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1. Genetic insights into resting heart rate and its role in cardiovascular disease.

Author

Vegte, Y.J. van de, Eppinga, R.N., Ende, M.Y. van der, Hagemeijer, Y.P., Mahendran, Y., Salfati, E., Smith, A.V., Tan, V.Y., Arking, D.E., Ntalla, I., Appel, E.V., Schurmann, C., Brody, J.A., Rueedi, R., Polasek, O., Sveinbjornsson, G., Lecoeur, C., Ladenvall, C., Zhao, J.H., Isaacs, A., Wang, L., Luan, Jian'an, Hwang, S.J., Mononen, N., Auro, K., Jackson, A.U., Bielak, L.F., Zeng, L., Shah, N., Nethander, M., Campbell, A., Rankinen, T., Pechlivanis, S., Qi, L., Zhao, Wei, Rizzi, F., Tanaka, T., Robino, A., Cocca, M., Lange, L., Müller-Nurasyid, M., Roselli, C., Zhang, W, Kleber, M.E., Guo, X., Lin, H.J., Pavani, F., Galesloot, T.E., Noordam, R., Milaneschi, Y., Schraut, K.E., Hoed, M. den, Degenhardt, F., Trompet, S., Berg, M.E. van den, Pistis, G., Tham, Y.C., Weiss, S., Sim, X.S., Li, H.L., Most, P.J. van der, Nolte, I.M., Lyytikäinen, L.P., Said, M.A., Witte, D.R., Iribarren, C., Launer, L., Ring, S.M., Vries, P.S. de, Sever, P., Linneberg, A., Bottinger, E.P., Padmanabhan, S., Psaty, B.M., Sotoodehnia, N., Kolcic, I., Arnar, D.O., Gudbjartsson, D.F., Holm, H., Balkau, B., Silva, C.T., Newton-Cheh, C.H., Nikus, K., Salo, P., Mohlke, K.L., Peyser, P.A., Schunkert, H., Lorentzon, M., Lahti, J., Rao, D.C., Cornelis, M.C., Faul, J.D., Smith, J.A., Stolarz-Skrzypek, K., Bandinelli, S., Concas, M.P., Sinagra, G., Meitinger, T., Waldenberger, M., Sinner, M.F., Strauch, K., Delgado, G.E., Taylor, K.D., Yao, J., Foco, L., Melander, O., Graaf, J. de, Mutsert, R. de, Geus, E.J.C. de, Johansson, Å., Joshi, P.K., Lind, L., Franke, A., Macfarlane, P.W., Tarasov, K.V., Tan, N., Felix, S.B., Tai, E.S., Quek, D.Q., Snieder, H., Ormel, J., Ingelsson, M., Lindgren, C., Morris, A.P., Raitakari, O.T., Hansen, T., Assimes, T., Gudnason, V., Timpson, N.J., Morrison, A.C., Munroe, P.B., Strachan, D.P., Grarup, N., Loos, R.J.F., Heckbert, S.R., Vollenweider, P., Hayward, C., Stefansson, K., Froguel, P., Groop, L., Wareham, N.J., Duijn, C.M. van, Feitosa, M.F., O'Donnell, C.J., Kähönen, M., Perola, M., Boehnke, M., Kardia, S.L.R., Erdmann, J., Palmer, C.N.A., Ohlsson, C., Porteous, D.J., Eriksson, J.G., Bouchard, C., Moebus, S., Kraft, P., Weir, D.R., Cusi, D., Ferrucci, L., Ulivi, S., Girotto, G., Correa, A., Kääb, S., Peters, A., Chambers, J.C., Kooner, J.S., März, W., Rotter, J.I., Hicks, A.A., Smith, J.G., Kiemeney, L.A.L.M., Mook-Kanamori, D.O., Penninx, B.W.J.H., Gyllensten, U., Wilson, J.F., Burgess, S., Sundström, J., Lieb, W., Jukema, J.W., Eijgelsheim, M., Lakatta, E.L.M., Cheng, C.Y., Dörr, M., Wong, T.Y., Sabanayagam, C., Oldehinkel, A.J., Riese, H., Lehtimäki, T., Verweij, N., Harst, P. van der, Vegte, Y.J. van de, Eppinga, R.N., Ende, M.Y. van der, Hagemeijer, Y.P., Mahendran, Y., Salfati, E., Smith, A.V., Tan, V.Y., Arking, D.E., Ntalla, I., Appel, E.V., Schurmann, C., Brody, J.A., Rueedi, R., Polasek, O., Sveinbjornsson, G., Lecoeur, C., Ladenvall, C., Zhao, J.H., Isaacs, A., Wang, L., Luan, Jian'an, Hwang, S.J., Mononen, N., Auro, K., Jackson, A.U., Bielak, L.F., Zeng, L., Shah, N., Nethander, M., Campbell, A., Rankinen, T., Pechlivanis, S., Qi, L., Zhao, Wei, Rizzi, F., Tanaka, T., Robino, A., Cocca, M., Lange, L., Müller-Nurasyid, M., Roselli, C., Zhang, W, Kleber, M.E., Guo, X., Lin, H.J., Pavani, F., Galesloot, T.E., Noordam, R., Milaneschi, Y., Schraut, K.E., Hoed, M. den, Degenhardt, F., Trompet, S., Berg, M.E. van den, Pistis, G., Tham, Y.C., Weiss, S., Sim, X.S., Li, H.L., Most, P.J. van der, Nolte, I.M., Lyytikäinen, L.P., Said, M.A., Witte, D.R., Iribarren, C., Launer, L., Ring, S.M., Vries, P.S. de, Sever, P., Linneberg, A., Bottinger, E.P., Padmanabhan, S., Psaty, B.M., Sotoodehnia, N., Kolcic, I., Arnar, D.O., Gudbjartsson, D.F., Holm, H., Balkau, B., Silva, C.T., Newton-Cheh, C.H., Nikus, K., Salo, P., Mohlke, K.L., Peyser, P.A., Schunkert, H., Lorentzon, M., Lahti, J., Rao, D.C., Cornelis, M.C., Faul, J.D., Smith, J.A., Stolarz-Skrzypek, K., Bandinelli, S., Concas, M.P., Sinagra, G., Meitinger, T., Waldenberger, M., Sinner, M.F., Strauch, K., Delgado, G.E., Taylor, K.D., Yao, J., Foco, L., Melander, O., Graaf, J. de, Mutsert, R. de, Geus, E.J.C. de, Johansson, Å., Joshi, P.K., Lind, L., Franke, A., Macfarlane, P.W., Tarasov, K.V., Tan, N., Felix, S.B., Tai, E.S., Quek, D.Q., Snieder, H., Ormel, J., Ingelsson, M., Lindgren, C., Morris, A.P., Raitakari, O.T., Hansen, T., Assimes, T., Gudnason, V., Timpson, N.J., Morrison, A.C., Munroe, P.B., Strachan, D.P., Grarup, N., Loos, R.J.F., Heckbert, S.R., Vollenweider, P., Hayward, C., Stefansson, K., Froguel, P., Groop, L., Wareham, N.J., Duijn, C.M. van, Feitosa, M.F., O'Donnell, C.J., Kähönen, M., Perola, M., Boehnke, M., Kardia, S.L.R., Erdmann, J., Palmer, C.N.A., Ohlsson, C., Porteous, D.J., Eriksson, J.G., Bouchard, C., Moebus, S., Kraft, P., Weir, D.R., Cusi, D., Ferrucci, L., Ulivi, S., Girotto, G., Correa, A., Kääb, S., Peters, A., Chambers, J.C., Kooner, J.S., März, W., Rotter, J.I., Hicks, A.A., Smith, J.G., Kiemeney, L.A.L.M., Mook-Kanamori, D.O., Penninx, B.W.J.H., Gyllensten, U., Wilson, J.F., Burgess, S., Sundström, J., Lieb, W., Jukema, J.W., Eijgelsheim, M., Lakatta, E.L.M., Cheng, C.Y., Dörr, M., Wong, T.Y., Sabanayagam, C., Oldehinkel, A.J., Riese, H., Lehtimäki, T., Verweij, N., and Harst, P. van der

Abstract

Contains fulltext : 296013.pdf (Publisher’s version ) (Open Access), Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Published
2023

3. Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation

Author

Strawbridge, R.J., Silveira, A., Hoed, M. den, Gustafsson, S., Luan, J.A., Rybin, D., Dupuis, J., Li-Gao, R.F., Kavousi, M., Dehghan, A., Haljas, K., Lahti, J., Gadin, J.R., Backlund, A., Faire, U. de, Gertow, K., Giral, P., Goel, A., Humphries, S.E., Kurl, S., Langenberg, C., Lannfelt, L.L., Lind, L., Lindgren, C.C.M., Mannarino, E., Mook-Kanamori, D.O., Morris, A.P., Mutsert, R. de, Rauramaa, R., Saliba-Gustafsson, P., Sennblad, B., Smit, A.J., Syvanen, A.C., Tremoli, E., Veglia, F., Zethelius, B., Bjorck, H.M., Eriksson, J.G., Hofman, A., Franco, O.H., Watkins, H., Jukema, J.W., Florez, J.C., Wareham, N.J., Meigs, J.B., Ingelsson, E., Baldassarre, D., Hamsten, A., IMPROVE Study Grp, Medicum, Department of Psychology and Logopedics, University of Helsinki, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Developmental Psychology Research Group, Luan, Jian'an [0000-0003-3137-6337], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Carotid Artery Diseases, Male, EXPRESSION, endocrine system, Genetic variants, endocrine system diseases, Quantitative Trait Loci, PATHOPHYSIOLOGY, DEPENDENT DIABETES-MELLITUS, Vascular Remodeling, Carotid Intima-Media Thickness, Polymorphism, Single Nucleotide, INTIMA-MEDIA THICKNESS, Gene Frequency, Risk Factors, Intima-media-thickness, Humans, Genetic Predisposition to Disease, CORONARY-HEART-DISEASE, COHORT, cardiovascular diseases, Mendelian randomisation, EUROPEAN POPULATION, COMMON, Genetic Association Studies, Chromosomes, Human, Pair 15, MEN, Single nucleotide polymorphisms, Mendelian Randomization Analysis, Atherosclerosis, INSULIN, Europe, Phenotype, 3121 General medicine, internal medicine and other clinical medicine, Asymptomatic Diseases, Linear Models, Female, hormones, hormone substitutes, and hormone antagonists, Proinsulin
Abstract

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.

Published
2017

4. Towards sustainability through energy efficient buildings' design : Semantic labels

Author

Traversari, A.A.L., Hoed, M. den, Giulio, R. Di, and Bomhof, F.W.

Subjects
Fluid & Solid Mechanics ICT, TS - Technical Sciences, Energy efficiency, Sustainability, Semantic technology, Design rules, BIM, Early design, IB - Innovatiecentrum Bouw MNS - Media & Network Services, Architecture and Building
Abstract

When designing buildings, it is a challenge to take into account Energy Efficiency in the early design stage. This is especially difficult for hospital designs, because these buildings comprise many different room types and functions. This greatly increases the number of design directions available. Choices made early on in the design process have a large impact on the final performance of the building. However, the lack of detailing available in early designs makes it hard to evaluate them in terms of Key Performance Indicators. The Semantic Labels developed as part of the STREAMER project provide a way to address this problem, by allowing structured capture of the most relevant aspects of the Program of Requirements. Using this method, design rules can be applied to early building designs to detect and correct inconsistencies or suboptimal solutions. Also, using default values for label values, an early design can already be evaluated using simulation tools. The Semantic labels describe standard values for Construction (floor height and strength, accessibility), Hygiene class (from public spaces to operational theatres), Equipment (electric power requirements, safety), User profile (when the room is used), Comfort class (like daylight) and Access security (who can enter). Design rules may express conditions like the preferred spatial separation between rooms, or whether rooms should be placed at outer walls, but may also highlight incompatibilities in e.g. access requirements and user profiles. The Early Design Configurator, also under development as part of the STREAMER project, uses the Semantic Labels to allow automatic conversion of a Programme of Requirements, into an initial Building Information Modeling (BIM) design proposal that respects the design rules.

Published
2017

8. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

Author

Hoed, M. den, Eijgelsheim, M., Esko, T., Brundel, B.J., Peal, D.S., Evans, D.M., Nolte, I.M., Segre, A.V., Holm, H., Handsaker, R.E., Westra, H.J., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J.H., Kim, Y. J., Go, M.J., Almgren, P., Bochud, M., Boucher, G., Cornelis, M.C., Gudbjartsson, D., Hadley, D., Harst, P. van der, Hayward, C., Heijer, M. den, Igl, W., Jackson, A.U., Kutalik, Z., Luan, J., Kemp, J.P., Kristiansson, K., Ladenvall, C., Lorentzon, M., Montasser, M.E., Njajou, O.T., O'Reilly, P.F., Padmanabhan, S., Pourcain, B. St, Rankinen, T., Salo, P., Tanaka, T., Timpson, N.J., Vitart, V., Waite, L., Wheeler, W., Zhang, W., Draisma, H.H., Feitosa, M.F., Kerr, K.F., Lind, P.A., Mihailov, E., Onland-Moret, N.C., Song, C., Weedon, M.N., Xie, W., Yengo, L., Absher, D., Albert, C.M., Alonso, A., Arking, D.E., Bakker, P.I. de, Balkau, B., Barlassina, C., Benaglio, P., Bis, J.C., Bouatia-Naji, N., Brage, S., Chanock, S.J., Chines, P.S., Chung, M., Darbar, D., Dina, C., Dorr, M., Elliott, P., Felix, S.B., Fischer, K., Fuchsberger, C., Geus, E.J. de, Goyette, P., Gudnason, V., Harris, T.B., Hartikainen, A.L., Havulinna, A.S., Heckbert, S.R., Hicks, A.A., Hofman, A., Holewijn, S., Hoogstra-Berends, F., Hottenga, J.J., Jensen, M.K., Johansson, A, Junttila, J., Kaab, S., Kanon, B., Ketkar, S., Khaw, K.T., Knowles, J.W., Kooner, A.S., Graaf, J. de, Kiemeney, L.A.L.M., et al., Hoed, M. den, Eijgelsheim, M., Esko, T., Brundel, B.J., Peal, D.S., Evans, D.M., Nolte, I.M., Segre, A.V., Holm, H., Handsaker, R.E., Westra, H.J., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J.H., Kim, Y. J., Go, M.J., Almgren, P., Bochud, M., Boucher, G., Cornelis, M.C., Gudbjartsson, D., Hadley, D., Harst, P. van der, Hayward, C., Heijer, M. den, Igl, W., Jackson, A.U., Kutalik, Z., Luan, J., Kemp, J.P., Kristiansson, K., Ladenvall, C., Lorentzon, M., Montasser, M.E., Njajou, O.T., O'Reilly, P.F., Padmanabhan, S., Pourcain, B. St, Rankinen, T., Salo, P., Tanaka, T., Timpson, N.J., Vitart, V., Waite, L., Wheeler, W., Zhang, W., Draisma, H.H., Feitosa, M.F., Kerr, K.F., Lind, P.A., Mihailov, E., Onland-Moret, N.C., Song, C., Weedon, M.N., Xie, W., Yengo, L., Absher, D., Albert, C.M., Alonso, A., Arking, D.E., Bakker, P.I. de, Balkau, B., Barlassina, C., Benaglio, P., Bis, J.C., Bouatia-Naji, N., Brage, S., Chanock, S.J., Chines, P.S., Chung, M., Darbar, D., Dina, C., Dorr, M., Elliott, P., Felix, S.B., Fischer, K., Fuchsberger, C., Geus, E.J. de, Goyette, P., Gudnason, V., Harris, T.B., Hartikainen, A.L., Havulinna, A.S., Heckbert, S.R., Hicks, A.A., Hofman, A., Holewijn, S., Hoogstra-Berends, F., Hottenga, J.J., Jensen, M.K., Johansson, A, Junttila, J., Kaab, S., Kanon, B., Ketkar, S., Khaw, K.T., Knowles, J.W., Kooner, A.S., Graaf, J. de, Kiemeney, L.A.L.M., and et al.

Abstract

Item does not contain fulltext, Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Published
2013

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