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6. Potential benefits of the use of sympathomimetics for asthmatic disease, on semen quality in men of subfertile couples

Author

Oostingh, E.C. (Eline), Otte-Huijgen, N.A. (Nicole), Koedooder, R. (Rivka), Dohle, G.R. (Gert), Stricker, B.H.Ch. (Bruno), Steegers-Theunissen, R.P.M. (Régine), Oostingh, E.C. (Eline), Otte-Huijgen, N.A. (Nicole), Koedooder, R. (Rivka), Dohle, G.R. (Gert), Stricker, B.H.Ch. (Bruno), and Steegers-Theunissen, R.P.M. (Régine)

Abstract

Research question: Is there an association between the use of sympathomimetics for asthmatic disease and semen quality in humans? Design: Between 2007 and 2012 a prospective cohort study was conducted among couples visiting the preconception counselling clinic at a tertiary hospital in the Netherlands. The study included 882 men of subfertile couples and information on medication use was obtained from self-administered questionnaires. Moreover, data on semen parameters were retrieved from medical records. Results: The study population of men revealed a mean (± SD) age of 34 ± 4 years with a mean body mass index (BMI) of 26.1 ± 2.3 kg/m2, and sympathomimetic use was reported by 3.6%. The use of sympathomimetics was positively associated with a 10% higher sperm motility (beta 10.265; 95% confidence interval [CI] 3.258–17.272) after adjustment for smoking, alcohol use, age, geographic background, BMI, folic acid supplement use, the four astronomical seasons and asthma/bronchitis. Subgroup analysis between men with total motile sperm count (TMSC) < or ≥10 million showed that this association remained (P ≤ 0.001) after adjustment for these confounders. After adjustment for confounders the sperm concentration was also positively associated with the use of sympathomimetics, but only in men with TMSC ≥10 million (beta 0.300; 95% CI 0.032–0.568). Conclusions: These preliminary data show the potential benefits of the use of sympathomimetics to improve sperm motility in men of subfertile couples, which needs further investigation.

Published
2021
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14. Prevalence and incidence rate of hospital admissions related to medication between 2008 and 2013 in The Netherlands

Author

Lghoul-Oulad Saïd, F., Hek, K. (Karin), Flinterman, L.E., Herings, R.M.C., Warlé-van Herwaarden, M.F., Bie, S. (Sandra) de, Valkhoff, V.E. (Vera), Alsma, J. (Jelmer), Mosseveld, M., Vanrolleghem, A.M. (Ann M.), Stricker, B.H.Ch. (Bruno), Sturkenboom, M.C.J.M. (Miriam), Smet, P.A.G.M. (Peter), Bemt, P.M.L.A. (Patricia) van den, Lghoul-Oulad Saïd, F., Hek, K. (Karin), Flinterman, L.E., Herings, R.M.C., Warlé-van Herwaarden, M.F., Bie, S. (Sandra) de, Valkhoff, V.E. (Vera), Alsma, J. (Jelmer), Mosseveld, M., Vanrolleghem, A.M. (Ann M.), Stricker, B.H.Ch. (Bruno), Sturkenboom, M.C.J.M. (Miriam), Smet, P.A.G.M. (Peter), and Bemt, P.M.L.A. (Patricia) van den

Abstract

Purpose: In 2009 a Dutch guideline was published containing recommendations to reduce Hospital Admissions Related to Medications (HARMs). This study aims to examine t

Published
2020
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15. The Obesity Paradox in Lung Cancer: Associations With Body Size Versus Body Shape

Author

Ardesch, F.H. (F. H.), Ruiter, T.R. (Rikje), Mulder, M. (Marlies), Lahousse, L. (Lies), Stricker, B.H.Ch. (Bruno), Kiefte-de Jong, J.C. (Jessica), Ardesch, F.H. (F. H.), Ruiter, T.R. (Rikje), Mulder, M. (Marlies), Lahousse, L. (Lies), Stricker, B.H.Ch. (Bruno), and Kiefte-de Jong, J.C. (Jessica)

Abstract

Background: The association between obesity and lung cancer (LC) remains poorly understood. However, other indices of obesity on the basis of body shape instead of body size have not been examined yet. The aim of this study was to evaluate the association between different indices of body size and body shape and the risk of LC. In particular, this study examined the association between A Body Shape Index, a more precise indicator of abdominal fat than traditional anthropometric measures, and the risk of LC. Methods: In the prospective cohort the Rotterdam Study, we analysed data of 9,689 participants. LC diagnoses were based on medical records and anthropometric measurements were assessed at baseline. Cox-regression analyses with corresponding Hazard Ratios were used to examine the association between the anthropometric measurements and the risk of LC with adjustment for potential confounders. Potential non-linear associations were explored with cubic splines using the Likelihood ratio (LR) test. Results: During follow-up, 319 participants developed LC. Body mass Index (BMI) was inversely associated with the risk of lung cancer (HR 0.94, 95% CI: 0.91–0.97) and persisted after excluding lung cancer cases during the first 10 years of follow-up. There was evidence for a non-linear association between BMI and the risk of lung cancer (0,04, df = 1), which indicated that the inverse association between BMI and lung cancer was mainly present in non-obese participants. Waist circumference (WC) (HR 1.03 95% CI: 1.01–1.05), Waist-to-Hip Ratio (WHR) (HR 1.23 95% CI: 1.09–1.38) and ABSI (A Body Shape Index) (HR 1.17 95% CI: 1.05–1.30) were positively and linearly associated with the risk of lung cancer. Conclusions: Body shape rather than body size may be an important risk indicator of LC. Future research should focus on the role of visceral fat and the risk of LC as well as the underlying mechanisms.

Published
2020
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16. Long-term effects of antimicrobial drugs on the composition of the human gut microbiota

Author

M. Mulder, Radjabzadeh, D., Kiefte-de Jong, J.C. (Jessica), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Stricker, B.H.Ch. (Bruno), Verbon, A. (Annelies), M. Mulder, Radjabzadeh, D., Kiefte-de Jong, J.C. (Jessica), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Stricker, B.H.Ch. (Bruno), and Verbon, A. (Annelies)

Abstract

Introduction: Antimicrobial drugs are known to have effects on the human gut microbiota. We studied the long-term temporal relationship between several antimicrobial drug groups and the composition of the human gut microbiota determined in feces samples. Methods: Feces samples were obtained from a community-dwelling cohort of middle-aged and elderly individuals (Rotterdam Study). Bacterial DNA was isolated and sequenced using V3/V4 16 S ribosomal RNA sequencing (Illumina MiSeq). The time between the last prescription of several antimicrobial drug groups and the day of sampling was categorized into 0–12, 12–2

Published
2020
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18. The systemic immune-inflammation index is associated with an increased risk of incident cancer-A population-based cohort study

Author

Fest, J. (Jesse), Ruiter, T.R. (Rikje), Mulder, M. (Marlies), Groot Koerkamp, B. (Bas), Ikram, M.A. (Arfan), Stricker, B.H.Ch. (Bruno), Eijck, C.H.J. (Casper) van, Fest, J. (Jesse), Ruiter, T.R. (Rikje), Mulder, M. (Marlies), Groot Koerkamp, B. (Bas), Ikram, M.A. (Arfan), Stricker, B.H.Ch. (Bruno), and Eijck, C.H.J. (Casper) van

Abstract

Several studies found that the systemic immune-inflammation index (SII) is a prognostic factor for mortality in patients with solid tumors. It is unknown whether an increased SII in generally healthy individuals reflects a risk for developing cancer. Our objective was to investigate the association between the SII and incident cancers in a prospective cohort study. Data were obtained from the Rotterdam Study; a population-based study of individuals aged ≥45 years, between 2002 and 2013. The SII at baseline was calculated from absolute blood counts. The association between the SII and the risk o

Published
2020
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19. Maternal Sociodemographic Factors Are Associated With Methylphenidate Initiation in Children in the Netherlands: A Population-Based Study

Author

Cheung, K., El Marroun, H. (Hanan), Dierckx, B. (Bram), Visser, L.E. (Loes), Stricker, B.H.Ch. (Bruno), Cheung, K., El Marroun, H. (Hanan), Dierckx, B. (Bram), Visser, L.E. (Loes), and Stricker, B.H.Ch. (Bruno)

Abstract

Multiple factors may contribute to the decision to initiate methylphenidate treatment in children such as maternal sociodemographic factors of which relatively little is known. The objective was to investigate the association between these factors and methylphenidate initiation. The study population included 4243 children from the Generation R Study in the Netherlands. Maternal sociodemographic characteristics were tested as determinants of methylphenidate initiation through a timedependent Cox regression analysis. Subsequently, we stratifed by mother-reported ADHD symptoms (present in 4.2% of the study population). When ADHD symptoms were absent, we found that girls (adjusted HR 0.25, 95%CI 0.16–0.39) and children born to a mother with a non-western ethnicity (compared to Dutch-Caucasian) (adjusted HR 0.42, 95%CI 015–0.68) were less likely to receive methylphenidate. They were more likely to receive methylphenidate when their mother completed a low (adjusted HR 2.29, 95%CI 1.10–4.77) or secondary (adjusted HR 1.71, 95%CI 1.16–2.54) education. In conclusion, boys and children born to a mother of Dutch-Caucasian ethnicity were more likely to receive methylphenidate, irrespective of the presence of ADHD symptoms.

Published
2020
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20. Validation of the BOADICEA model and a 313-variant polygenic risk score for breast cancer risk prediction in a Dutch prospective cohort

Author

Lakeman, I.M.M. (Inge M. M.), Rodríguez-Girondo, M. (Mar), Lee, A. (Andrew), Ruiter, T.R. (Rikje), Stricker, B.H.Ch. (Bruno), Wijnant, S.R.A. (Sara R. A.), Kavousi, M. (Maryam), Antoniou, A.C. (Antonis C.), Schmidt, M.K. (Marjanka), Uitterlinden, A.G. (André), Rooij, J.G.J. (Jeroen) van, Devilee, P. (Peter), Lakeman, I.M.M. (Inge M. M.), Rodríguez-Girondo, M. (Mar), Lee, A. (Andrew), Ruiter, T.R. (Rikje), Stricker, B.H.Ch. (Bruno), Wijnant, S.R.A. (Sara R. A.), Kavousi, M. (Maryam), Antoniou, A.C. (Antonis C.), Schmidt, M.K. (Marjanka), Uitterlinden, A.G. (André), Rooij, J.G.J. (Jeroen) van, and Devilee, P. (Peter)

Abstract

Purpose: We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)–associated variants (PRS313) and other, nongenetic risk factors. Methods: Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS313 was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS313 and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. Results: In total, 320 women developed BC. The PRS313 was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40–1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. Conclusions: The effect size of the PRS313 is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.

Published
2020
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21. A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Author

Prokić, I. (Ivana), Lahousse, L. (Lies), de Vries, M. (Maaike), Liu, J. (Jun), Kalaoja, M. (Marita), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), van Diemen, C.C. (Cleo C.), Spek, A. (Ashley) van der, Zhernakova, A. (Alexandra), Fu, J. (Jingyuan), Ghanbari, M. (Mohsen), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Havulinna, A.S. (Aki), Perola, M. (Markus), Salomaa, V. (Veikko), Kao, W.H.L. (Wen), Ärnlöv, J. (Johan), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Boezen, H.M. (H Marike), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), Prokić, I. (Ivana), Lahousse, L. (Lies), de Vries, M. (Maaike), Liu, J. (Jun), Kalaoja, M. (Marita), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), van Diemen, C.C. (Cleo C.), Spek, A. (Ashley) van der, Zhernakova, A. (Alexandra), Fu, J. (Jingyuan), Ghanbari, M. (Mohsen), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Havulinna, A.S. (Aki), Perola, M. (Markus), Salomaa, V. (Veikko), Kao, W.H.L. (Wen), Ärnlöv, J. (Johan), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Boezen, H.M. (H Marike), Duijn, C.M. (Cornelia) van, and Amin, N. (Najaf)

Abstract

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. METHODS: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. RESULTS: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally i

Published
2020
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22. The association of innate and adaptive immunity, subclinical atherosclerosis, and cardiovascular disease in the Rotterdam Study: A prospective cohort study

Author

Fani, L. (Lana), Willik, K.D. (Kimberly) van der, Bos, D. (Daniel), Leening, M.J.G. (Maarten J G), Koudstaal, P.J. (Peter), Rizopoulos, D. (Dimitris), Ruiter, T.R. (Rikje), Stricker, B.H.Ch. (Bruno), Kavousi, M. (Maryam), Ikram, M.A. (Arfan), Ikram, M.K. (Kamran), Fani, L. (Lana), Willik, K.D. (Kimberly) van der, Bos, D. (Daniel), Leening, M.J.G. (Maarten J G), Koudstaal, P.J. (Peter), Rizopoulos, D. (Dimitris), Ruiter, T.R. (Rikje), Stricker, B.H.Ch. (Bruno), Kavousi, M. (Maryam), Ikram, M.A. (Arfan), and Ikram, M.K. (Kamran)

Abstract

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association. METHODS AND FINDINGS: Granulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count [95% CI] = 1.78 [1.34-2.37], P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume [mm3] per SD increase in granulocyte count [95% CI] = 32.3 [9.9-54.7], P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated [95% CI] = 19.0% [-10% to 32.3%], P = 0.08) and intracranial artery calcification (14.9% [-10.9% to 19.1%], P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availabi

Published
2020
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23. Objectives, design and main findings until 2020 from the Rotterdam Study

Author

Ikram, M.A. (Arfan), Brusselle, G.G. (Guy), Ghanbari, M. (Mohsen), Goedegebure, A. (Andre), Ikram, M.K. (Kamran), Kavousi, M. (Maryam), Kieboom, B.C.T. (Brenda), Klaver, C.C.W. (Caroline), Knegt, R.J. (Robert) de, Luik, A.I. (Annemarie), Nijsten, T.E.C. (Tamar), Peeters, R.P. (Robin), Rooij, F.J.A. (Frank) van, Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Vernooij, M.W. (Meike), Voortman, R.G. (Trudy), Ikram, M.A. (Arfan), Brusselle, G.G. (Guy), Ghanbari, M. (Mohsen), Goedegebure, A. (Andre), Ikram, M.K. (Kamran), Kavousi, M. (Maryam), Kieboom, B.C.T. (Brenda), Klaver, C.C.W. (Caroline), Knegt, R.J. (Robert) de, Luik, A.I. (Annemarie), Nijsten, T.E.C. (Tamar), Peeters, R.P. (Robin), Rooij, F.J.A. (Frank) van, Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Vernooij, M.W. (Meike), and Voortman, R.G. (Trudy)

Abstract

The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases.As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

Published
2020
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24. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Ntalla, I. (Ioanna), Weng, L.-C., Cartwright, J.H. (James H.), Hall, A.W. (Amelia Weber), Sveinbjornsson, G. (Gardar), Tucker, N.R. (Nathan R.), Choi, S.H. (Seung Hoan), Chaffin, M.D. (Mark D.), Roselli, C. (Carolina), Barnes, M.J. (Michael), Mifsud, B. (Borbala), Warren, H.R. (Helen R.), Hayward, C. (Caroline), Marten, J. (Jonathan), Cranley, J.J. (James J.), Concas, M.P. (Maria Pina), Gasparini, P. (Paolo), Boutin, T. (Thibaud), Kolcic, I. (Ivana), Polasek, O. (Ozren), Rudan, I. (Igor), Araujo, N.M. (Nathalia M.), Lima-Costa, M.F. (Maria Fernanda), Ribeiro, A.L. (Antonio), Souza, R.P. (Renan P.), Tarazona-Santos, E. (Eduardo), Giedraitis, V. (Vilmantas), Ingelsson, E. (Erik), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Del Greco M, F. (Fabiola), Foco, L. (Luisa), Gögele, M. (Martin), Hicks, A.A. (Andrew A.), Cook, J.P. (James P.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Sundström, J. (Johan), Nelson, C.P. (Christopher P.), Riaz, M.B. (Muhammad B.), Samani, N.J. (Nilesh), Sinagra, G. (Gianfranco), Ulivi, S. (Shelia), Kähönen, M. (Mika), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Nikus, K. (Kjell), Caulfield, M. (Mark), Dominiczak, A. (Anna), Padmanabhan, S. (Sandosh), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Ryan, K. (Kathleen), Shuldiner, A.R. (Alan R.), Aeschbacher, S. (Stefanie), Conen, D. (David), Risch, L. (Lorenz), Thériault, S. (Sébastien), Hutri-Kähönen, N. (Nina), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Raitakari, O. (Olli), Barnes, C.L.K. (Catriona L. K.), Campbell, H. (Harry), Joshi, P.K. (Peter), Wilson, J.F. (James), Isaacs, A.J. (Aaron), Kors, J.A. (Jan), Duijn, C.M. (Cornelia) van, Huang, P.L. (Paul L.), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara B.), Launer, L.J. (Lenore), Smith, A.V. (Albert), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Nadkarni, G. (Girish), Preuss, M. (Michael), Correa, D.D., Mei, H. (Hao), Meitinger, T. (Thomas), Müller-Nurasyid, M. (Martina), Peters, A. (Annette), Waldenberger, M. (Melanie), Mangino, M. (Massimo), Spector, T.D. (Timothy), Rienstra, S.A., van de Vegte, Y.J. (Yordi J.), Harst, P. (Pim) van der, Verweij, N. (Niek), Kääb, S. (Stefan), Schramm, K. (Katharina), Sinner, M.F. (Moritz), Strauch, K. (Konstantin), Cutler, M.J. (Michael J.), Fatkin, D. (Diane), London, B. (Barry), Olesen, M.S. (Morten S.), Roden, D.M. (Dan M.), Benjamin Shoemaker, M. (M.), Gustav Smith, J. (J.), Biggs, M.L. (M.), Bis, J.C. (Joshua), Brody, J.A. (Jennifer A.), Psaty, B.M. (Bruce), Rice, K.M. (Kenneth), Sotoodehnia, N. (Nona), Grandi, A. (Alessandro) de, Fuchsberger, C. (Christian), Penninx, B.W.J.H., Pramstaller, P.P. (Peter Paul), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Macfarlane, P.W. (Peter W.), Trompet, S. (Stella), Dörr, M. (Marcus), Felix, S.B. (Stephan B.), Völker, U. (Uwe), Weiss, S. (Stefan), Havulinna, A.S. (Aki), Jula, A. (Antti), Sääksjärvi, K. (K.), Salomaa, V. (Veikko), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Lin, H.J. (Henry J.), Rotter, J.I. (Jerome I.), Taylor, K.D. (Kent), Yao, J. (Jie), Mutsert, R. (Reneé) de, Maan, A.C. (Arie C.), Mook-Kanamori, D.O. (Dennis O.), Noordam, R. (Raymond), Cucca, F. (Francesco), Ding, J. (Jun), Lakatta, E. (Edward), Qian, Y. (Yong), Tarasov, K.V. (Kirill V.), Levy, D. (Daniel), Lin, H. (Honghuang), Newton-Cheh, C. (Christopher), Lunetta, K.L. (Kathryn), Murray, A.D. (Alison D.), Porteous, D.J. (David J.), Smith, B.H. (Blair), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Berg, M.E. (Marten) van den, Haessler, J. (Jeff), Jackson, R.D. (Rebecca), Kooperberg, C. (Charles), Peters, U. (Ulrike), Reiner, A.P. (Alexander P.), Whitsel, E.A. (Eric), Alonso, A. (Alvaro), Arking, D.E. (Dan E.), Boerwinkle, E.A. (Eric), Ehret, G.B. (Georg B.), Soliman, E.Z. (Elsayed Z.), Avery, C.L., Gogarten, S.M., Kerr, K.F. (Kathleen), Laurie, C.C. (Cathy C.), Seyerle, A.A. (Amanda A.), Stilp, A. (Adrienne), Assa, S. (Solmaz), Abdullah Said, M. (M.), Yldau van der Ende, M. (M.), Lambiase, P.D. (Pier), Orini, M. (Michele), Ramirez, J. (Julia), Van Duijvenboden, S. (Stefan), Arnar, D.O. (David O.), Gudbjartsson, D.F. (Daniel), Holm, H. (Hilma), Sulem, P. (Patrick), Thorleifsson, G. (Gudmar), Thorolfsdottir, R.B. (Rosa B.), Thorsteinsdottir, U. (Unnur), Benjamin, E.J. (Emelia J.), Tinker, A. (Andrew), Zwart, J-A. (John-Anker), Ellinor, P.T. (Patrick), Jamshidi, Y. (Yalda), Lubitz, S.A. (Steven), Munroe, P. (Patricia), Ntalla, I. (Ioanna), Weng, L.-C., Cartwright, J.H. (James H.), Hall, A.W. (Amelia Weber), Sveinbjornsson, G. (Gardar), Tucker, N.R. (Nathan R.), Choi, S.H. (Seung Hoan), Chaffin, M.D. (Mark D.), Roselli, C. (Carolina), Barnes, M.J. (Michael), Mifsud, B. (Borbala), Warren, H.R. (Helen R.), Hayward, C. (Caroline), Marten, J. (Jonathan), Cranley, J.J. (James J.), Concas, M.P. (Maria Pina), Gasparini, P. (Paolo), Boutin, T. (Thibaud), Kolcic, I. (Ivana), Polasek, O. (Ozren), Rudan, I. (Igor), Araujo, N.M. (Nathalia M.), Lima-Costa, M.F. (Maria Fernanda), Ribeiro, A.L. (Antonio), Souza, R.P. (Renan P.), Tarazona-Santos, E. (Eduardo), Giedraitis, V. (Vilmantas), Ingelsson, E. (Erik), Mahajan, A. (Anubha), Morris, A.P. (Andrew), Del Greco M, F. (Fabiola), Foco, L. (Luisa), Gögele, M. (Martin), Hicks, A.A. (Andrew A.), Cook, J.P. (James P.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Sundström, J. (Johan), Nelson, C.P. (Christopher P.), Riaz, M.B. (Muhammad B.), Samani, N.J. (Nilesh), Sinagra, G. (Gianfranco), Ulivi, S. (Shelia), Kähönen, M. (Mika), Mishra, P.P. (Pashupati P.), Mononen, N. (Nina), Nikus, K. (Kjell), Caulfield, M. (Mark), Dominiczak, A. (Anna), Padmanabhan, S. (Sandosh), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Ryan, K. (Kathleen), Shuldiner, A.R. (Alan R.), Aeschbacher, S. (Stefanie), Conen, D. (David), Risch, L. (Lorenz), Thériault, S. (Sébastien), Hutri-Kähönen, N. (Nina), Lehtimäki, T. (Terho), Lyytikäinen, L.-P. (Leo-Pekka), Raitakari, O. (Olli), Barnes, C.L.K. (Catriona L. K.), Campbell, H. (Harry), Joshi, P.K. (Peter), Wilson, J.F. (James), Isaacs, A.J. (Aaron), Kors, J.A. (Jan), Duijn, C.M. (Cornelia) van, Huang, P.L. (Paul L.), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara B.), Launer, L.J. (Lenore), Smith, A.V. (Albert), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Nadkarni, G. (Girish), Preuss, M. (Michael), Correa, D.D., Mei, H. (Hao), Meitinger, T. (Thomas), Müller-Nurasyid, M. (Martina), Peters, A. (Annette), Waldenberger, M. (Melanie), Mangino, M. (Massimo), Spector, T.D. (Timothy), Rienstra, S.A., van de Vegte, Y.J. (Yordi J.), Harst, P. (Pim) van der, Verweij, N. (Niek), Kääb, S. (Stefan), Schramm, K. (Katharina), Sinner, M.F. (Moritz), Strauch, K. (Konstantin), Cutler, M.J. (Michael J.), Fatkin, D. (Diane), London, B. (Barry), Olesen, M.S. (Morten S.), Roden, D.M. (Dan M.), Benjamin Shoemaker, M. (M.), Gustav Smith, J. (J.), Biggs, M.L. (M.), Bis, J.C. (Joshua), Brody, J.A. (Jennifer A.), Psaty, B.M. (Bruce), Rice, K.M. (Kenneth), Sotoodehnia, N. (Nona), Grandi, A. (Alessandro) de, Fuchsberger, C. (Christian), Penninx, B.W.J.H., Pramstaller, P.P. (Peter Paul), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Macfarlane, P.W. (Peter W.), Trompet, S. (Stella), Dörr, M. (Marcus), Felix, S.B. (Stephan B.), Völker, U. (Uwe), Weiss, S. (Stefan), Havulinna, A.S. (Aki), Jula, A. (Antti), Sääksjärvi, K. (K.), Salomaa, V. (Veikko), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Lin, H.J. (Henry J.), Rotter, J.I. (Jerome I.), Taylor, K.D. (Kent), Yao, J. (Jie), Mutsert, R. (Reneé) de, Maan, A.C. (Arie C.), Mook-Kanamori, D.O. (Dennis O.), Noordam, R. (Raymond), Cucca, F. (Francesco), Ding, J. (Jun), Lakatta, E. (Edward), Qian, Y. (Yong), Tarasov, K.V. (Kirill V.), Levy, D. (Daniel), Lin, H. (Honghuang), Newton-Cheh, C. (Christopher), Lunetta, K.L. (Kathryn), Murray, A.D. (Alison D.), Porteous, D.J. (David J.), Smith, B.H. (Blair), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Berg, M.E. (Marten) van den, Haessler, J. (Jeff), Jackson, R.D. (Rebecca), Kooperberg, C. (Charles), Peters, U. (Ulrike), Reiner, A.P. (Alexander P.), Whitsel, E.A. (Eric), Alonso, A. (Alvaro), Arking, D.E. (Dan E.), Boerwinkle, E.A. (Eric), Ehret, G.B. (Georg B.), Soliman, E.Z. (Elsayed Z.), Avery, C.L., Gogarten, S.M., Kerr, K.F. (Kathleen), Laurie, C.C. (Cathy C.), Seyerle, A.A. (Amanda A.), Stilp, A. (Adrienne), Assa, S. (Solmaz), Abdullah Said, M. (M.), Yldau van der Ende, M. (M.), Lambiase, P.D. (Pier), Orini, M. (Michele), Ramirez, J. (Julia), Van Duijvenboden, S. (Stefan), Arnar, D.O. (David O.), Gudbjartsson, D.F. (Daniel), Holm, H. (Hilma), Sulem, P. (Patrick), Thorleifsson, G. (Gudmar), Thorolfsdottir, R.B. (Rosa B.), Thorsteinsdottir, U. (Unnur), Benjamin, E.J. (Emelia J.), Tinker, A. (Andrew), Zwart, J-A. (John-Anker), Ellinor, P.T. (Patrick), Jamshidi, Y. (Yalda), Lubitz, S.A. (Steven), and Munroe, P. (Patricia)

Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduc

Published
2020
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29. Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing

Author

Floyd, J.S. (James S.), Bloch, K.M. (Katarzyna M.), Brody, J.A. (Jennifer A.), Maroteau, C. (Cyrielle), Siddiqui, M.K. (Moneeza K.), Gregory, R. (Richard), Carr, D.F. (Daniel F.), Molokhia, M. (Mariam), Liu, X. (Xiaoming), Bis, J.C. (Joshua), Ahmed, A. (Ammar), Liu, X. (Xuan), Hallberg, P. (Pär), Yue, Q. (Qunying), Magnusson, P.K. (Patrik), Brisson, D. (Diane), Wiggins, K.L. (Kerri L.), Morrison, A.C. (Alanna C.), Khoury, E. (Etienne), Mckeigue, P.M. (Paul), Stricker, B.H.Ch. (Bruno), Lapeyre-Mestre, M. (Maryse), Heckbert, S.R. (Susan), Gallagher, A.M. (Arlene M.), Chinoy, H. (Hector), Gibbs, R.A. (Richard), Bondon-Guitton, E. (Emmanuelle), Tracy, R.P. (Russell), Boerwinkle, E.A. (Eric), Gaudet, D. (Daniel), Conforti, A. (Anita), Staa, T.P. (Tjeerd) van, Sitlani, C.M. (Colleen M.), Rice, K.M. (Kenneth M.), Maitland-van der Zee, A-H. (Anke-Hilse), Wadelius, M. (Mia), Morris, A.P. (Andrew), Pirmohamed, M. (Munir), Palmer, C.A.N. (Colin A N), Psaty, B.M. (Bruce M.), Alfirevic, A. (Ana), Floyd, J.S. (James S.), Bloch, K.M. (Katarzyna M.), Brody, J.A. (Jennifer A.), Maroteau, C. (Cyrielle), Siddiqui, M.K. (Moneeza K.), Gregory, R. (Richard), Carr, D.F. (Daniel F.), Molokhia, M. (Mariam), Liu, X. (Xiaoming), Bis, J.C. (Joshua), Ahmed, A. (Ammar), Liu, X. (Xuan), Hallberg, P. (Pär), Yue, Q. (Qunying), Magnusson, P.K. (Patrik), Brisson, D. (Diane), Wiggins, K.L. (Kerri L.), Morrison, A.C. (Alanna C.), Khoury, E. (Etienne), Mckeigue, P.M. (Paul), Stricker, B.H.Ch. (Bruno), Lapeyre-Mestre, M. (Maryse), Heckbert, S.R. (Susan), Gallagher, A.M. (Arlene M.), Chinoy, H. (Hector), Gibbs, R.A. (Richard), Bondon-Guitton, E. (Emmanuelle), Tracy, R.P. (Russell), Boerwinkle, E.A. (Eric), Gaudet, D. (Daniel), Conforti, A. (Anita), Staa, T.P. (Tjeerd) van, Sitlani, C.M. (Colleen M.), Rice, K.M. (Kenneth M.), Maitland-van der Zee, A-H. (Anke-Hilse), Wadelius, M. (Mia), Morris, A.P. (Andrew), Pirmohamed, M. (Munir), Palmer, C.A.N. (Colin A N), Psaty, B.M. (Bruce M.), and Alfirevic, A. (Ana)

Abstract

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

Published
2019
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30. KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

Author

Teumer, A. (Alexander), Trenkwalder, T. (Teresa), Kessler, T. (Thorsten), Jamshidi, Y. (Yalda), Berg, M.E. (Marten) van den, Kaess, B. (Bernhard), Nelson, C.P. (Christopher P.), Bastiaenen, R. (Rachel), de Bortoli, M. (Marzia), Rossini, A. (Alessandra), Deisenhofer, I. (Isabel), Stark, K. (Klaus), Assa, S. (Solmaz), Braund, P.S. (Peter), Cabrera, C. (Claudia), Dominiczak, A.F. (Anna F.), Gögele, M. (Martin), Hall, L.M. (Leanne M.), Ikram, M.A. (Arfan), Kavousi, M. (Maryam), Lackner, K.J. (Karl), Study, L.C. (Lifelines Cohort), Müller, C., Münzel, T. (Thomas), Nauck, M. (Matthias), Padmanabhan, S. (Sandosh), Pfeiffer, A.F.H. (Andreas), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Verweij, N. (Niek), Völker, U. (Uwe), Warren, H. (Helen), Zafar, M. (Mobeen), Felix, S.B. (Stephan), Kors, J.A. (Jan), Snieder, H. (Harold), Munroe, P. (Patricia), Penninx, B.W.J.H., Fuchsberger, C. (Christian), Schmidt, G. (Georg), Nolte, I.M. (Ilja), Schunkert, H. (Heribert), Pramstaller, P.P. (Peter Paul), Wild, P.S. (Philipp), Harst, P. (Pim) van der, Stricker, B.H.Ch. (Bruno), Schnabel, R.B. (Renate), Samani, N.J. (Nilesh), Hengstenberg, C. (Christian), Dörr, M. (Marcus), Behr, E.R. (Elijah), Reinhard, W. (Wibke), Teumer, A. (Alexander), Trenkwalder, T. (Teresa), Kessler, T. (Thorsten), Jamshidi, Y. (Yalda), Berg, M.E. (Marten) van den, Kaess, B. (Bernhard), Nelson, C.P. (Christopher P.), Bastiaenen, R. (Rachel), de Bortoli, M. (Marzia), Rossini, A. (Alessandra), Deisenhofer, I. (Isabel), Stark, K. (Klaus), Assa, S. (Solmaz), Braund, P.S. (Peter), Cabrera, C. (Claudia), Dominiczak, A.F. (Anna F.), Gögele, M. (Martin), Hall, L.M. (Leanne M.), Ikram, M.A. (Arfan), Kavousi, M. (Maryam), Lackner, K.J. (Karl), Study, L.C. (Lifelines Cohort), Müller, C., Münzel, T. (Thomas), Nauck, M. (Matthias), Padmanabhan, S. (Sandosh), Pfeiffer, A.F.H. (Andreas), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Verweij, N. (Niek), Völker, U. (Uwe), Warren, H. (Helen), Zafar, M. (Mobeen), Felix, S.B. (Stephan), Kors, J.A. (Jan), Snieder, H. (Harold), Munroe, P. (Patricia), Penninx, B.W.J.H., Fuchsberger, C. (Christian), Schmidt, G. (Georg), Nolte, I.M. (Ilja), Schunkert, H. (Heribert), Pramstaller, P.P. (Peter Paul), Wild, P.S. (Philipp), Harst, P. (Pim) van der, Stricker, B.H.Ch. (Bruno), Schnabel, R.B. (Renate), Samani, N.J. (Nilesh), Hengstenberg, C. (Christian), Dörr, M. (Marcus), Behr, E.R. (Elijah), and Reinhard, W. (Wibke)

Abstract

BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS. We identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. CONCLUSIONS: In this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.

Published
2019
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31. Pathology-confirmed versus non pathology-confirmed cancer diagnoses: incidence, participant characteristics, and survival

Author

Willik, K.D. (Kimberly) van der, Rojas-Saunero, L.P. (Liliana P.), Labrecque, J.A. (Jeremy A.), Ikram, M.A. (Arfan), Schagen, S.B. (Sanne), Stricker, B.H.Ch. (Bruno), Ruiter, T.R. (Rikje), Willik, K.D. (Kimberly) van der, Rojas-Saunero, L.P. (Liliana P.), Labrecque, J.A. (Jeremy A.), Ikram, M.A. (Arfan), Schagen, S.B. (Sanne), Stricker, B.H.Ch. (Bruno), and Ruiter, T.R. (Rikje)

Abstract

Cancer diagnoses which are not confirmed by pathology are often under-registered in cancer registries compared to pathology-confirmed diagnoses. It is unknown how many patients have a non pathology-confirmed cancer diagnosis, and whether their characteristics and survival differ from patients with a pathology-confirmed diagnosis. Participants from the prospective population-based Rotterdam Study were followed between 1989 and 2013 for the diagnosis of cancer. Cancer diagnoses were classified into pathology-confirmed versus non pathology-confirmed (i.e., based on imaging or tumour markers). We compared participant characteristics and the distribution of cancers at different sites. Furthermore, we investigated differences in overall survival using survival curves adjusted for age and sex. During a median (interquartile range) follow-up of 10.7 (6.3–15.9) years, 2698 out of 14,024 participants were diagnosed with cancer, of which 316 diagnoses (11.7%) were non pathology-confirmed. Participants with non pathology-confirmed diagnoses were older, more often women, and had a lower education. Most frequently non pathology-confirmed cancer sites included central nervous system (66.7%), hepato-pancreato-biliary (44.5%), and unknown primary origin (31.2%). Survival of participants with non pathology-confirmed diagnoses after 1 year was lower compared to survival of participants with pathology-confirmed diagnoses (32.6% vs. 63.4%; risk difference of 30.8% [95% CI 25.2%; 36.2%]). Pathological confirmation of cancer is related to participant characteristics and cancer site. Furthermore, participants with non pathology-confirmed diagnoses have worse survival than participants with pathology-confirmed diagnoses. Missing data on non pathology-confirmed diagnoses may result in underestimation of cancer incidence and in an overestimation of survival in cancer registries, and may introduce bias in aetiological research.

Published
2019
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32. Atherosclerotic calcification in major vessel beds in chronic obstructive pulmonary disease: The Rotterdam Study

Author

Lahousse, L. (Lies), Bos, D. (Daniel), Wijnant, S.R.A. (Sara R.A.), Kavousi, M. (Maryam), Stricker, B.H.Ch. (Bruno), Lugt, A. (Aad) van der, Vernooij, M.W. (Meike W.), Brusselle, G.G. (Guy), Lahousse, L. (Lies), Bos, D. (Daniel), Wijnant, S.R.A. (Sara R.A.), Kavousi, M. (Maryam), Stricker, B.H.Ch. (Bruno), Lugt, A. (Aad) van der, Vernooij, M.W. (Meike W.), and Brusselle, G.G. (Guy)

Abstract

Background and aims: COPD is associated with an increased risk of cardiovascular morbidity and mortality, potentially by mechanisms of atherosclerosis. Insight into location-specific vulnerability to atherosclerosis in COPD, including intracranial arteries, is lacking. We aimed to investigate the relation between COPD and atherosclerosis in multiple vessel beds within a large population-based cohort study. Methods: From 2003 to 2006, a random sample of 2187 elderly participants (mean age, 69.6 ± 6.8 years; 50.9% female; 11.7% COPD) from the population-based Rotterdam Study underwent computed tomography to quantify atherosclerotic coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial carotid artery calcification (ECAC), and intracranial carotid artery calcification (ICAC). We investigated the association of COPD [ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) < 70%] with the presence of calcification and with calcification volumes in each vessel bed using logistic and linear regression, with adjustments for cardiovascular risk factors including smoking. Results: The prevalence of CAC, AAC and ECAC was significantly higher in subjects with COPD compared to those without. After adjusting for age and smoking, COPD remained associated with the presence of ECAC (odds ratio 1.46 [95% confidence interval, 1.02–2.07, p = 0.037]). COPD was significantly associated with larger calcification volumes in all four vessel beds in people in whom calcification was present. Conclusions: The results of this study suggest that COPD plays a role in extracranial carotid artery atherosclerosis initiation and systemic atherosclerosis aggravation.

Published
2019
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33. Ascertainment of cancer in longitudinal research: The concordance between the Rotterdam Study and the Netherlands Cancer Registry

Author

Willik, K.D. (Kimberly) van der, Ruiter, T.R. (Rikje), Rooij, F.J.A. (Frank) van, Verkroost-Van Heemst, J. (Jolande), Hogewoning, S.J. (Sander J.), Timmermans, K.C.A.A. (Karin C.A.A.), Visser, O. (Otto), Schagen, S.B. (Sanne), Ikram, M.A. (Arfan), Stricker, B.H.Ch. (Bruno), Willik, K.D. (Kimberly) van der, Ruiter, T.R. (Rikje), Rooij, F.J.A. (Frank) van, Verkroost-Van Heemst, J. (Jolande), Hogewoning, S.J. (Sander J.), Timmermans, K.C.A.A. (Karin C.A.A.), Visser, O. (Otto), Schagen, S.B. (Sanne), Ikram, M.A. (Arfan), and Stricker, B.H.Ch. (Bruno)

Abstract

Complete and accurate registration of cancer is needed to provide reliable data on cancer incidence and to investigate aetiology. Such data can be derived from national cancer registries, but also from large population-based cohort studies. Yet, the concordance and discordance between these two data sources remain unknown. We evaluated completeness and accuracy of cancer registration by studying the concordance between the population-based Rotterdam Study (RS) and the Netherlands Cancer Registry (NCR) between 1989 and 2012 using the independent case ascertainment method. We compared all incident cancers in participants of the RS (aged ≥45 years) to registered cancers in the NCR in the same persons based on the date of diagnosis and the International Classification of Diseases (ICD) code. In total, 2,977 unique incident cancers among 2,685 persons were registered. Two hundred eighty-eight cancers (9.7%) were coded by the RS that were not present in the NCR. These were mostly nonpathology-confirmed lung and haematological cancers. Furthermore, 116 cancers were coded by the NCR, but not by the RS (3.9%), of which 20.7% were breast cancers. Regarding pathology-confirmed cancer diagnoses, completeness was >95% in both registries. Eighty per cent of the cancers registered in both registries were coded with the same date of diagnosis and ICD code. Of the remaining cancers, 344 (14.5%) were misclassified with regard to date of diagnosis and 72 (3.0%) with regard to ICD code. Our findings indicate that multiple sources on cancer are complementary and should be combined to ensure reliable data on cancer incidence.

Published
2019
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35. Corrigendum: Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages (Frontiers in Physiology, (2018), 9, (424), 10.3389/fphys.2018.00424)

Author

Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Hofman, A. (Albert), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H.L. (Hans), Swenne, C.A. (Cees), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), Kors, J.A. (Jan), Berg, M.E. (Marten) van den, Rijnbeek, P.R. (Peter), Niemeijer, M.N. (Maartje), Hofman, A. (Albert), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H.L. (Hans), Swenne, C.A. (Cees), Eijgelsheim, M. (Mark), Stricker, B.H.Ch. (Bruno), and Kors, J.A. (Jan)

Abstract

In the original article, there was a mistake in Table S5 as published. The normal values for “SDNN” were given instead of for “RMSSD.” The corrected Table S5 appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Published
2019
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36. Normal Values of QT Variability in 10-s Electrocardiograms for all Ages

Author

Berg, M.E. (Marten) van den, Kors, J.A. (Jan), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H. (Hans), Swenne, C.A. (Cees), Stricker, B.H.Ch. (Bruno), Rijnbeek, P.R. (Peter), Berg, M.E. (Marten) van den, Kors, J.A. (Jan), Herpen, G. (Gerard) van, Bots, M.L. (Michiel), Hillege, H. (Hans), Swenne, C.A. (Cees), Stricker, B.H.Ch. (Bruno), and Rijnbeek, P.R. (Peter)

Abstract

Aims: QT variability is a promising electrocardiographic marker. It has been studied as a screening tool for coronary artery disease and left ventricular hypertrophy, and increased QT variability is a known risk factor for sudden cardiac death. Considering that comprehensive normal values for QT variability were lacking, we set out to establish these in standard 10-s electrocardiograms (ECGs) covering both sexes and all ages. Methods: Ten-second, 12-lead ECGs were provided by five Dutch population studies (Pediatric Normal ECG Study, Leiden University Einthoven Science Project, Prevention of Renal and Vascular End-stage Disease Study, Utrecht Health Project, Rotterdam Study). ECGs were recorded digitally and processed by well-validated analysis software. We selected cardiologically healthy participants, 46% being women. Ages ranged from 11 days to 91 years. After quality control, 13,828 ECGs were available. We assessed three markers: standard deviation of QT intervals (SDqt), short-term QT variability (STVqt), and QT variability index (QTVI). Results: For SDqt and STVqt, the median and the lower limit of normal remained stable with age. The upper limit of normal declined until around age 45, and increased strongly in the elderly, notably so in women. This implies that a subset of the population, small enough not to have appreciable effect on the median, shows a high degree of QT variability with a possible risk of arrhythmias or worse, especially in women. Otherwise, sex differences were negligible in all three measurements. For QTVI, median, and normal limits decreased until age 20, and steadily went up afterwards except for the lower limit of normal, which flattens off after age 65. Conclusion: We report the first set of normal values for QT variability based on 10-s ECGs, for all ages and both sexes.

Published
2019
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37. Search for Early Pancreatic Cancer Blood Biomarkers in Five European Prospective Population Biobanks Using Metabolomics

Author

Fest, J. (Jesse), Vijfhuizen, L.S. (Lisanne S.), Goeman, J.J. (Jelle), Veth, O. (Olga), Joensuu, A. (Anni), Perola, M. (Markus), Männistö, S. (Satu), Ness-Jensen, E. (Eivind), Hveem, K. (Kristian), Haller, T. (Toomas), Tonisson, N. (Neeme), Mikkel, K. (Kairit), Metspalu, A. (Andres), Duijn, C.M. (Cornelia) van, Ikram, M.A. (Arfan), Stricker, B.H.Ch. (Bruno), Ruiter, T.R. (Rikje), Eijck, C.H.J. (Casper) van, Ommen, G.J. (Gert) van, ʼt Hoen, P.A.C. (Peter A C), Fest, J. (Jesse), Vijfhuizen, L.S. (Lisanne S.), Goeman, J.J. (Jelle), Veth, O. (Olga), Joensuu, A. (Anni), Perola, M. (Markus), Männistö, S. (Satu), Ness-Jensen, E. (Eivind), Hveem, K. (Kristian), Haller, T. (Toomas), Tonisson, N. (Neeme), Mikkel, K. (Kairit), Metspalu, A. (Andres), Duijn, C.M. (Cornelia) van, Ikram, M.A. (Arfan), Stricker, B.H.Ch. (Bruno), Ruiter, T.R. (Rikje), Eijck, C.H.J. (Casper) van, Ommen, G.J. (Gert) van, and ʼt Hoen, P.A.C. (Peter A C)

Abstract

Most patients with pancreatic cancer present with advanced disease and die within the first year after diagnosis. Predictive biomarkers that signal the presence of pancreatic cancer in an early stage are desperately needed. We aimed to identify new and validate previously found plasma metabolomic biomarkers associated with early stages of pancreatic cancer. Prediagnostic blood samples from individuals who were to receive a diagnosis of pancreatic

Published
2019
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38. Trends of prescribing antimicrobial drugs for urinary tract infections in primary care in the Netherlands: a population-based cohort study

Author

Mulder, M. (Marlies), E. Baan (Esmé), Verbon, A. (Annelies), Stricker, B.H.Ch. (Bruno), Verhamme, K.M.C. (Katia), Mulder, M. (Marlies), E. Baan (Esmé), Verbon, A. (Annelies), Stricker, B.H.Ch. (Bruno), and Verhamme, K.M.C. (Katia)

Abstract

Objective Urinary tract infections (UTIs) are an important reason to consult a general practitioner (GP). Here, we describe antimicrobial drug prescribing patterns for UTIs by GPs in relation to the Dutch primary care guidelines. Methods We conducted a population-based cohort study in the Dutch Integrated Primary Care Information (IPCI) database, which encompasses approximately 2.5million patients. All patients aged ≥12 years with at least 1 year of follow-up from 1996 to 2014 were extracted from the database. The number of prescriptions and choice of drug type were investigated over time and in different age categories. The choice of antimicrobial drug classes for UTIs and the duration of nitrofurantoin use in women were compared with the Dutch primary care guidelines of 1989, 1999, 2005 and 2013. Results The source population comprised 1 755 085 patients who received 2 019 335 antimicrobial drug prescriptions; 401 655 (35.1%) prescriptions were for UTIs (45.2% in women and 12.6% in men). The proportion of prescriptions for UTIs within all prescriptions with an indication code increased from 5.2% in 1996 to 14% in 2014 in men and from 28% in 1996 to 50% in 2014 in women. In men, UTIs were most frequently treated with fluoroquinolones during the entire study period, whereas fluoroquinolones were only advised as first choice in the latest guideline of 2013. In women, UTIs were increasingly (p<0.05) treated with nitrofuran derivatives with a statistically significant difference after implementation of the guideline of 2005. Compliance to the advised duration of nitrofurantoin prescriptions in women has increased since the guideline of 2005. Conclusions Antimicrobial drug prescribing for UTIs seemed to have increased over time. Prescribing in line with the UTI guidelines increased with regard to choice and duration of antimicrobial drugs. We showed that databases like IPCI, in which prescription and indication are monitored, can be valuable antibiotic stewardship tools

Published
2019
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39. Prediction of response to pemetrexed in non-small-cell lung cancer with immunohistochemical phenotyping based on gene expression profiles

Author

Visser, S., Hou, J., Bezemer, K. (Koen), Vogel, L. (Lisette) de, Hegmans, J.P.J.J. (Joost), Stricker, B.H.Ch. (Bruno), Philipsen, J.N.J. (Sjaak), Aerts, J.G.J.V. (Joachim), Visser, S., Hou, J., Bezemer, K. (Koen), Vogel, L. (Lisette) de, Hegmans, J.P.J.J. (Joost), Stricker, B.H.Ch. (Bruno), Philipsen, J.N.J. (Sjaak), and Aerts, J.G.J.V. (Joachim)

Abstract

Background: Palliative pemetrexed-based chemotherapy remains a standard of care treatment for the majority of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Currently, no predictive markers for pemetrexed treatment are available. Methods: Resected tumour samples from pemetrexed-naïve NSCLC patients were collected. Gene expression profiling with respect to predicted sensitivity to pemetrexed classified predicted responders (60%) and nonresponders (40%) based on differentially expressed genes encoding for pemetrexed target enzymes. Genes showing a strong correlation with these target genes were selected for measurement of corresponding protein expressions by immunohistochemical (IHC) staining. A semi-quantitative IHC scoring method was applied to construct a prediction model for response to pemetrexed. A retrospective cohort of patients with advanced NSCLC treated with first-line pemetrexed-based chemotherapy was used for external validation. Results: From ninety-one patients resected tumour samples were collected. The majority of patients had early or locally advanced NSCLC (96.3%). Gene expression profiling revealed five markers, which mRNA levels strongly correlated to pemetrexed target genes mRNA levels: TPX2, CPA3, EZH2, MCM2 and TOP2A. Of 63 (69%) patients IHC staining scores of these markers were obtained, which significantly differed between predicted non-responders and responders (P < 0.05). The optimized prediction model included EZH2 (OR = 0.56, 95% CI 0.35–0.90) and TPX2 (OR = 0.55, 95% CI 0.30–1.01). The model had a sensitivity of 86.8%, specificity of 63.6% and showed a good ability to distinct between responders and non-responders (C-index 0.86). In the external study population (N = 23) the majority of patients had metastatic NSCLC (95.7%). Partial response (PR) was established in 26.1%. The sensitivity decreased drastically to 33.3%, with a specificity of 82.4% and a C-index of 0.73. Conclusions: Using external validation this

Published
2019
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40. Prenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and neurodevelopmental outcomes in children

Author

Markovic, M. (Maja), Swanson, S.A. (Sonja), Stricker, B.H.Ch. (Bruno), Jaddoe, V.W.V. (Vincent), Verhulst, F.C. (Frank), Tiemeier, H.W. (Henning), El Marroun, H. (Hanan), Markovic, M. (Maja), Swanson, S.A. (Sonja), Stricker, B.H.Ch. (Bruno), Jaddoe, V.W.V. (Vincent), Verhulst, F.C. (Frank), Tiemeier, H.W. (Henning), and El Marroun, H. (Hanan)

Abstract

___Purpose:___ Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used during pregnancy. Findings that prenatal NSAID exposure may affect offspring neurodevelopment have been inconsistent. We investigated the effect of prenatal NSAID exposure on childhood neurodevelopment and explored the susceptibility of our effect estimates to forms of bias via negative exposure, negative outcome, and multi-informant analyses. ___Methods:___ In a cohort of pregnant women (n = 6876), perinatal NSAID use was assessed by prescriptions and self-report. Primary neurodevelopmental outcomes included attention problems using maternal reports at 1½, 3, and 5 years. To explore potential systematic biases, we compared estimates from maternally reported attention problems to a teacher's report and a measure of nonverbal intelligence assessed at a clinic visit at age 6 years; we also used NSAID use before pregnancy and somatic problems as a “negative” exposure and outcome, respectively. ___Results:___ Maternal reports suggested that prenatal exposure to NSAIDs was associated with more attention problems at younger ages (eg, at age 3: mean difference in attention problems score: 0.30; 95% CI 0.12, 0.48). However, no strong association with attention problems was found in the teacher report, and a similarly strong association between prenatal NSAID exposure and somatic complaints suggests residual confounding by indication likely remains. Moreover, prenatal exposure to NSAIDs was not associated with an observed measure of IQ (mean difference in IQ score: −0.32; 95% CI: −1.82, 1.19). ___Conclusions:___ Jointly, our results suggest that the observed associations between prenatal exposure to NSAIDs and child attention problems reflect systematic biases of a null or small effect.

Published
2019
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44. Chronic obstructive pulmonary disease and the development of atrial fibrillation

Author

Grymonprez, M. (Maxim), Vakaet, V. (Vincent), Kavousi, M. (Maryam), Stricker, B.H.Ch. (Bruno), Ikram, M.A. (Arfan), Heeringa, J. (Jan), Franco, O.H. (Oscar), Brusselle, G.G. (Guy), Lahousse, L. (Lies), Grymonprez, M. (Maxim), Vakaet, V. (Vincent), Kavousi, M. (Maryam), Stricker, B.H.Ch. (Bruno), Ikram, M.A. (Arfan), Heeringa, J. (Jan), Franco, O.H. (Oscar), Brusselle, G.G. (Guy), and Lahousse, L. (Lies)

Abstract

Background: Chronic obstructive pulmonary disease (COPD) has been associated with atrial fibrillation (AF). More insight into the epidemiology and underlying mechanisms is required to optimize management. Methods: The Rotterdam Study is a large, population-based cohort study with long-term follow-up. Time dependent Cox proportional hazard models were constructed to study the effect of COPD on incident AF, adjusted for age, sex and pack years of cigarette smoking, and additionally stratified according to exacerbation frequency, left atrial size and baseline systemic inflammatory levels. Results: 1369 of 10,943 subjects had COPD, of whom 804 developed AF. The AF incidence rate was 14 per 1000 person years in COPD and 8 per 1000 person years in subjects without COPD. The adjusted hazard ratio (HR) for COPD subjects to develop AF as compared to subjects without COPD was 1.28 (95%CI [1.04, 1.57]). COPD subjects with frequent exacerbations had a twofold increased AF risk (HR 1.99 [1.42, 2.79]) and COPD subjects with a left atrial size ≥40 mm also had an elevated AF risk (HR 1.77 [1.07, 2.94]). COPD subjects with baseline systemic inflammatory levels above the median had significantly increased AF risks (hsCRP≥1.83 mg/L: HR 1.51 [1.13, 2.03] and IL6 ≥ 1.91 ng/L: HR 2.49 [1.18, 5.28]), whereas COPD subjects below the median had in both analyses no significantly increased AF risk. Conclusions: COPD subjects had a 28% increased AF risk, which further increased with frequent exacerbations and an enlarged left atrium. The risk was driven by COPD subjects having elevated systemic inflammatory levels.

Published
2018
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45. ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Author

Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Albert), Warren, H. (Helen), Lin, H. (Honghuang), Isaacs, A. (Aaron), Liu, C.-T. (Ching-Ti), Marten, J. (Jonathan), Radmanesh, F. (Farid), Hall, L.M. (Leanne M.), Grarup, N. (Niels), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Huffman, J.E. (Jennifer E.), Verweij, N. (Niek), Guo, X. (Xiuqing), Yao, J. (Jie), Li-Gao, R. (Ruifang), Berg, M.E. (Marten) van den, Weiss, S. (Stefan), Prins, B.P. (Bram P.), Setten, J. (Jessica) van, Haessler, J. (Jeff), Lyytikäinen, L.-P. (Leo-Pekka), Li, M. (Man), Alonso, A. (Alvaro), Soliman, E.Z. (Elsayed Z.), Bis, J.C. (Joshua), Austin, T. (Tom), Chen, Y.D.I. (Yii-Der Ida), Psaty, B.M. (Bruce M.), Harrris, T.B. (Tamara B.), Launer, L.J. (Lenore), Padmanabhan, S. (Sandosh), Dominiczak, A. (Anna), Huang, P.L. (Paul L.), Xie, Z. (Zhijun), Ellinor, P.T. (Patrick), Kors, J.A. (Jan), Campbell, A. (Archie), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Tobin, M.D. (Martin), Bork-Jensen, J. (Jette), Hansen, T. (Torben), Pedersen, O. (Oluf), Linneberg, A. (Allan), Sinner, M.F. (Moritz), Peters, A. (Annette), Waldenberger, M. (Melanie), Meitinger, T. (Thomas), Perz, S. (Siegfried), Kolcic, I. (Ivana), Rudan, I. (Igor), Boer, R.A. (Rudolf) de, Meer, P. (Peter) van der, Lin, H.J. (Henry J.), Taylor, K.D. (Kent), Mutsert, R. (Reneé) de, Trompet, S. (Stella), Jukema, J.W. (Jan Wouter), Maan, A.C. (Arie C.), Stricker, B.H.Ch. (Bruno), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A. (André), Völker, U. (Uwe), Homuth, G. (Georg), Völzke, H. (Henry), Felix, S.B. (Stephan), Mangino, M. (Massimo), Spector, T.D. (Timothy), Bots, M.L. (Michiel), Perez, M. (Marco), Raitakari, O. (Olli), Kähönen, M. (Mika), Mononen, N. (Nina), Gudnason, V. (Vilmundur), Munroe, P. (Patricia), Lubitz, S.A. (Steven A.), Duijn, C.M. (Cornelia) van, Newton-Cheh, C. (Christopher), Hayward, C. (Caroline), Rosand, J. (Jonathan), Samani, N.J. (Nilesh J.), Kanters, J.K., Wilson, J.F. (James), Kääb, S. (Stefan), Polasek, O. (Ozren), van der Harst, P. (Pim), Heckbert, S.R. (Susan), Rotter, J.I. (Jerome I.), Mook-Kanamori, D.O. (Dennis O.), Eijgelsheim, M. (Mark), Dörr, M. (Marcus), Jamshidi, Y. (Yalda), Asselbergs, F.W. (Folkert W.), Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Arking, D.E. (Dan), Sotoodehnia, N. (Nona), Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Albert), Warren, H. (Helen), Lin, H. (Honghuang), Isaacs, A. (Aaron), Liu, C.-T. (Ching-Ti), Marten, J. (Jonathan), Radmanesh, F. (Farid), Hall, L.M. (Leanne M.), Grarup, N. (Niels), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Huffman, J.E. (Jennifer E.), Verweij, N. (Niek), Guo, X. (Xiuqing), Yao, J. (Jie), Li-Gao, R. (Ruifang), Berg, M.E. (Marten) van den, Weiss, S. (Stefan), Prins, B.P. (Bram P.), Setten, J. (Jessica) van, Haessler, J. (Jeff), Lyytikäinen, L.-P. (Leo-Pekka), Li, M. (Man), Alonso, A. (Alvaro), Soliman, E.Z. (Elsayed Z.), Bis, J.C. (Joshua), Austin, T. (Tom), Chen, Y.D.I. (Yii-Der Ida), Psaty, B.M. (Bruce M.), Harrris, T.B. (Tamara B.), Launer, L.J. (Lenore), Padmanabhan, S. (Sandosh), Dominiczak, A. (Anna), Huang, P.L. (Paul L.), Xie, Z. (Zhijun), Ellinor, P.T. (Patrick), Kors, J.A. (Jan), Campbell, A. (Archie), Murray, A.D. (Alison D.), Nelson, C.P. (Christopher P.), Tobin, M.D. (Martin), Bork-Jensen, J. (Jette), Hansen, T. (Torben), Pedersen, O. (Oluf), Linneberg, A. (Allan), Sinner, M.F. (Moritz), Peters, A. (Annette), Waldenberger, M. (Melanie), Meitinger, T. (Thomas), Perz, S. (Siegfried), Kolcic, I. (Ivana), Rudan, I. (Igor), Boer, R.A. (Rudolf) de, Meer, P. (Peter) van der, Lin, H.J. (Henry J.), Taylor, K.D. (Kent), Mutsert, R. (Reneé) de, Trompet, S. (Stella), Jukema, J.W. (Jan Wouter), Maan, A.C. (Arie C.), Stricker, B.H.Ch. (Bruno), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A. (André), Völker, U. (Uwe), Homuth, G. (Georg), Völzke, H. (Henry), Felix, S.B. (Stephan), Mangino, M. (Massimo), Spector, T.D. (Timothy), Bots, M.L. (Michiel), Perez, M. (Marco), Raitakari, O. (Olli), Kähönen, M. (Mika), Mononen, N. (Nina), Gudnason, V. (Vilmundur), Munroe, P. (Patricia), Lubitz, S.A. (Steven A.), Duijn, C.M. (Cornelia) van, Newton-Cheh, C. (Christopher), Hayward, C. (Caroline), Rosand, J. (Jonathan), Samani, N.J. (Nilesh J.), Kanters, J.K., Wilson, J.F. (James), Kääb, S. (Stefan), Polasek, O. (Ozren), van der Harst, P. (Pim), Heckbert, S.R. (Susan), Rotter, J.I. (Jerome I.), Mook-Kanamori, D.O. (Dennis O.), Eijgelsheim, M. (Mark), Dörr, M. (Marcus), Jamshidi, Y. (Yalda), Asselbergs, F.W. (Folkert W.), Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Arking, D.E. (Dan), and Sotoodehnia, N. (Nona)

Abstract

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

Published
2018
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46. The neutrophil-to-lymphocyte ratio is associated with mortality in the general population: The Rotterdam Study

Author

Fest, J. (Jesse), Ruiter, T.R. (Rikje), Groot Koerkamp, B. (Bas), Rizopoulos, D. (Dimitris), Ikram, M.A. (Arfan), Eijck, C.H.J. (Casper) van, Stricker, B.H.Ch. (Bruno), Fest, J. (Jesse), Ruiter, T.R. (Rikje), Groot Koerkamp, B. (Bas), Rizopoulos, D. (Dimitris), Ikram, M.A. (Arfan), Eijck, C.H.J. (Casper) van, and Stricker, B.H.Ch. (Bruno)

Abstract

Inflammation is a risk factor for morbidity and mortality in the elderly. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that integrates the information of the leukocyte differentials into one variable. We aimed to assess whether the NLR is a risk indicator for overall and cause-specific mortality in the general population. We analyzed data (2002–2014) from the Rotterdam Study, a long-standing, population-based, prospective cohort study in a community-dwelling ageing population. The association between the NLR and time to all-cause mortality was assessed with Cox proportional hazard models. We additionally assessed cardiovascular, cancer and other mortality. The multivariable analyses were adjusted for age, gender, socio-economic status (SES), smoking status, body mass index, type 2 diabetes, and history of cancer and cardiovascular disease (CVD). Data of 8715 individuals were included. The mean age was 65.9 years (SD 10.5) and the majority were women (57.1%). The NLR was higher in men, higher age categories, smokers and among individuals with lower SES, prevalent diabetes, or a history of cancer or CVD. During the 11.7 years follow-up period, 1641 individuals

Published
2018
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47. Filled prescriptions of age-related contraindicated drugs in children: a one-year nationwide cohort study in the Netherlands

Author

Cheung, K. (Kiki), Teichert, M. (Martina), Moll, H.A. (Henriëtte), Stricker, B.H.Ch. (Bruno), Visser, L.E. (L. E.), Cheung, K. (Kiki), Teichert, M. (Martina), Moll, H.A. (Henriëtte), Stricker, B.H.Ch. (Bruno), and Visser, L.E. (L. E.)

Abstract

Background Children are still prescribed age contraindicated drugs, but information about the number and type of these drugs dispensed for children in the Netherlands is limited. Objective To determine the incidence and prevalence of contraindicated drugs that were dispensed for the use by children. Setting The study was conducted in the Netherlands with routinely collected data from 95% of all community pharmacies. Method We performed a one-year nationwide observational study where all patients aged 17 years or younger who have received at least one prescription in 2016 were included. Contraindicated drugs were selected, according to the 5th level of ATC code, using different information sources. Main outcome measure The proportion of (newly) contraindicated drugs that were dispensed to children. Results In total, 3.9% of all children received at least one drug that was contraindicated for their age. The highest percentage of contraindicated drugs that was dispensed, was observed in patients aged 1–2 years and 13–17 years (7.0 and 5.7%, respectively) and the percentage of contraindicated drugs that were dispensed was higher in female than in male patients (4.3 and 3.6%, respectively; p value < 0.001). Conclusion The results of this study show that a substantial percentage of children received a drug that was conta-indicated for their age, and it happes more in female than in male patients. Furthermore, the information about this type of contraindications is limited and inconsistent.

Published
2018
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48. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Setten, J. (Jessica) van, Brody, J.A. (Jennifer A.), Jamshidi, Y. (Yalda), Swenson, B.R. (Brenton R.), Butler, A.M. (Anne M.), Campbell, H. (Harry), Del Greco, F.M. (Fabiola), Evans, D.S. (Daniel), Gibson, Q. (Quince), Gudbjartsson, D.F. (Daniel), Kerr, K.F. (Kathleen), Krijthe, B.P. (Bouwe), Lyytikäinen, L.-P. (Leo-Pekka), Müller, C. (Christian), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Padmanabhan, S. (Sandosh), Ritchie, M.D. (Marylyn D.), Robino, A. (Antonietta), Smith, A.V. (Albert), Steri, M. (Maristella), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), Ulivi, S. (Sheila), Verweij, N. (Niek), Yin, X. (Xiaoyan), Arnar, D.O. (David O.), Asselbergs, F.W. (Folkert W.), Bader, J.S. (Joel), Barnard, J. (John), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boerwinkle, E. (Eric), Bradford, Y. (Yuki), Buckley, B.M. (Brendan M.), Chung, M.K. (Mina), Crawford, D. (Dana), Hoed, M. (Marcel) den, Denny, J.C. (Joshua C.), Dominiczak, A. (Anna), Ehret, G.B. (Georg B.), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Felix, S.B. (Stephan), Franco, O.H. (Oscar), Franke, L. (Lude), Harris, T.B. (Tamara), Holm, H. (Hilma), Ilaria, G. (Gandin), Iorio, A. (Annamaria), Kähönen, M. (Mika), Kolcic, I. (Ivana), Kors, J.A. (Jan), Lakatta, E. (Edward), Launer, L.J. (Lenore), Lin, H. (Honghuang), Lin, H.J. (Henry J.), Loos, R.J.F. (Ruth), Lubitz, S.A. (Steven A.), MacFarlane, P.W. (Peter), Magnani, J.W. (Jared), Leach, I.M. (Irene Mateo), Meitinger, T. (Thomas), Mitchell, B.D. (Braxton), Munzel, T. (Thomas), Papanicolaou, G.J. (George J.), Peters, A. (Annette), Pfeufer, A. (Arne), Pramstaller, P.P. (Peter Paul), Raitakari, O. (Olli), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Schlessinger, D. (David), Silva Aldana, C.T. (Claudia), Sinner, M.F. (Moritz), Smith, J.D. (Jonathan), Snieder, H. (Harold), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Stott, D.J. (David. J.), Strauch, K. (Konstantin), Tarasov, K.V. (Kirill V.), Thorsteinsdottir, U. (Unnur), Uitterlinden, A.G. (André), Wagoner, D.R. (David) van, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Jan Westra, H. (Harm), Wild, P.S. (Philipp), Zeller, T. (Tanja), Alonso, A. (Alvaro), Avery, C.L., Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Cucca, F. (Francesco), Dörr, M. (Marcus), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Gudnason, V. (Vilmundur), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Hicks, A.A. (Andrew A.), Jukema, J.W. (Jan Wouter), Kääb, S. (Stefan), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Munroe, P. (Patricia), Parsa, A. (Afshin), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Roden, D.M. (Dan), Schnabel, R.B. (Renate), Sinagra, G. (Gianfranco), Zwart, J-A. (John-Anker), Stricker, B.H.Ch. (Bruno), van der Harst, P. (Pim), Duijn, C.M. (Cornelia) van, Wilson, J.F. (James F.), Gharib, S.A. (Sina), Bakker, P.I.W. (Paul) de, Isaacs, A. (Aaron), Arking, D.E. (Dan), Sotoodehnia, N. (Nona), Setten, J. (Jessica) van, Brody, J.A. (Jennifer A.), Jamshidi, Y. (Yalda), Swenson, B.R. (Brenton R.), Butler, A.M. (Anne M.), Campbell, H. (Harry), Del Greco, F.M. (Fabiola), Evans, D.S. (Daniel), Gibson, Q. (Quince), Gudbjartsson, D.F. (Daniel), Kerr, K.F. (Kathleen), Krijthe, B.P. (Bouwe), Lyytikäinen, L.-P. (Leo-Pekka), Müller, C. (Christian), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Padmanabhan, S. (Sandosh), Ritchie, M.D. (Marylyn D.), Robino, A. (Antonietta), Smith, A.V. (Albert), Steri, M. (Maristella), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), Ulivi, S. (Sheila), Verweij, N. (Niek), Yin, X. (Xiaoyan), Arnar, D.O. (David O.), Asselbergs, F.W. (Folkert W.), Bader, J.S. (Joel), Barnard, J. (John), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boerwinkle, E. (Eric), Bradford, Y. (Yuki), Buckley, B.M. (Brendan M.), Chung, M.K. (Mina), Crawford, D. (Dana), Hoed, M. (Marcel) den, Denny, J.C. (Joshua C.), Dominiczak, A. (Anna), Ehret, G.B. (Georg B.), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Felix, S.B. (Stephan), Franco, O.H. (Oscar), Franke, L. (Lude), Harris, T.B. (Tamara), Holm, H. (Hilma), Ilaria, G. (Gandin), Iorio, A. (Annamaria), Kähönen, M. (Mika), Kolcic, I. (Ivana), Kors, J.A. (Jan), Lakatta, E. (Edward), Launer, L.J. (Lenore), Lin, H. (Honghuang), Lin, H.J. (Henry J.), Loos, R.J.F. (Ruth), Lubitz, S.A. (Steven A.), MacFarlane, P.W. (Peter), Magnani, J.W. (Jared), Leach, I.M. (Irene Mateo), Meitinger, T. (Thomas), Mitchell, B.D. (Braxton), Munzel, T. (Thomas), Papanicolaou, G.J. (George J.), Peters, A. (Annette), Pfeufer, A. (Arne), Pramstaller, P.P. (Peter Paul), Raitakari, O. (Olli), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Schlessinger, D. (David), Silva Aldana, C.T. (Claudia), Sinner, M.F. (Moritz), Smith, J.D. (Jonathan), Snieder, H. (Harold), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Stott, D.J. (David. J.), Strauch, K. (Konstantin), Tarasov, K.V. (Kirill V.), Thorsteinsdottir, U. (Unnur), Uitterlinden, A.G. (André), Wagoner, D.R. (David) van, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Jan Westra, H. (Harm), Wild, P.S. (Philipp), Zeller, T. (Tanja), Alonso, A. (Alvaro), Avery, C.L., Bandinelli, S. (Stefania), Benjamin, E.J. (Emelia), Cucca, F. (Francesco), Dörr, M. (Marcus), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Gudnason, V. (Vilmundur), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Hicks, A.A. (Andrew A.), Jukema, J.W. (Jan Wouter), Kääb, S. (Stefan), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Munroe, P. (Patricia), Parsa, A. (Afshin), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Roden, D.M. (Dan), Schnabel, R.B. (Renate), Sinagra, G. (Gianfranco), Zwart, J-A. (John-Anker), Stricker, B.H.Ch. (Bruno), van der Harst, P. (Pim), Duijn, C.M. (Cornelia) van, Wilson, J.F. (James F.), Gharib, S.A. (Sina), Bakker, P.I.W. (Paul) de, Isaacs, A. (Aaron), Arking, D.E. (Dan), and Sotoodehnia, N. (Nona)

Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Published
2018
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49. Reference values for white blood-cell-based inflammatory markers in the Rotterdam Study

Author

Fest, J. (Jesse), Ruiter, T.R. (Rikje), Ikram, M.A. (Arfan), Voortman, R.G. (Trudy), Eijck, C.H.J. (Casper) van, Stricker, B.H.Ch. (Bruno), Fest, J. (Jesse), Ruiter, T.R. (Rikje), Ikram, M.A. (Arfan), Voortman, R.G. (Trudy), Eijck, C.H.J. (Casper) van, and Stricker, B.H.Ch. (Bruno)

Abstract

Novel prognostic inflammatory markers of cancer survival and cardiovascular disease are; the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the systemic immune-i

Published
2018
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50. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author

Prins, B.P. (Bram P.), Mead, T.J. (Timothy J.), Brody, J.A. (Jennifer A.), Sveinbjornsson, G. (Gardar), Ntalla, I. (Ioanna), Bihlmeyer, N.A. (Nathan A.), Berg, M.E. (Marten) van den, Bork-Jensen, J. (Jette), Cappellani, S. (Stefania), Van Duijvenboden, S. (Stefan), Klena, N.T. (Nikolai T.), Gabriel, G.C. (George C.), Liu, X. (Xiaoqin), Gulec, C. (Cagri), Grarup, N. (Niels), Haessler, J. (Jeff), Hall, L.M. (Leanne M.), Iorio, A. (Annamaria), Isaacs, A. (Aaron), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Liu, C.-T. (Ching-Ti), Lyytikäinen, L.-P. (Leo-Pekka), Marten, J. (Jonathan), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Orini, M. (Michele), Padmanabhan, S. (Sandosh), Radmanesh, F. (Farid), Ramirez, J. (Julia), Robino, A. (Antonietta), Schwartz, M. (Molly), Setten, J. (Jessica) van, Smith, A.V. (Albert), Verweij, N. (Niek), Warren, H. (Helen), Weiss, S. (Stefan), Alonso, A. (Alvaro), Arnar, D.O. (David O.), Bots, M.L. (Michiel), Boer, R.A. (Rudolf) de, Dominiczak, A. (Anna), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Guo, X. (Xiuqing), Felix, S.B. (Stephan), Harris, T.B. (Tamara), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kors, J.A. (Jan), Lambiase, P.D. (Pier), Launer, L.J. (Lenore), Li, M. (Man), Linneberg, A. (Allan), Nelson, C.P. (Christopher P.), Pedersen, O. (Oluf), Perez, M. (Marco), Peters, A. (Annette), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Raitakari, O. (Olli), Rice, K.M. (Kenneth), Rotter, J.I. (Jerome I.), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Strauch, K. (Konstantin), Thorsteinsdottir, U. (Unnur), Tinker, A. (Andrew), Trompet, S. (Stella), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Meer, P. (Peter) van der, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Wilson, J.F. (James), Xie, Z. (Zhijun), Asselbergs, F.W. (Folkert W.), Dörr, M. (Marcus), Duijn, C.M. (Cornelia) van, Gasparini, P. (Paolo), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hansen, T. (Torben), Kääb, S. (Stefan), Kanters, J.K., Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Lin, H.J. (Henry J.), Lubitz, S.A. (Steven A.), Mook-Kanamori, D.O. (Dennis O.), Conti, F.J. (Francesco J.), Newton-Cheh, C. (Christopher), Rosand, J. (Jonathan), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Sinagra, G. (Gianfranco), Smith, B.H. (Blair), Holm, H. (Hilma), Stricker, B.H.Ch. (Bruno), Ulivi, S. (Sheila), Sotoodehnia, N. (Nona), Apte, S.S. (Suneel S.), van der Harst, P. (Pim), Zwart, J-A. (John-Anker), Munroe, P. (Patricia), Arking, D.E. (Dan), Lo, C.W. (Cecilia W.), Jamshidi, Y. (Yalda), Prins, B.P. (Bram P.), Mead, T.J. (Timothy J.), Brody, J.A. (Jennifer A.), Sveinbjornsson, G. (Gardar), Ntalla, I. (Ioanna), Bihlmeyer, N.A. (Nathan A.), Berg, M.E. (Marten) van den, Bork-Jensen, J. (Jette), Cappellani, S. (Stefania), Van Duijvenboden, S. (Stefan), Klena, N.T. (Nikolai T.), Gabriel, G.C. (George C.), Liu, X. (Xiaoqin), Gulec, C. (Cagri), Grarup, N. (Niels), Haessler, J. (Jeff), Hall, L.M. (Leanne M.), Iorio, A. (Annamaria), Isaacs, A. (Aaron), Li-Gao, R. (Ruifang), Lin, H. (Honghuang), Liu, C.-T. (Ching-Ti), Lyytikäinen, L.-P. (Leo-Pekka), Marten, J. (Jonathan), Mei, H. (Hao), Müller-Nurasyid, M. (Martina), Orini, M. (Michele), Padmanabhan, S. (Sandosh), Radmanesh, F. (Farid), Ramirez, J. (Julia), Robino, A. (Antonietta), Schwartz, M. (Molly), Setten, J. (Jessica) van, Smith, A.V. (Albert), Verweij, N. (Niek), Warren, H. (Helen), Weiss, S. (Stefan), Alonso, A. (Alvaro), Arnar, D.O. (David O.), Bots, M.L. (Michiel), Boer, R.A. (Rudolf) de, Dominiczak, A. (Anna), Eijgelsheim, M. (Mark), Ellinor, P.T. (Patrick), Guo, X. (Xiuqing), Felix, S.B. (Stephan), Harris, T.B. (Tamara), Hayward, C. (Caroline), Heckbert, S.R. (Susan), Huang, P.L. (Paul L.), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kors, J.A. (Jan), Lambiase, P.D. (Pier), Launer, L.J. (Lenore), Li, M. (Man), Linneberg, A. (Allan), Nelson, C.P. (Christopher P.), Pedersen, O. (Oluf), Perez, M. (Marco), Peters, A. (Annette), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Raitakari, O. (Olli), Rice, K.M. (Kenneth), Rotter, J.I. (Jerome I.), Sinner, M.F. (Moritz), Soliman, E.Z. (Elsayed Z.), Spector, T.D. (Timothy), Strauch, K. (Konstantin), Thorsteinsdottir, U. (Unnur), Tinker, A. (Andrew), Trompet, S. (Stella), Uitterlinden, A.G. (André), Vaartjes, I. (Ilonca), Meer, P. (Peter) van der, Völker, U. (Uwe), Völzke, H. (Henry), Waldenberger, M. (Melanie), Wilson, J.F. (James), Xie, Z. (Zhijun), Asselbergs, F.W. (Folkert W.), Dörr, M. (Marcus), Duijn, C.M. (Cornelia) van, Gasparini, P. (Paolo), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hansen, T. (Torben), Kääb, S. (Stefan), Kanters, J.K., Kooperberg, C. (Charles), Lehtimäki, T. (Terho), Lin, H.J. (Henry J.), Lubitz, S.A. (Steven A.), Mook-Kanamori, D.O. (Dennis O.), Conti, F.J. (Francesco J.), Newton-Cheh, C. (Christopher), Rosand, J. (Jonathan), Rudan, I. (Igor), Samani, N.J. (Nilesh J.), Sinagra, G. (Gianfranco), Smith, B.H. (Blair), Holm, H. (Hilma), Stricker, B.H.Ch. (Bruno), Ulivi, S. (Sheila), Sotoodehnia, N. (Nona), Apte, S.S. (Suneel S.), van der Harst, P. (Pim), Zwart, J-A. (John-Anker), Munroe, P. (Patricia), Arking, D.E. (Dan), Lo, C.W. (Cecilia W.), and Jamshidi, Y. (Yalda)

Abstract

Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

Published
2018
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