lipoprotein cholesterol similarly in patients with or without HF. However, alirocumab reduced MACE among patients without a history of HF, but not in those with a history of HF. Take Home Message The current hypothesis-generating analysis does not provide a basis to recommend PCSK9 inhibitors to patients with recent ACS and a history of HF. A prospective placebo-controlled evaluation of PCSK9 inhibition in this setting is warranted.

Published
2021

9. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

Gorski, M. (Mathias), Jung, B. (Bettina), Li, Y. (Yong), Matias-Garcia, P.R. (Pamela R.), Wuttke, M. (Matthias), Coassin, S. (Stefan), Thio, C.H.L. (Chris H.L.), Kleber, M.E. (Marcus E.), Winkler, T.W. (Thomas W.), Wanner, V. (Veronika), Chai, J.-F. (Jin-Fang), Chu, A.Y. (Audrey Y), Cocca, M. (Massimiliano), Feitosa, M.F. (Mary Furlan), Ghasemi, S. (Sahar), Hoppmann, A. (Anselm), Horn, K. (Katrin), Li, M. (Man), Nutile, T. (Teresa), Scholz, M. (Markus), Sieber, K.B. (Karsten B.), Teumer, A. (Alexander), Tin, A. (Adrienne), Wang, J. (Judy), Tayo, B. (Bamidele), Ahluwalia, T.S. (Tarunveer Singh), Almgren, P. (Peter), Bakker, S.J.L. (Stephan), Banas, B. (Bernhard), Bansal, N. (Nisha), Biggs, M.L. (M.), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin), Brenner, H. (Hermann), Carroll, R.J. (Robert J.), Chalmers, J. (John), Chee, M.-L. (Miao-Li), Chee, M.-L. (Miao-Ling), Cheng, C.-Y. (Ching-Yu), Coresh, J. (Josef), de Borst, M.H. (Martin H.), Degenhardt, F. (Frauke), Eckardt, K.-U. (Kai-Uwe), Endlich, K. (Karlhans), Franke, A. (Andre), Freitag-Wolf, S. (Sandra), Gampawar, P. (Piyush), Gansevoort, R.T. (Ron), Ghanbari, M. (Mohsen), Gieger, C. (Christian), Hamet, P. (Pavel), Ho, K. (Kevin), Hofer, E. (Edith), Holleczek, B. (B.), Xian Foo, V.H. (Valencia Hui), Hutri-Kähönen, N. (Nina), Hwang, S.-J. (Shih-Jen), Ikram, M.A. (Arfan), Josyula, N.S. (Navya Shilpa), Kähönen, M. (Mika), Khor, C.C., Koenig, W. (Wolfgang), Kramer, H. (Holly), Krämer, B.K. (Bernhard), Kuhnel, B. (Brigitte), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Lieb, W. (Wolfgang), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (H. Marike), Franke, L. (Lude), van der Harst, P. (Pim), Matullo, G., Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M. (Morris), Wolffenbuttel, B.H.R. (Bruce), Wijmenga, C. (Cisca), Abecasis, G.R. (Gonçalo), Baras, A. (Aris), Cantor, M. (Michael), Coppola, G. (Giovanni), Economides, A. (Aris), Lotta, L.A. (Luca A.), Overton, J.D. (John D.), Reid, J.G. (Jeffrey G.), Shuldiner, A. (Alan), Beechert, C. (Christina), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Lattari, M. (Michael), Lopez, A. (Alexander), Schleicher, T.D. (Thomas D.), Padilla, M.S. (Maria Sotiropoulos), Toledo, K. (Karina), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Pradhan, M. (Manasi), Manoochehri, K. (Kia), Ulloa, R.H. (Ricardo H.), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Barnard, L. (Leland), Blumenfeld, A. (Andrew), Eom, G. (Gisu), Habegger, L. (Lukas), Hawes, A. (Alicia), Khalid, S. (Shareef), Maxwell, E.K. (Evan K.), Salerno, W. (William), Staples, J.C. (Jeffrey C.), Jones, M.B. (Marcus B.), Mitnaul, L.J. (Lyndon), Loos, R.J.F. (Ruth J.F.), Lukas, M.A. (Mary Ann), Lyytikäinen, L.-P. (Leo-Pekka), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Milaneschi, Y. (Yuri), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Mychaleckyj, J.C. (Josyf), Nadkarni, G. (Girish), Nauck, M. (Matthias), Nikus, K. (Kjell), Ning, B. (Boting), Nolte, I.M. (Ilja), O'Donoghue, M.L. (Michelle L.), Orho-Melander, M. (Marju), Pendergrass, S.A. (Sarah), Penninx, B.W.J.H. (Brenda), Preuss, M. (Michael), Psaty, B.M. (Bruce M.), Raffield, L.M. (Laura M.), Raitakari, O. (Olli), Rettig, R. (Rainer), Rheinberger, M. (Myriam), Rice, K.M. (Kenneth M.), Rosenkranz, A.R. (Alexander R.), Rossing, K., Rotter, J.I. (Jerome I.), Sabanayagam, C. (Charumathi), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Schöttker, B. (Ben), Schulz, C.A. (Christina Alexandra), Sedaghat, S. (Sanaz), Shaffer, C.M. (Christian M.), Strauch, K. (Konstantin), Szymczak, S. (Silke), Taylor, K.D. (Kent D.), Tremblay, J. (Johanne), Chaker, L. (Layal), Most, P.J. (Peter) van der, Verweij, N. (Niek), Völker, U. (Uwe), Waldenberger, M. (Melanie), Wallentin, L.C. (Lars), Waterworth, D.M. (Dawn M.), White, H.D. (Harvey), Wilson, J.G. (James G.), Wong, T.-Y. (Tien-Yin), Woodward, M. (Mark), Yang, Q. (Qiong), Yasuda, M. (Masayuki), Yerges-Armstrong, L.M. (Laura), Zhang, Y. (Yan), Wanner, C. (Christoph), Böger, C.A. (Carsten), Köttgen, A. (Anna), Kronenberg, F. (Florian), Penninx, B.W.J.H., Heid, I.M. (Iris), Gorski, M. (Mathias), Jung, B. (Bettina), Li, Y. (Yong), Matias-Garcia, P.R. (Pamela R.), Wuttke, M. (Matthias), Coassin, S. (Stefan), Thio, C.H.L. (Chris H.L.), Kleber, M.E. (Marcus E.), Winkler, T.W. (Thomas W.), Wanner, V. (Veronika), Chai, J.-F. (Jin-Fang), Chu, A.Y. (Audrey Y), Cocca, M. (Massimiliano), Feitosa, M.F. (Mary Furlan), Ghasemi, S. (Sahar), Hoppmann, A. (Anselm), Horn, K. (Katrin), Li, M. (Man), Nutile, T. (Teresa), Scholz, M. (Markus), Sieber, K.B. (Karsten B.), Teumer, A. (Alexander), Tin, A. (Adrienne), Wang, J. (Judy), Tayo, B. (Bamidele), Ahluwalia, T.S. (Tarunveer Singh), Almgren, P. (Peter), Bakker, S.J.L. (Stephan), Banas, B. (Bernhard), Bansal, N. (Nisha), Biggs, M.L. (M.), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin), Brenner, H. (Hermann), Carroll, R.J. (Robert J.), Chalmers, J. (John), Chee, M.-L. (Miao-Li), Chee, M.-L. (Miao-Ling), Cheng, C.-Y. (Ching-Yu), Coresh, J. (Josef), de Borst, M.H. (Martin H.), Degenhardt, F. (Frauke), Eckardt, K.-U. (Kai-Uwe), Endlich, K. (Karlhans), Franke, A. (Andre), Freitag-Wolf, S. (Sandra), Gampawar, P. (Piyush), Gansevoort, R.T. (Ron), Ghanbari, M. (Mohsen), Gieger, C. (Christian), Hamet, P. (Pavel), Ho, K. (Kevin), Hofer, E. (Edith), Holleczek, B. (B.), Xian Foo, V.H. (Valencia Hui), Hutri-Kähönen, N. (Nina), Hwang, S.-J. (Shih-Jen), Ikram, M.A. (Arfan), Josyula, N.S. (Navya Shilpa), Kähönen, M. (Mika), Khor, C.C., Koenig, W. (Wolfgang), Kramer, H. (Holly), Krämer, B.K. (Bernhard), Kuhnel, B. (Brigitte), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Lieb, W. (Wolfgang), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (H. Marike), Franke, L. (Lude), van der Harst, P. (Pim), Matullo, G., Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M. (Morris), Wolffenbuttel, B.H.R. (Bruce), Wijmenga, C. (Cisca), Abecasis, G.R. (Gonçalo), Baras, A. (Aris), Cantor, M. (Michael), Coppola, G. (Giovanni), Economides, A. (Aris), Lotta, L.A. (Luca A.), Overton, J.D. (John D.), Reid, J.G. (Jeffrey G.), Shuldiner, A. (Alan), Beechert, C. (Christina), Forsythe, C. (Caitlin), Fuller, E.D. (Erin D.), Gu, Z. (Zhenhua), Lattari, M. (Michael), Lopez, A. (Alexander), Schleicher, T.D. (Thomas D.), Padilla, M.S. (Maria Sotiropoulos), Toledo, K. (Karina), Widom, L. (Louis), Wolf, S.E. (Sarah E.), Pradhan, M. (Manasi), Manoochehri, K. (Kia), Ulloa, R.H. (Ricardo H.), Bai, X. (Xiaodong), Balasubramanian, S. (Suganthi), Barnard, L. (Leland), Blumenfeld, A. (Andrew), Eom, G. (Gisu), Habegger, L. (Lukas), Hawes, A. (Alicia), Khalid, S. (Shareef), Maxwell, E.K. (Evan K.), Salerno, W. (William), Staples, J.C. (Jeffrey C.), Jones, M.B. (Marcus B.), Mitnaul, L.J. (Lyndon), Loos, R.J.F. (Ruth J.F.), Lukas, M.A. (Mary Ann), Lyytikäinen, L.-P. (Leo-Pekka), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Milaneschi, Y. (Yuri), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Mychaleckyj, J.C. (Josyf), Nadkarni, G. (Girish), Nauck, M. (Matthias), Nikus, K. (Kjell), Ning, B. (Boting), Nolte, I.M. (Ilja), O'Donoghue, M.L. (Michelle L.), Orho-Melander, M. (Marju), Pendergrass, S.A. (Sarah), Penninx, B.W.J.H. (Brenda), Preuss, M. (Michael), Psaty, B.M. (Bruce M.), Raffield, L.M. (Laura M.), Raitakari, O. (Olli), Rettig, R. (Rainer), Rheinberger, M. (Myriam), Rice, K.M. (Kenneth M.), Rosenkranz, A.R. (Alexander R.), Rossing, K., Rotter, J.I. (Jerome I.), Sabanayagam, C. (Charumathi), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Schöttker, B. (Ben), Schulz, C.A. (Christina Alexandra), Sedaghat, S. (Sanaz), Shaffer, C.M. (Christian M.), Strauch, K. (Konstantin), Szymczak, S. (Silke), Taylor, K.D. (Kent D.), Tremblay, J. (Johanne), Chaker, L. (Layal), Most, P.J. (Peter) van der, Verweij, N. (Niek), Völker, U. (Uwe), Waldenberger, M. (Melanie), Wallentin, L.C. (Lars), Waterworth, D.M. (Dawn M.), White, H.D. (Harvey), Wilson, J.G. (James G.), Wong, T.-Y. (Tien-Yin), Woodward, M. (Mark), Yang, Q. (Qiong), Yasuda, M. (Masayuki), Yerges-Armstrong, L.M. (Laura), Zhang, Y. (Yan), Wanner, C. (Christoph), Böger, C.A. (Carsten), Köttgen, A. (Anna), Kronenberg, F. (Florian), Penninx, B.W.J.H., and Heid, I.M. (Iris)

Abstract

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized varia

Published
2021
Full Text
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10. Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Author

Hamilton-Craig I., Pang J., Ademi Z., Ardill J.J., Barnett W., Bates T.R., Beilin L.J., Bishop W., Black J.A., Brett P., Brown A., Burnett J.R., Bursill C.A., Colley A., Clifton P.M., Ekinci E.I., Elias L., Figtree G.A., Forge B.H., Garton-Smith J., Graham D.F., Hamilton-Craig C.R., Heal C., Hespe C.M., Hooper A.J., Howes L.G., Ingles J., Irvin J., Janus E.D., Kangaharan N., Keech A.C., Kirke A.B., Kritharides L., Kyle C.V., Lacaze P., Lambert K., Li S.C.H., Malan W., Maticevic S., McQuillan B.M., Mirzaee S., Mori T.A., Morton A.C., Colquhoun D.M., Moullin J.C., Nestel P.J., Nowak K.J., O'Brien R.C., Pachter N., Page M.M., Pedrotti A., Psaltis P.J., Radford J., Reid N.J., Robertson E.N., Ryan J.D.M., Sarkies M.N., Schultz C.J., Scott R.S., Semsarian C., Simons L.A., Spinks C., Tonkin A.M., van Bockxmeer F., Waddell-Smith K.E., Ward N.C., White H.D., Wilson A.M., Winship I., Woodward A.M., Nicholls S.J., Watts G.F., Sullivan D.R., Hare D.L., Kostner K.M., Horton A.E., Bell D.A., Brett T., Trent R.J., Poplawski N.K., Martin A.C., Srinivasan S., Justo R.N., Chow C.K., Hamilton-Craig I., Pang J., Ademi Z., Ardill J.J., Barnett W., Bates T.R., Beilin L.J., Bishop W., Black J.A., Brett P., Brown A., Burnett J.R., Bursill C.A., Colley A., Clifton P.M., Ekinci E.I., Elias L., Figtree G.A., Forge B.H., Garton-Smith J., Graham D.F., Hamilton-Craig C.R., Heal C., Hespe C.M., Hooper A.J., Howes L.G., Ingles J., Irvin J., Janus E.D., Kangaharan N., Keech A.C., Kirke A.B., Kritharides L., Kyle C.V., Lacaze P., Lambert K., Li S.C.H., Malan W., Maticevic S., McQuillan B.M., Mirzaee S., Mori T.A., Morton A.C., Colquhoun D.M., Moullin J.C., Nestel P.J., Nowak K.J., O'Brien R.C., Pachter N., Page M.M., Pedrotti A., Psaltis P.J., Radford J., Reid N.J., Robertson E.N., Ryan J.D.M., Sarkies M.N., Schultz C.J., Scott R.S., Semsarian C., Simons L.A., Spinks C., Tonkin A.M., van Bockxmeer F., Waddell-Smith K.E., Ward N.C., White H.D., Wilson A.M., Winship I., Woodward A.M., Nicholls S.J., Watts G.F., Sullivan D.R., Hare D.L., Kostner K.M., Horton A.E., Bell D.A., Brett T., Trent R.J., Poplawski N.K., Martin A.C., Srinivasan S., Justo R.N., and Chow C.K.

Abstract

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits

Published
2021

11. Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective

Author

Watts, G.F., Sullivan, D.R., Hare, D.L., Kostner, K.M., Horton, A.E., Bell, D.A., Brett, T., Trent, R.J., Poplawski, N.K., Martin, A.C., Srinivasan, S., Justo, R.N., Chow, C.K., Pang, J., Ademi, Z., Ardill, J.J., Barnett, W., Bates, T.R, Beilin, L.J., Bishop, W., Black, J.A., Brown, A., Burnett, J.R., Bursill, C.A., Colley, A., Clifton, P.M., Ekinci, E.I., Figtree, G.A., Forge, B.H., Garton-Smith, J., Graham, D.F., Hamilton-Craig, I., Hamilton-Craig, C.R., Heal, C., Hespe, C.M., Hooper, A.J., Howes, L.G., Ingles, J., Janus, E.D., Kangaharan, N., Keech, A.C., Kirke, A.B., Kritharides, L., Kyle, C.V., Lacaze, P., Li, S.C.H., Maticevic, S., McQuillan, B.M., Mirzaee, S., Mori, T.A., Morton, A.C., Colquhoun, D.M., Moullin, J.C., Nestel, P.J., Nowak, K.J., O'Brien, R.C., Pachter, N., Page, M.M., Psaltis, P.J., Radford, J., Reid, N.J., Robertson, E.N., Ryan, J.D.M., Sarkies, M.N., Schultz, C.J., Scott, R.S., Semsarian, C., Simons, L.A., Spinks, C., Tonkin, A.M., van Bockxmeer, F., Waddell-Smith, K.E., Ward, N.C., White, H.D., Wilson, A.M., Winship, I., Woodward, A.M., Nicholls, S.J., Brett, P., Elias, L., Malan, W., Irvin, J., Lambert, K., Pedrotti, A., Watts, G.F., Sullivan, D.R., Hare, D.L., Kostner, K.M., Horton, A.E., Bell, D.A., Brett, T., Trent, R.J., Poplawski, N.K., Martin, A.C., Srinivasan, S., Justo, R.N., Chow, C.K., Pang, J., Ademi, Z., Ardill, J.J., Barnett, W., Bates, T.R, Beilin, L.J., Bishop, W., Black, J.A., Brown, A., Burnett, J.R., Bursill, C.A., Colley, A., Clifton, P.M., Ekinci, E.I., Figtree, G.A., Forge, B.H., Garton-Smith, J., Graham, D.F., Hamilton-Craig, I., Hamilton-Craig, C.R., Heal, C., Hespe, C.M., Hooper, A.J., Howes, L.G., Ingles, J., Janus, E.D., Kangaharan, N., Keech, A.C., Kirke, A.B., Kritharides, L., Kyle, C.V., Lacaze, P., Li, S.C.H., Maticevic, S., McQuillan, B.M., Mirzaee, S., Mori, T.A., Morton, A.C., Colquhoun, D.M., Moullin, J.C., Nestel, P.J., Nowak, K.J., O'Brien, R.C., Pachter, N., Page, M.M., Psaltis, P.J., Radford, J., Reid, N.J., Robertson, E.N., Ryan, J.D.M., Sarkies, M.N., Schultz, C.J., Scott, R.S., Semsarian, C., Simons, L.A., Spinks, C., Tonkin, A.M., van Bockxmeer, F., Waddell-Smith, K.E., Ward, N.C., White, H.D., Wilson, A.M., Winship, I., Woodward, A.M., Nicholls, S.J., Brett, P., Elias, L., Malan, W., Irvin, J., Lambert, K., and Pedrotti, A.

Abstract

Introduction Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.

Published
2021

12. Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians

Author

Watts, G.F., Sullivan, D.R., Hare, D.L., Kostner, K.M., Horton, A.E., Bell, D.A., Brett, T., Trent, R.J., Poplawski, N.K., Martin, A.C., Srinivasan, S., Justo, R.N., Chow, C.K., Pang, J., Ademi, Z., Ardill, J.J., Barnett, W., Bates, T.R., Beilin, L.J., Bishop, W., Black, J.A., Brown, A., Burnett, J.R., Bursill, C.A., Colley, A., Clifton, P.M., Ekinci, E.I., Figtree, G.A., Forge, B.H., Garton‐Smith, J., Graham, D.F., Hamilton‐Craig, I., Hamilton‐Craig, C.R., Heal, C., Hespe, C.M., Hooper, A.J., Howes, L.G., Ingles, J., Janus, E.D., Kangaharan, N., Keech, A.C., Kirke, A.B., Kritharides, L., Kyle, C.V., Lacaze, P., Li, S.C.H., Maticevic, S., McQuillan, B.M., Mirzaee, S., Mori, T.A., Morton, A.C., Colquhoun, D.M., Moullin, J.C., Nestel, P.J., Nowak, K.J., O'Brien, R.C., Pachter, N., Page, M.M., Psaltis, P.J., Radford, J., Reid, N.J., Robertson, E.N., Ryan, J.D.M., Sarkies, M.N., Schultz, C.J., Semsarian, C., Simons, L.A., Spinks, C., Tonkin, A.M., van Bockxmeer, F., Waddell‐Smith, K.E., Ward, N.C., White, H.D., Wilson, A.M., Winship, I., Woodward, A.M., Nicholls, S.J., Elias, L., Malan, W., Irvin, J., Lambert, K., Pedrotti, A., Watts, G.F., Sullivan, D.R., Hare, D.L., Kostner, K.M., Horton, A.E., Bell, D.A., Brett, T., Trent, R.J., Poplawski, N.K., Martin, A.C., Srinivasan, S., Justo, R.N., Chow, C.K., Pang, J., Ademi, Z., Ardill, J.J., Barnett, W., Bates, T.R., Beilin, L.J., Bishop, W., Black, J.A., Brown, A., Burnett, J.R., Bursill, C.A., Colley, A., Clifton, P.M., Ekinci, E.I., Figtree, G.A., Forge, B.H., Garton‐Smith, J., Graham, D.F., Hamilton‐Craig, I., Hamilton‐Craig, C.R., Heal, C., Hespe, C.M., Hooper, A.J., Howes, L.G., Ingles, J., Janus, E.D., Kangaharan, N., Keech, A.C., Kirke, A.B., Kritharides, L., Kyle, C.V., Lacaze, P., Li, S.C.H., Maticevic, S., McQuillan, B.M., Mirzaee, S., Mori, T.A., Morton, A.C., Colquhoun, D.M., Moullin, J.C., Nestel, P.J., Nowak, K.J., O'Brien, R.C., Pachter, N., Page, M.M., Psaltis, P.J., Radford, J., Reid, N.J., Robertson, E.N., Ryan, J.D.M., Sarkies, M.N., Schultz, C.J., Semsarian, C., Simons, L.A., Spinks, C., Tonkin, A.M., van Bockxmeer, F., Waddell‐Smith, K.E., Ward, N.C., White, H.D., Wilson, A.M., Winship, I., Woodward, A.M., Nicholls, S.J., Elias, L., Malan, W., Irvin, J., Lambert, K., and Pedrotti, A.

Abstract

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.

Published
2021

13. Integrated guidance for enhancing the care of familial hypercholesterolaemia in Australia

Author

Watts, G.F., Sullivan, D.R., Hare, D.L., Kostner, K.M., Horton, A.E., Bell, D.A., Brett, T., Trent, R.J., Poplawski, N.K., Martin, A.C., Srinivasan, S., Justo, R.N., Chow, C.K., Pang, J., Ademi, Z., Ardill, J.J., Barnett, W., Bates, T.R., Beilin, L.J., Bishop, W., Black, J.A., Brett, P., Brown, A., Burnett, J.R., Bursill, C.A., Colley, A., Clifton, P.M., Ekinci, E.I., Elias, L., Figtree, G.A., Forge, B.H., Garton-Smith, J., Graham, D.F., Hamilton-Craig, I., Hamilton-Craig, C.R., Heal, C., Hespe, C.M., Hooper, A.J., Howes, L.G., Ingles, J., Irvin, J., Janus, E.D., Kangaharan, N., Keech, A.C., Kirke, A.B., Kritharides, L., Kyle, C.V., Lacaze, P., Lambert, K., Li, S.C.H., Malan, W., Maticevic, S., McQuillan, B.M., Mirzaee, S., Mori, T.A., Morton, A.C., Colquhoun, D.M., Moullin, J.C., Nestel, P.J., Nowak, K.J., O'Brien, R.C., Pachter, N., Page, M.M., Pedrotti, A., Psaltis, P.J., Radford, J., Reid, N.J., Robertson, E.N., Ryan, J.D.M., Sarkies, M.N., Schultz, C.J., Scott, R.S., Semsarian, C., Simons, L.A., Spinks, C., Tonkin, A.M., van Bockxmeer, F., Waddell-Smith, K.E., Ward, N.C., White, H.D., Wilson, A.M., Winship, I., Woodward, A.M., Nicholls, S.J., Watts, G.F., Sullivan, D.R., Hare, D.L., Kostner, K.M., Horton, A.E., Bell, D.A., Brett, T., Trent, R.J., Poplawski, N.K., Martin, A.C., Srinivasan, S., Justo, R.N., Chow, C.K., Pang, J., Ademi, Z., Ardill, J.J., Barnett, W., Bates, T.R., Beilin, L.J., Bishop, W., Black, J.A., Brett, P., Brown, A., Burnett, J.R., Bursill, C.A., Colley, A., Clifton, P.M., Ekinci, E.I., Elias, L., Figtree, G.A., Forge, B.H., Garton-Smith, J., Graham, D.F., Hamilton-Craig, I., Hamilton-Craig, C.R., Heal, C., Hespe, C.M., Hooper, A.J., Howes, L.G., Ingles, J., Irvin, J., Janus, E.D., Kangaharan, N., Keech, A.C., Kirke, A.B., Kritharides, L., Kyle, C.V., Lacaze, P., Lambert, K., Li, S.C.H., Malan, W., Maticevic, S., McQuillan, B.M., Mirzaee, S., Mori, T.A., Morton, A.C., Colquhoun, D.M., Moullin, J.C., Nestel, P.J., Nowak, K.J., O'Brien, R.C., Pachter, N., Page, M.M., Pedrotti, A., Psaltis, P.J., Radford, J., Reid, N.J., Robertson, E.N., Ryan, J.D.M., Sarkies, M.N., Schultz, C.J., Scott, R.S., Semsarian, C., Simons, L.A., Spinks, C., Tonkin, A.M., van Bockxmeer, F., Waddell-Smith, K.E., Ward, N.C., White, H.D., Wilson, A.M., Winship, I., Woodward, A.M., and Nicholls, S.J.

Abstract

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits

Published
2021

14. Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial

Author

Bhatt, D.L., Briggs, A.H., Reed, S.D., Annemans, L., Szarek, M., Bittner, V.A., Diaz, R., Goodman, S.G., Harrington, R.A., Higuchi, K., Joulain, F., Jukema, J.W., Li, Q.H., Mahaffey, K.W., Sanchez, R.J., Roe, M.T., Lopes, R.D., White, H.D., Zeiher, A.M., Schwartz, G.G., Steg, P.G., and ODYSSEY OUTCOMES Investigators

Subjects
Adult, Aged, 80 and over, Male, Cost-Benefit Analysis, Hypercholesterolemia, cholesterol, alirocumab, Cholesterol, LDL, Middle Aged, Antibodies, Monoclonal, Humanized, economic analysis, Treatment Outcome, Double-Blind Method, Humans, Drug Therapy, Combination, Female, acute coronary syndromes, lipids (amino acids, peptides, and proteins), Acute Coronary Syndrome, cost-effectiveness, Aged
Abstract

BACKGROUND Cholesterol reduction with proprotein convertase subtitisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.OBJECTIVES This study sought to determine whether further cholesterol reduction with atirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.METHODS A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Atirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline tow-density lipoprotein cholesterol (LDL-C) level >= 70 mg/l, non-high-density lipoprotein cholesterol >= 100 mg/dl, or apotipoprotein B >= 80 mg/l. Atirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Atirocumab was blindly titrated to 150 mg if LDL-C remained >= 50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were = 100 mg/dl.RESULTS Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C >= 100 mg/dl, whereas in those with LDL-C >= 100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C a100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.CONCLUSIONS In patients with a recent acute coronary syndrome on optimal statin therapy, atirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C mg/dt but less economic value with LDL-C >= 100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Atirocumab [ODYSSEY OUTCOMES]; NCT01663402) (J Am Colt Cardiol 2020;75:2297-308) (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Published
2020

15. Memorando *

Author

Currie, L.B., Ellsworth, P.T., and White, H.D.

Published
2006

16. Temperature and ligand dependence of conformation and helical order in myosin filaments

Author

Xu, S., Offer, G., Gu, J., White, H.D., and Yu, L.C.

Subjects
Myosin -- Analysis, Conformational analysis -- Physiological aspects, Ligand binding (Biochemistry) -- Influence, Temperature -- Influence, Biological sciences, Chemistry
Abstract

Results indicate that one ordered conformation and two disordered conformations, each with distinct thermodynamic properties, exist under temperature and ligand restraints in myosin . Data show that low temperatures favor one disordered conformation, whereas high temperatures favor the ordered conformation and a second disordered conformation.

Published
2003

17. Low-density lipoprotein cholesterol <50 mg/dL is an appropriate target after acute coronary syndrome: propensity score-matched analysis of the ODYSSEY OUTCOMES trial

Author

Schwartz, G.G, primary, Szarek, M, additional, Bhatt, D.L, additional, Bittner, V.A, additional, Diaz, R, additional, Goodman, S.G, additional, Harrington, R.A, additional, Jukema, J.W, additional, Kim, Y.U, additional, Li, Q.H, additional, Manvelian, G, additional, White, H.D, additional, Zeiher, A.M, additional, and Steg, P.G, additional

Published
2020
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18. Effect of alirocumab on incidence of atrial fibrillation after acute coronary syndromes: insights from ODYSSEY OUTCOMES

Author

Lopes, R, primary, Steg, P.G, additional, Bhatt, D.L, additional, Bittner, V.A, additional, Dauchy, A, additional, Diaz, R, additional, Goodman, S.G, additional, Harrington, R.A, additional, Jukema, J.W, additional, Pordy, R, additional, Sourdille, T, additional, Szarek, M, additional, White, H.D, additional, Zeiher, A.M, additional, and Schwartz, G.G, additional

Published
2020
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24. Relationship of QRS duration at baseline and changes over 60 min after fibrinolysis to 30-day mortality with different locations of ST elevation myocardial infarction: results from the Hirulog and Early Reperfusion or Occlusion-2 trial

Author

Wong, C.-K., Gao, W., Stewart, R.A.H., French, J.K., Aylward, P.E.G., and White, H.D.

Subjects
Heart conduction system -- Research, Heart conduction system -- Physiological aspects, Fibrinolysis -- Usage, Fibrinolysis -- Patient outcomes, Heart attack -- Patient outcomes, Heart attack -- Diagnosis, Health
Published
2009

25. Short- and long-term outcomes following atrial fibrillation in patients with acute coronary syndromes with or without ST-segment elevation

Author

Lopes, R.D., Pieper, K.S., Horton, J.R., Al-Khatib, S. M, Newby, L.K., Mehta, R.H., Van de Werf, F., Armstrong, P.W., Mahaffey, K.W., Harrington, R.A., Ohman, E.M., White, H.D., Wallentin, L., and Granger, C.B.

Subjects
Atrial fibrillation -- Research, Atrial fibrillation -- Physiological aspects, Atrial fibrillation -- Patient outcomes, Heart attack -- Complications and side effects, Health
Published
2008

27. Flexibility within myosin heads revealed by negative stain and single-particle analysis

Author

Burgess, S.A., Walker, M.L., White, H.D., and Trinick, J.

Subjects
Electron microscopy -- Usage, Myosin -- Research, Molecules -- Research, Biological sciences
Abstract

Experiment was conducted to investigate the electron microscopy of negatively stained myosin which revealed three discrete regions within the heads of the molecule in previous studies. Single-particle image processing and classified heads were applied into homogeneous groups which revealed significantly improved detail. The image averages were then compared to a model simulating negative staining of the atomic structure of subfragment-1. Result indicate considerable flexibility between the motor an regulatory domains despite the absence of nucleotide.

Published
1997

28. Effects of alirocumab on types of myocardial infarction: Insights from the ODYSSEY OUTCOMES trial

Author

White, H.D., Gabriel, Steg Ph., Szarek, M., Bhatt, D.L., Bittner, V.A., Diaz, R., Edelberg, J.M., Erglis, A., Goodman, S.G., Hanotin, C., Harrington, R.A., Wouter, Jukema J., Lopes, R.D., Mahaffey, K.W., Moryusef, A., Pordy, R., Roe, M.T., Sritara, P., Tricoci, P., Zeiher, A.M., Schwartz, G.G., ODYSSEY, OUTCOMES Investigators, White, H.D., Gabriel, Steg Ph., Szarek, M., Bhatt, D.L., Bittner, V.A., Diaz, R., Edelberg, J.M., Erglis, A., Goodman, S.G., Hanotin, C., Harrington, R.A., Wouter, Jukema J., Lopes, R.D., Mahaffey, K.W., Moryusef, A., Pordy, R., Roe, M.T., Sritara, P., Tricoci, P., Zeiher, A.M., Schwartz, G.G., and ODYSSEY, OUTCOMES Investigators

Abstract

Aims The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (=1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Published
2019
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29. International variation in characteristics and clinical outcomes of patients with type 2 diabetes and heart failure: Insights from TECOS

Author

Bhatt, A.S., Luo, N., Solomon, N., Pagidipati, N.J., Ambrosio, G., Green, J.B., McGuire, D.K., Standl, E., Cornel, J.H., Halvorsen, S., Lopes, R.D., White, H.D., Holman, R.R., Peterson, E.D., Mentz, R.J., Bhatt, A.S., Luo, N., Solomon, N., Pagidipati, N.J., Ambrosio, G., Green, J.B., McGuire, D.K., Standl, E., Cornel, J.H., Halvorsen, S., Lopes, R.D., White, H.D., Holman, R.R., Peterson, E.D., and Mentz, R.J.

Abstract

Item does not contain fulltext, International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N=1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF >/=40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF>/=40%. beta-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF>/=40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF>/=40%. These data may inform the design of future international trials.

Published
2019

30. Fourth universal definition of myocardial infarction (2018)

Author

Thygesen, K., Alpert, J.S., Jaffe, A.S., Chaitman, B.R., Bax, J.J., Damman, P., Morrow, D.A., White, H.D., Thygesen, K., Alpert, J.S., Jaffe, A.S., Chaitman, B.R., Bax, J.J., Damman, P., Morrow, D.A., and White, H.D.

Abstract

Contains fulltext : 202657.pdf (publisher's version ) (Closed access)

Published
2019

32. Associations between ST depression, four year mortality, and in-hospital revascularisation in unselected patients with non-ST elevation acute coronary syndromes. (Cardiovascular Medicine)

Author

Hyde, T.A., French, J.K., Wong, C-K, Edwards, C., Whitlock, R.M.L., and White, H.D.

Subjects
Heart diseases -- Research, Health
Abstract

Objective: To determine the associations between changes on the presenting ECG, in-hospital revascularisation, and four year mortality in patients with non-ST elevation acute coronary syndromes. Design: Prospective evaluation of all [...]

Published
2003

33. Relation between blood pressure after an acute coronary event and subsequent cardiovascular risk. (Editorial)

Author

Wong, C-K. and White, H.D.

Subjects
Coronary heart disease -- Risk factors, Blood pressure -- Health aspects -- Physiological aspects, Blood vessels -- Physiological aspects -- Health aspects, Aging -- Physiological aspects -- Health aspects, Antihypertensive drugs -- Physiological aspects -- Health aspects, Health, Physiological aspects, Risk factors, Health aspects
Abstract

Evidence is accumulating that after an acute coronary event, assiduous control of both systolic and diastolic pressure is indicated ********** Concepts about the relation between blood pressure and outcomes have [...]

Published
2002

34. Management and outcome of patients with atrial fibrillation during acute myocardial infarction: the GUSTO-III experience. (Cardiovascular Medicine)

Author

Wong, C-K, White, H.D., Wilcox, R.G., Criger, D.A., Califf, R.M., Topol, E.J., and Ohman, E.M.

Subjects
Atrial fibrillation -- Drug therapy -- Statistics -- Care and treatment, Anti-arrhythmia drugs -- Usage -- Statistics, Cardiac patients -- Drug therapy -- Care and treatment, Health, Drug therapy, Statistics, Care and treatment, Usage
Abstract

Objective: To investigate the use of antiarrhythmic agents and electrical cardioversion in the management of patients with atrial fibrillation complicating acute myocardial infarction, and their relation to 30 day and [...]

Published
2002

37. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

Author

Schwartz, G.G., Steg, P.G., Szarek, M., Bhatt, D.L., Bittner, V.A., Diaz, R., Edelberg, J.M., Goodman, S.G., Hanotin, C., Harrington, R.A., Jukema, J.W., Lecorps, G., Mahaffey, K.W., Moryusef, A., Pordy, R., Quintero, K., Roe, M.T., Sasiela, W.J., Tamby, J.F., Tricoci, P., Suryapranata, H., White, H.D., Zeiher, A.M., Schwartz, G.G., Steg, P.G., Szarek, M., Bhatt, D.L., Bittner, V.A., Diaz, R., Edelberg, J.M., Goodman, S.G., Hanotin, C., Harrington, R.A., Jukema, J.W., Lecorps, G., Mahaffey, K.W., Moryusef, A., Pordy, R., Quintero, K., Roe, M.T., Sasiela, W.J., Tamby, J.F., Tricoci, P., Suryapranata, H., White, H.D., and Zeiher, A.M.

Abstract

Item does not contain fulltext, BACKGROUND: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS: The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg o

Published
2018

42. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome

Author

Valgimigli, M. (Marco), Costa, F. (Francesco), Lokhnygina, Y. (Yuliya), Clare, R.M. (Robert M.), Wallentin, L.C. (Lars), Moliterno, D.J. (David), Armstrong, P.W. (Paul), White, H.D. (Harvey), Held, C. (Claes), Aylward, P.E. (Philip Edmund), Van DeWerf, F. (Frans), Harrington, R.A. (Robert A.), Mahaffey, K.W. (Kenneth), Tricoci, P. (Pierluigi), Valgimigli, M. (Marco), Costa, F. (Francesco), Lokhnygina, Y. (Yuliya), Clare, R.M. (Robert M.), Wallentin, L.C. (Lars), Moliterno, D.J. (David), Armstrong, P.W. (Paul), White, H.D. (Harvey), Held, C. (Claes), Aylward, P.E. (Philip Edmund), Van DeWerf, F. (Frans), Harrington, R.A. (Robert A.), Mahaffey, K.W. (Kenneth), and Tricoci, P. (Pierluigi)

Abstract

Aims Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS. Methods and results In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding Occurring>30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P<0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P =0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P=0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P<0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event. Conclusion In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding.

Published
2017
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43. Recognising 'painless' heart attacks

Author

Wong, C-K and White, H.D.

Subjects
Heart attack -- Diagnosis, Health, Diagnosis
Abstract

Heart attacks without chest pain all too often go unrecognised and untreated Ischaemic chest pain has been the hallmark of the clinical presentation of patients with acute coronary syndromes. New [...]

Published
2002

45. P858Women with stable coronary artery disease have better clinical outcomes than men, but this association is modified by degree of depression: insights from the STABILITY trial

Author

Oliveira Guimaraes, P., primary, Granger, C.B., additional, Chiswell, K., additional, Stebbins, A., additional, Held, C., additional, Hochman, J.S., additional, Krug-Gourley, S., additional, Lonn, E., additional, Lopes, R.L., additional, Stewart, R.A.H., additional, Vinereanu, D., additional, Wallentin, L., additional, White, H.D., additional, and Danchin, N., additional

Published
2017
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46. 3111Genetic variability in PAR4 platelet response in relation to bleeding and ischemic outcomes: a genetic substudy of the TRACER trial

Author

Tricoci, P., primary, Neely, M., additional, Whitley, M., additional, Edelstein, L., additional, Simon, L.M., additional, Shaw, C., additional, Moliterno, D.J., additional, Armstrong, P.W., additional, White, H.D., additional, Van de Werf, F., additional, Jennings, L.K., additional, Wallentin, L., additional, Harrington, R.A., additional, Mahaffey, K.W., additional, and Bray, P.F., additional

Published
2017
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49. Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Author

Chami, N. (Nathalie), Chen, M.-H. (Ming-Huei), Slater, A.J. (Andrew J.), Eicher, J.D. (John D.), Evangelou, E. (Evangelos), Tajuddin, S.M. (Salman M.), Love-Gregory, L. (Latisha), Kacprowski, T. (Tim), Schick, U.M. (Ursula), Nomura, A. (Akihiro), Giri, A. (Ayush), Lessard, S. (Samuel), Brody, J.A. (Jennifer A.), Schurmann, C. (Claudia), Pankratz, V.S. (Shane), Yanek, L.R. (Lisa), Manichaikul, A. (Ani), Pazoki, R. (Raha), Mihailov, E. (Evelin), Hill, W.D. (W. David), Raffield, L.M. (Laura M.), Burt, A.D. (Alastair), Bartz, T.M. (Traci M.), Becker, D.M. (Diane), Becker, L.C. (Lewis), Boerwinkle, E.A. (Eric), Bork-Jensen, J. (Jette), Bottinger, E.P. (Erwin), O'Donoghue, M.L. (Michelle L.), Crosslin, D.R. (David), de Denus, S. (Simon), Dubé, M.-P. (Marie-Pierre), Elliott, P. (Paul), Engström, G., Evans, M.K. (Michele), Floyd, J. (James), Fornage, M. (Myriam), Gao, H. (He), Greinacher, A. (Andreas), Gudnason, V. (Vilmundur), Hansen, T. (T.), Harris, T.B. (Tamara), Hayward, C. (Caroline), Hernesniemi, J. (Jussi), Highland, H. (Heather), Hirschhorn, J.N. (Joel), Hofman, A. (Albert), Irvin, M.R. (Marguerite R.), Kähönen, M. (Mika), Lange, E.M. (Ethan), Launer, L.J. (Lenore J.), Lehtimäki, T. (Terho), Li, J. (Jin), Liewald, D.C.M. (David), Linneberg, A. (Allan), Liu, Y. (YongMei), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mägi, R. (Reedik), Mathias, J. (Jasmine), Melander, O. (Olle), Metspalu, A. (Andres), Mononen, K. (Kari), Nalls, M.A. (Michael), Nickerson, D.A. (Deborah), Nikus, K. (Kjell), O'Donnell, C.J. (Christopher), Orho-Melander, M. (Marju), Pedersen, O. (Oluf), Petersmann, A. (Astrid), Polfus, L. (Linda), Psaty, B.M. (Bruce), Raitakari, O.T. (Olli T.), Raitoharju, E. (Emma), Richard, M. (Melissa), Rice, K.M. (Kenneth), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome I.), Schmidt, F. (Frank), Smith, A.V. (Albert Vernon), Starr, J.M. (John), Taylor, K.D. (Kent), Teumer, A. (Alexander), Thuesen, B.H. (Betina H.), Torstenson, E.S. (Eric S.), Tracy, R.P. (Russell), Tzoulaki, I., Zakai, N.A. (Neil), Vacchi-Suzzi, C. (Caterina), Duijn, C.M. (Cornelia) van, Rooij, F.J.A. (Frank) van, Cushman, M. (Mary Ann), Deary, I.J. (Ian), Velez Edwards, D.R. (Digna R.), Vergnaud, A.-C. (Anne-Claire), Wallentin, L.C. (Lars), Waterworth, D. (Dawn), White, H.D. (Harvey D.), Wilson, J.F. (James), Zonderman, A.B., Kathiresan, S. (Sekar), Grarup, N. (Niels), Esko, T. (Tõnu), Loos, R.J.F. (Ruth), Lange, L.A. (Leslie), Faraday, N. (Nauder), Abumrad, N.A. (Nada A.), Edwards, T.L. (Todd L.), Ganesh, S.K. (Santhi), Auer, P. (Paul), Johnson, A.D. (Andrew), Reiner, A. (Alexander), Lettre, G. (Guillaume), Chami, N. (Nathalie), Chen, M.-H. (Ming-Huei), Slater, A.J. (Andrew J.), Eicher, J.D. (John D.), Evangelou, E. (Evangelos), Tajuddin, S.M. (Salman M.), Love-Gregory, L. (Latisha), Kacprowski, T. (Tim), Schick, U.M. (Ursula), Nomura, A. (Akihiro), Giri, A. (Ayush), Lessard, S. (Samuel), Brody, J.A. (Jennifer A.), Schurmann, C. (Claudia), Pankratz, V.S. (Shane), Yanek, L.R. (Lisa), Manichaikul, A. (Ani), Pazoki, R. (Raha), Mihailov, E. (Evelin), Hill, W.D. (W. David), Raffield, L.M. (Laura M.), Burt, A.D. (Alastair), Bartz, T.M. (Traci M.), Becker, D.M. (Diane), Becker, L.C. (Lewis), Boerwinkle, E.A. (Eric), Bork-Jensen, J. (Jette), Bottinger, E.P. (Erwin), O'Donoghue, M.L. (Michelle L.), Crosslin, D.R. (David), de Denus, S. (Simon), Dubé, M.-P. (Marie-Pierre), Elliott, P. (Paul), Engström, G., Evans, M.K. (Michele), Floyd, J. (James), Fornage, M. (Myriam), Gao, H. (He), Greinacher, A. (Andreas), Gudnason, V. (Vilmundur), Hansen, T. (T.), Harris, T.B. (Tamara), Hayward, C. (Caroline), Hernesniemi, J. (Jussi), Highland, H. (Heather), Hirschhorn, J.N. (Joel), Hofman, A. (Albert), Irvin, M.R. (Marguerite R.), Kähönen, M. (Mika), Lange, E.M. (Ethan), Launer, L.J. (Lenore J.), Lehtimäki, T. (Terho), Li, J. (Jin), Liewald, D.C.M. (David), Linneberg, A. (Allan), Liu, Y. (YongMei), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mägi, R. (Reedik), Mathias, J. (Jasmine), Melander, O. (Olle), Metspalu, A. (Andres), Mononen, K. (Kari), Nalls, M.A. (Michael), Nickerson, D.A. (Deborah), Nikus, K. (Kjell), O'Donnell, C.J. (Christopher), Orho-Melander, M. (Marju), Pedersen, O. (Oluf), Petersmann, A. (Astrid), Polfus, L. (Linda), Psaty, B.M. (Bruce), Raitakari, O.T. (Olli T.), Raitoharju, E. (Emma), Richard, M. (Melissa), Rice, K.M. (Kenneth), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome I.), Schmidt, F. (Frank), Smith, A.V. (Albert Vernon), Starr, J.M. (John), Taylor, K.D. (Kent), Teumer, A. (Alexander), Thuesen, B.H. (Betina H.), Torstenson, E.S. (Eric S.), Tracy, R.P. (Russell), Tzoulaki, I., Zakai, N.A. (Neil), Vacchi-Suzzi, C. (Caterina), Duijn, C.M. (Cornelia) van, Rooij, F.J.A. (Frank) van, Cushman, M. (Mary Ann), Deary, I.J. (Ian), Velez Edwards, D.R. (Digna R.), Vergnaud, A.-C. (Anne-Claire), Wallentin, L.C. (Lars), Waterworth, D. (Dawn), White, H.D. (Harvey D.), Wilson, J.F. (James), Zonderman, A.B., Kathiresan, S. (Sekar), Grarup, N. (Niels), Esko, T. (Tõnu), Loos, R.J.F. (Ruth), Lange, L.A. (Leslie), Faraday, N. (Nauder), Abumrad, N.A. (Nada A.), Edwards, T.L. (Todd L.), Ganesh, S.K. (Santhi), Auer, P. (Paul), Johnson, A.D. (Andrew), Reiner, A. (Alexander), and Lettre, G. (Guillaume)

Abstract

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10−10 for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10−8 for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribut

Published
2016
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50. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

Author

Eicher, J.D. (John D.), Chami, N. (Nathalie), Kacprowski, T. (Tim), Nomura, A. (Akihiro), Chen, M.-H. (Ming-Huei), Yanek, L.R. (Lisa), Tajuddin, S.M. (Salman M.), Schick, U.M. (Ursula), Slater, A.J. (Andrew J.), Pankratz, V.S. (Shane), Polfus, L. (Linda), Schurmann, C. (Claudia), Giri, A. (Ayush), Brody, J.A. (Jennifer A.), Lange, L.A. (Leslie), Manichaikul, A. (Ani), Hill, W.D. (W. David), Pazoki, R. (Raha), Elliot, P. (Paul), Evangelou, E. (Evangelos), Tzoulaki, I., Gao, H. (He), Vergnaud, A.-C. (Anne-Claire), Mathias, J. (Jasmine), Becker, D.M. (Diane), Becker, L.C. (Lewis), Burt, A.D. (Alastair), Crosslin, D.R. (David), Lyytikäinen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Hernesniemi, J. (Jussi), Kähönen, M. (Mika), Raitoharju, E. (Emma), Mononen, K. (Kari), Raitakari, O.T. (Olli T.), Lehtimäki, T. (Terho), Cushman, M. (Mary Ann), Zakai, N.A. (Neil), Nickerson, D.A. (Deborah), Raffield, L.M. (Laura M.), Quarells, R. (Rakale), Willer, C.J. (Cristen), Peloso, G.M. (Gina), Abecasis, G.R. (Gonçalo), Liu, D. (Dajiang), Deloukas, P. (Panagiotis), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Erdmann, J. (Jeanette), Fornage, M. (Myriam), Richard, M. (Melissa), Tardif, J.-C. (Jean-Claude), Rioux, J.D. (John D.), Dube, M.-P. (Marie-Pierre), de Denus, S. (Simon), Lu, Y. (Yingchang), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Smith, A.V. (Albert Vernon), Harris, T.B. (Tamara), Launer, L.J. (Lenore J.), Gudnason, V. (Vilmundur), Velez Edwards, D.R. (Digna R.), Torstenson, E.S. (Eric S.), Liu, Y. (YongMei), Tracy, R.P. (Russell), Rotter, J.I. (Jerome I.), Rich, S.S. (Stephen), Highland, H. (Heather), Boerwinkle, E.A. (Eric), Li, J. (Jin), Lange, E.M. (Ethan), Wilson, J.F. (James), Mihailov, E. (Evelin), Mägi, R. (Reedik), Hirschhorn, J.N. (Joel), Metspalu, A. (Andres), Esko, T. (Tõnu), Vacchi-Suzzi, C. (Caterina), Nalls, M.A. (Michael), Zonderman, A.B., Evans, M.K. (Michele), Engström, G., Orho-Melander, M. (Marju), Melander, O. (Olle), O'Donoghue, M.L. (Michelle L.), Waterworth, D. (Dawn), Wallentin, L.C. (Lars), White, H.D. (Harvey D.), Floyd, J. (James), Bartz, T.M. (Traci M.), Rice, K.M. (Kenneth), Psaty, B.M. (Bruce), Starr, J.M. (John), Liewald, D.C.M. (David), Hayward, C. (Caroline), Deary, I.J. (Ian), Greinacher, A. (Andreas), Völker, U. (Uwe), Thiele, T. (Thomas), Völzke, H. (Henry), Rooij, F.J.A. (Frank) van, Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Ganesh, S.K. (Santhi), Kathiresan, S. (Sekar), Faraday, N. (Nauder), Auer, P. (Paul), Reiner, A. (Alexander), Lettre, G. (Guillaume), Johnson, A.D. (Andrew), Eicher, J.D. (John D.), Chami, N. (Nathalie), Kacprowski, T. (Tim), Nomura, A. (Akihiro), Chen, M.-H. (Ming-Huei), Yanek, L.R. (Lisa), Tajuddin, S.M. (Salman M.), Schick, U.M. (Ursula), Slater, A.J. (Andrew J.), Pankratz, V.S. (Shane), Polfus, L. (Linda), Schurmann, C. (Claudia), Giri, A. (Ayush), Brody, J.A. (Jennifer A.), Lange, L.A. (Leslie), Manichaikul, A. (Ani), Hill, W.D. (W. David), Pazoki, R. (Raha), Elliot, P. (Paul), Evangelou, E. (Evangelos), Tzoulaki, I., Gao, H. (He), Vergnaud, A.-C. (Anne-Claire), Mathias, J. (Jasmine), Becker, D.M. (Diane), Becker, L.C. (Lewis), Burt, A.D. (Alastair), Crosslin, D.R. (David), Lyytikäinen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Hernesniemi, J. (Jussi), Kähönen, M. (Mika), Raitoharju, E. (Emma), Mononen, K. (Kari), Raitakari, O.T. (Olli T.), Lehtimäki, T. (Terho), Cushman, M. (Mary Ann), Zakai, N.A. (Neil), Nickerson, D.A. (Deborah), Raffield, L.M. (Laura M.), Quarells, R. (Rakale), Willer, C.J. (Cristen), Peloso, G.M. (Gina), Abecasis, G.R. (Gonçalo), Liu, D. (Dajiang), Deloukas, P. (Panagiotis), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Erdmann, J. (Jeanette), Fornage, M. (Myriam), Richard, M. (Melissa), Tardif, J.-C. (Jean-Claude), Rioux, J.D. (John D.), Dube, M.-P. (Marie-Pierre), de Denus, S. (Simon), Lu, Y. (Yingchang), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Smith, A.V. (Albert Vernon), Harris, T.B. (Tamara), Launer, L.J. (Lenore J.), Gudnason, V. (Vilmundur), Velez Edwards, D.R. (Digna R.), Torstenson, E.S. (Eric S.), Liu, Y. (YongMei), Tracy, R.P. (Russell), Rotter, J.I. (Jerome I.), Rich, S.S. (Stephen), Highland, H. (Heather), Boerwinkle, E.A. (Eric), Li, J. (Jin), Lange, E.M. (Ethan), Wilson, J.F. (James), Mihailov, E. (Evelin), Mägi, R. (Reedik), Hirschhorn, J.N. (Joel), Metspalu, A. (Andres), Esko, T. (Tõnu), Vacchi-Suzzi, C. (Caterina), Nalls, M.A. (Michael), Zonderman, A.B., Evans, M.K. (Michele), Engström, G., Orho-Melander, M. (Marju), Melander, O. (Olle), O'Donoghue, M.L. (Michelle L.), Waterworth, D. (Dawn), Wallentin, L.C. (Lars), White, H.D. (Harvey D.), Floyd, J. (James), Bartz, T.M. (Traci M.), Rice, K.M. (Kenneth), Psaty, B.M. (Bruce), Starr, J.M. (John), Liewald, D.C.M. (David), Hayward, C. (Caroline), Deary, I.J. (Ian), Greinacher, A. (Andreas), Völker, U. (Uwe), Thiele, T. (Thomas), Völzke, H. (Henry), Rooij, F.J.A. (Frank) van, Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Ganesh, S.K. (Santhi), Kathiresan, S. (Sekar), Faraday, N. (Nauder), Auer, P. (Paul), Reiner, A. (Alexander), Lettre, G. (Guillaume), and Johnson, A.D. (Andrew)

Abstract

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets’ important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Published
2016
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