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P. van der Harst

Bio: P. van der Harst is an academic researcher from University Medical Center Groningen. The author has contributed to research in topics: Genome-wide association study & Heart failure. The author has an hindex of 19, co-authored 54 publications receiving 2516 citations. Previous affiliations of P. van der Harst include Greifswald University Hospital & University of Groningen.

Papers published on a yearly basis

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Journal ArticleDOI
Daniel I. Swerdlow1, Michael V. Holmes1, Karoline Kuchenbaecker2, Engmann Jel.1, Tina Shah1, Reecha Sofat1, Yiran Guo, C Chung1, Anne Peasey1, Roman Pfister3, Simon P. Mooijaart4, Helen Ireland1, Maarten Leusink5, Claudia Langenberg3, KaWah Li1, Jutta Palmen1, Phil Howard1, Jackie A. Cooper1, Fotios Drenos1, John Hardy1, Mike A. Nalls6, Yun Li7, Gordon D.O. Lowe8, Marlene C. W. Stewart9, S. J. Bielinski10, Julian Peto11, Nicholas J. Timpson12, John Gallacher13, Malcolm G. Dunlop9, Richard S. Houlston, Ian Tomlinson14, Ioanna Tzoulaki15, Jian'an Luan2, Boer Jma.2, Nita G. Forouhi2, N. C. Onland-Moret5, Y. T. van der Schouw16, Renate B. Schnabel16, Jaroslav A. Hubacek, Růžena Kubínová, Migle Baceviciene17, Abdonas Tamosiunas17, Andrzej Pajak18, Roman Topor-Madry18, Sofia Malyutina19, Damiano Baldassarre, Bengt Sennblad20, Elena Tremoli, U de Faire21, Luigi Ferrucci21, S Bandenelli, Tetsu Tanaka21, James F. Meschia10, AB Singleton6, Gerjan Navis22, I. Mateo Leach22, Bakker Sjl.22, Ron T. Gansevoort, Ian Ford8, Stephen E. Epstein23, Mary-Susan Burnett23, Joe Devaney23, Johan Wouter Jukema4, Westendorp Rgj.5, G Jan de Borst5, Y. van der Graaf5, P A de Jong5, Mailand-van der Zee A-H.5, Olaf H. Klungel5, A. de Boer5, P. A. Doevendans5, Jeffrey W. Stephens24, Charles B. Eaton25, Jennifer G. Robinson26, JoAnn E. Manson27, F G Fowkes28, Timothy M. Frayling28, Jenna Price9, Peter H. Whincup11, Richard W Morris1, Debbie A Lawlor12, George Davey Smith12, Yoav Ben-Shlomo12, Susan Redline27, Leslie A. Lange29, Meena Kumari1, Nicholas J. Wareham2, Verschuren Wmm.30, Emelia J. Benjamin30, John C. Whittaker11, Anders Hamsten20, Frank Dudbridge11, Delaney Jac.31, Andrew Wong31, Diana Kuh31, Rebecca Hardy31, Berta Almoguera Castillo7, John Connolly7, P. van der Harst, Eric J. Brunner1, Michael Marmot1, Christina L. Wassel32, Steve E. Humphries1, P.J. Talmud1, Mika Kivimäki1, Folkert W. Asselbergs5, Mikhail I. Voevoda19, Martin Bobak1, Hynek Pikhart1, James G. Wilson33, Hakon Hakonarson7, Alexander P. Reiner34, Brendan J. Keating7, Naveed Sattar8, Aroon D. Hingorani1, Juan P. Casas11 
TL;DR: IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials and could help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.

891 citations

Journal ArticleDOI
TL;DR: The fibrosis marker galectin‐3 and outcome in the general population and in the University of Groningen patients indicates that cystic fibrosis is more common in women than in men.
Abstract: . de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, Bakker SJL, van der Harst P (University of Groningen). The fibrosis marker galectin-3 and outcome in the general population. J Intern Med 2012; 272: 5564. Objective. Galectin-3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin-3 and cardiovascular (CV) risk factors and mortality in the general population. Design and subjects. This study included 7968 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, with a median follow-up of approximately 10 years. Plasma galectin-3 was measured in baseline samples. Main outcome measures. We investigated the relationships between galectin-3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all-cause, CV and cancer mortality. Results. The mean age of the population was 50 +/- 13 years. Mean blood pressure was 129/74 mmHg, mean cholesterol was 5.7 +/- 1.1 mmol L-1 and median galectin-3 was 10.9 ng mL-1 [interquartile range (IQR) 9.013.1]. Galectin-3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N-terminal pro-B-type natriuretic peptide (P <0.0001). We observed a strong association between galectin-3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin-3 levels (11.0 ng mL-1, IQR 9.113.4 vs. men (n = 3967) 10.7 ng mL-1, IQR 8.912.8; P <0.0001), and galectin-3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin-3 levels independently predicted all-cause mortality (hazard ratio per SD galectin-3 1.09, 95% CI 1.011.19; P = 0.036), but not CV and cancer mortality separately. Conclusions. Galectin-3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin-3 predicts all-cause mortality in the general population.

334 citations

Journal ArticleDOI
Sonia Shah1, Albert Henry2, Carolina Roselli3, Honghuang Lin4  +164 moreInstitutions (58)
TL;DR: Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension.
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

326 citations

Journal ArticleDOI
TL;DR: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.
Abstract: Introduction: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection–fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. Methods and results: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50–99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43–2.01; for beta-blocker: HR 1.70; 95% CI 1.36–2.05). Conclusion: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

292 citations

Journal ArticleDOI
Yukinori Okada, Xueling Sim1, Xueling Sim2, Min Jin Go  +411 moreInstitutions (19)
TL;DR: A meta-analysis of genome-wide association studies for kidney function–related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN), identified 17 loci newly associated with kidney function-related traits.
Abstract: Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

271 citations


Cited by
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TL;DR: Antiinflammatory therapy targeting the interleukin‐1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid‐level lowering.
Abstract: BackgroundExperimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. MethodsWe conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. ResultsAt 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in t...

5,660 citations

Journal ArticleDOI
TL;DR: The Statistical Update represents the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA's My Life Check - Life’s Simple 7, which include core health behaviors and health factors that contribute to cardiovascular health.
Abstract: Each chapter listed in the Table of Contents (see next page) is a hyperlink to that chapter. The reader clicks the chapter name to access that chapter. Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA’s My Life Check - Life’s Simple 7 (Figure1), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents …

5,102 citations

Journal ArticleDOI
TL;DR: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascul...
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascul...

3,034 citations

Journal ArticleDOI
TL;DR: It is concluded that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual‐level data, although the necessary assumptions cannot be so fully assessed.
Abstract: Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene–gene interactions, linkage disequilibrium, and ‘weak instruments’ on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene–gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than , then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed.

2,003 citations

Journal ArticleDOI
Yukinori Okada1, Yukinori Okada2, Di Wu3, Di Wu1, Di Wu2, Gosia Trynka1, Gosia Trynka2, Towfique Raj2, Towfique Raj1, Chikashi Terao4, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura4, Akari Suzuki, Shinji Yoshida, Robert R. Graham5, A. Manoharan5, Ward Ortmann5, Tushar Bhangale5, Joshua C. Denny6, Robert J. Carroll6, Anne E. Eyler6, Jeff Greenberg7, Joel M. Kremer, Dimitrios A. Pappas8, Lei Jiang9, Jian Yin9, Lingying Ye9, Ding Feng Su9, Jian Yang10, Gang Xie11, E.C. Keystone11, Harm-Jan Westra12, Tõnu Esko13, Tõnu Esko2, Tõnu Esko1, Andres Metspalu13, Xuezhong Zhou14, Namrata Gupta1, Daniel B. Mirel1, Eli A. Stahl15, Dorothee Diogo1, Dorothee Diogo2, Jing Cui1, Jing Cui2, Katherine P. Liao1, Katherine P. Liao2, Michael H. Guo1, Michael H. Guo2, Keiko Myouzen, Takahisa Kawaguchi4, Marieke J H Coenen16, Piet L. C. M. van Riel16, Mart A F J van de Laar17, Henk-Jan Guchelaar18, Tom W J Huizinga18, Philippe Dieudé19, Xavier Mariette20, S. Louis Bridges21, Alexandra Zhernakova18, Alexandra Zhernakova12, René E. M. Toes18, Paul P. Tak22, Paul P. Tak23, Paul P. Tak24, Corinne Miceli-Richard20, So Young Bang25, Hye Soon Lee25, Javier Martin26, Miguel A. Gonzalez-Gay, Luis Rodriguez-Rodriguez27, Solbritt Rantapää-Dahlqvist28, Lisbeth Ärlestig28, Hyon K. Choi29, Hyon K. Choi2, Yoichiro Kamatani30, Pilar Galan19, Mark Lathrop31, Steve Eyre32, Steve Eyre33, John Bowes33, John Bowes32, Anne Barton33, Niek de Vries23, Larry W. Moreland34, Lindsey A. Criswell35, Elizabeth W. Karlson2, Atsuo Taniguchi, Ryo Yamada4, Michiaki Kubo, Jun Liu2, Sang Cheol Bae25, Jane Worthington32, Jane Worthington33, Leonid Padyukov36, Lars Klareskog36, Peter K. Gregersen37, Soumya Raychaudhuri2, Soumya Raychaudhuri1, Barbara E. Stranger38, Philip L. De Jager1, Philip L. De Jager2, Lude Franke12, Peter M. Visscher10, Matthew A. Brown10, Hisashi Yamanaka, Tsuneyo Mimori4, Atsushi Takahashi, Huji Xu9, Timothy W. Behrens5, Katherine A. Siminovitch11, Shigeki Momohara, Fumihiko Matsuda4, Kazuhiko Yamamoto39, Robert M. Plenge2, Robert M. Plenge1 
20 Feb 2014-Nature
TL;DR: A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.
Abstract: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

1,910 citations