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1. The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population

Author

Helena Grauen Larsen, Jiangming Sun, Marketa Sjögren, Yan Borné, Gunnar Engström, Peter Nilsson, Marju Orho-Melander, Isabel Goncalves, Jan Nilsson, Olle Melander, and Alexandru Schiopu

Subjects
Medicine, Science
Abstract

Abstract The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02–1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.

Published
2024
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2. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author

Viktoria Gusarova, Colm O’Dushlaine, Tanya M. Teslovich, Peter N. Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V. Van Hout, Michael F. Murray, Anubha Mahajan, Jonas B. Nielsen, Lars Fritsche, Anders Berg Wulff, Daniel F. Gudbjartsson, Marketa Sjögren, Connor A. Emdin, Robert A. Scott, Wen-Jane Lee, Aeron Small, Lydia C. Kwee, Om Prakash Dwivedi, Rashmi B. Prasad, Shannon Bruse, Alexander E. Lopez, John Penn, Anthony Marcketta, Joseph B. Leader, Christopher D. Still, H. Lester Kirchner, Uyenlinh L. Mirshahi, Amr H. Wardeh, Cassandra M. Hartle, Lukas Habegger, Samantha N. Fetterolf, Teresa Tusie-Luna, Andrew P. Morris, Hilma Holm, Valgerdur Steinthorsdottir, Patrick Sulem, Unnur Thorsteinsdottir, Jerome I. Rotter, Lee-Ming Chuang, Scott Damrauer, David Birtwell, Chad M. Brummett, Amit V. Khera, Pradeep Natarajan, Marju Orho-Melander, Jason Flannick, Luca A. Lotta, Cristen J. Willer, Oddgeir L. Holmen, Marylyn D. Ritchie, David H. Ledbetter, Andrew J. Murphy, Ingrid B. Borecki, Jeffrey G. Reid, John D. Overton, Ola Hansson, Leif Groop, Svati H. Shah, William E. Kraus, Daniel J. Rader, Yii-Der I. Chen, Kristian Hveem, Nicholas J. Wareham, Sekar Kathiresan, Olle Melander, Kari Stefansson, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Goncalo R. Abecasis, David Altshuler, Jose C. Florez, Michael Boehnke, Mark I. McCarthy, George D. Yancopoulos, David J. Carey, Alan R. Shuldiner, Aris Baras, Frederick E. Dewey, and Jesper Gromada

Subjects
Science
Abstract

Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4 −/− mice on a high-fat diet show improved insulin sensitivity.

Published
2018
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3. Polygenetic risk for coronary artery disease increases hospitalization burden and mortality

Author

Marketa Sjögren, Peter Almgren, and Olle Melander

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Coronary artery disease (CAD) is a leading cause of death worldwide and increasing cost for society. Genome wide association studies (GWAS) have identified common variants associated with CAD. Combining single nucleotide polymorphisms (SNPs) into a genetic risk score (GRS) can estimate an individual's genetic burden. Objectives: To investigate whether GRS for CAD can predict hospitalization and mortality. Methods: 23,594 individuals without CAD at baseline and with full data for all covariates from the population based prospective study Malmö diet and cancer study were investigated. The association between hospitalizations was calculated by negative binomial regression and risk of mortality was calculated by Cox proportional hazards regression. The GRS was constructed from 50 SNPs. Results: The study population was divided into quintiles according to the value of GRS. During the mean follow-up time of 17.8 years, 17,254 individuals were hospitalized at least once. Individuals in the highest quintile of GRS were hospitalized 10% more often than individuals in the lowest quintile (IRR: 1.10 [95% CI 1.04–1.16], p = 0.001), mainly for cardiovascular reasons (IRR: 1.31 [95% CI 1.20–1.43], p = 5.17 × 10−10). These individuals had highly increased risk of CVD mortality (HR: 1.44 [1.25–1.66], p = 6.56 × 10−7) but not the risk of mortality due to other causes. Conclusion: Our results suggest that genetic predisposition for CAD can predict hospitalization burden and mortality, especially due to cardiovascular causes, independently of traditional risk factors. As the risk conferred by the GRS is partially modifiable, our results may help to reduce societal costs, individual suffering and prolong life. Keywords: Genetic risk score (GRS), Coronary artery disease (CAD), Hospitalization, Mortality

Published
2019
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4. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.

Author

J Gustav Smith, Janine F Felix, Alanna C Morrison, Andreas Kalogeropoulos, Stella Trompet, Jemma B Wilk, Olof Gidlöf, Xinchen Wang, Michael Morley, Michael Mendelson, Roby Joehanes, Symen Ligthart, Xiaoyin Shan, Joshua C Bis, Ying A Wang, Marketa Sjögren, Julius Ngwa, Jeffrey Brandimarto, David J Stott, David Aguilar, Kenneth M Rice, Howard D Sesso, Serkalem Demissie, Brendan M Buckley, Kent D Taylor, Ian Ford, Chen Yao, Chunyu Liu, CHARGE-SCD consortium, EchoGen consortium, QT-IGC consortium, CHARGE-QRS consortium, Nona Sotoodehnia, Pim van der Harst, Bruno H Ch Stricker, Stephen B Kritchevsky, Yongmei Liu, J Michael Gaziano, Albert Hofman, Christine S Moravec, André G Uitterlinden, Manolis Kellis, Joyce B van Meurs, Kenneth B Margulies, Abbas Dehghan, Daniel Levy, Björn Olde, Bruce M Psaty, L Adrienne Cupples, J Wouter Jukema, Luc Djousse, Oscar H Franco, Eric Boerwinkle, Laurie A Boyer, Christopher Newton-Cheh, Javed Butler, Ramachandran S Vasan, Thomas P Cappola, and Nicholas L Smith

Subjects
Genetics, QH426-470
Abstract

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

Published
2016
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5. The Gly82Ser polymorphism in the receptor for advanced glycation end products is associated with increased risk for coronary events in the general population

Author

Gunnar Engström, Jan-Åke Nilsson, Marketa Sjögren, Peter M. Nilsson, H. Grauen Larsen, Olle Melander, Alexandru Schiopu, and Marju Orho-Melander

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Population, Endocrinology, Increased risk, Glycation, Internal medicine, medicine, cardiovascular diseases, Cardiology and Cardiovascular Medicine, Receptor, business, education
Abstract

Background/Introduction Activation of the receptor for advanced glycation end products (RAGE) by AGEs and various immune mediators has pro-inflammatory and pro-atherogenic effects. RAGE also exists in a soluble form, sRAGE, that acts as a decoy receptor for RAGE ligands. Low plasma sRAGE has previously been found to be associated with a higher risk for major adverse coronary events (MACE) in the population. Purpose The purpose of our study was to examine the causality of the association, by exploring whether genetic variants that influence sRAGE are associated with atherosclerosis progression and incident MACE and mortality in the population. Methods We performed a genome-wide association study (GWAS) in 4192 individuals from a randomly selected subgroup of a population-based cohort. Subsequently, we explored the associations between the identified single nucleotide polymorphims (SNPs) associated with plasma sRAGE levels, baseline intima media thickness (IMT) and IMT progression in the common carotid artery during a median follow-up of 16.5 years. Further, we analyzed the prospective relationships between the sRAGE-associated SNPs, incident MACE and mortality in the entire population-based cohort of 29245 individuals. The median follow-up time from baseline was 21.2 years for MACE and 21.6 years for total mortality (time to event or end of follow-up). Results We found the minor alleles of two single nucleotide polymorphisms (SNPs), rs2070600 and rs204993, to be independently associated with lower plasma sRAGE. While rs204993 is a silent intronic mutation, rs2070600 is known to cause a Gly82Ser polymorphism in the ligand binding domain, enhancing RAGE propensity for activation. In Cox regression analyses, we found an association between the minor T (vs. C) allele of rs2070600 and increased risk for first-time MACE [HR 1.12 (1.02–1.23); P=0.023]. The association was independent of traditional cardiovascular risk factors, blood pressure-lowering medication and lipid-lowering medication at baseline. rs204993 was not associated with MACE. Neither SNP was associated with carotid IMT at baseline or with IMT progression. We did not identify any relationships with total mortality. Conclusions We demonstrate for the first time an independent link between a genetic RAGE determinant and the risk for MACE in the population. Despite both identified SNPs being associated with lower sRAGE levels, only the functional rs2070600 mutation was associated with MACE, suggesting that the link is probably due to the enhancement of RAGE function rather than to the sRAGE lowering effect. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by grants from the Swedish Research Council and the Swedish Heart and Lung foundation.

Published
2020
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6. Genomic evaluation of circulating proteins for drug target characterisation and precision medicine

Author

Tõnu Esko, Lars Wallentin, Andrew D. Bretherick, Adam S. Butterworth, Jesper R. Gådin, Anders Hamsten, Anders Mälarstig, Gunnar Engström, Johan Ärnlöv, Andres Ingason, Céline Fernandez, Jian Yang, Peter M. Nilsson, George Davey-Smith, Weidong Zhang, Agneta Siegbahn, Lasse Folkersen, Thibaud Boutin, Michael V. Holmes, Lars Lind, Julie Lee, Erik Ingelsson, James F. Wilson, Olle Melander, Eric B. Fauman, Lude Franke, Amira Quazi, John Danesh, Ozren Polasek, Niclas Ericsson, Sarah E. Bergen, Mika Ala-Korpela, Andrew J. Schork, Marketa Sjögren, Seung Hoan Choi, Jan Nilsson, Åsa K Hedman, Cecilia M. Lindgren, Bram P. Prins, Daria V. Zhernakova, Yang Wu, Karl Michaëlsson, James E. Peters, Andrew P. Morris, Marju Orho-Melander, Stefan Enroth, Reedik Mägi, Stefan Gustafsson, Mikael Landén, Martin Magnusson, Qin Wang, Steven A. Lubitz, Johan Sundström, Federico De Masi, Jingyuan Fu, Rasmus Wernersson, Thomas Werge, Praveen Surendran, Tom Palmer, Paul W. Franks, Caroline Hayward, Daniel Hvidberg Hansen, Ulf Gyllensten, Vilmantas Giedraitis, Ljubica Perisic Matic, Urmo Võsa, Åsa Johansson, Alexandra Zhernakova, Bianca E. Suur, Karen Page, Gustav Smith, Erik Pålsson, Ting Qi, Harm-Jan Westra, Michael W. Nagle, Erin Macdonald-Dunlop, Annique Claringbould, Peter K. Joshi, Sölve Elmståhl, Anettne Kalnapenkis, Yan Chen, Chris Haley, and Jeremy D. Gale

Subjects
Drug, 0303 health sciences, media_common.quotation_subject, Drug target, Disease, Computational biology, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Precision medicine, 3. Good health, 03 medical and health sciences, Human health, 0302 clinical medicine, Mendelian randomization, Gene, 030304 developmental biology, media_common
Abstract

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping usingtrans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.

Published
2020
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7. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author

Teresa Tusié-Luna, Svati H. Shah, Wen-Jane Lee, Amit Khera, Gonçalo R. Abecasis, Olle Melander, Alan R. Shuldiner, Connor A. Emdin, Kari Stefansson, Jesper Gromada, Andrew P. Morris, Lee-Ming Chuang, Omri Gottesman, Lars G. Fritsche, Pradeep Natarajan, Marju Orho-Melander, Daniel F. Gudbjartsson, Anubha Mahajan, Marylyn D. Ritchie, William E. Kraus, Tooraj Mirshahi, Colm O'Dushlaine, Jason Flannick, Nicholas J. Wareham, Anne Tybjærg-Hansen, Anders Berg Wulff, Rashmi B. Prasad, Aris Baras, Jonas B. Nielsen, Valgerdur Steinthorsdottir, Yii-Der Ida Chen, Jerome I. Rotter, Lukas Habegger, Samantha N. Fetterolf, David Altshuler, Om Prakash Dwivedi, Tanya M. Teslovich, Cristen J. Willer, Luca A. Lotta, Andrew J. Murphy, Joseph B. Leader, Cristopher V. Van Hout, Christopher D. Still, Ola Hansson, David Birtwell, Alexander Lopez, Daniel J. Rader, John D. Overton, Anthony Marcketta, Patrick Sulem, Peter N. Benotti, Jose C. Florez, Lydia Coulter Kwee, David J. Carey, Oddgeir L. Holmen, Kristian Hveem, Leif Groop, Sekar Kathiresan, Viktoria Gusarova, Unnur Thorsteinsdottir, Cassandra M. Hartle, Uyenlinh L. Mirshahi, H. Lester Kirchner, Shannon Bruse, Robert A. Scott, Michael F. Murray, Marketa Sjögren, Jeffrey G. Reid, Aeron Small, Børge G. Nordestgaard, Amr H. Wardeh, Chad M. Brummett, Mark I. McCarthy, Frederick E. Dewey, David H. Ledbetter, John Penn, Ingrid B. Borecki, Scott M. Damrauer, Hilma Holm, Michael Boehnke, George D. Yancopoulos, Institute for Molecular Medicine Finland, University of Helsinki, Centre of Excellence in Complex Disease Genetics, and HUS Abdominal Center

Subjects
Blood Glucose, Male, 0301 basic medicine, Insulin Resistance/genetics, General Physics and Astronomy, Type 2 diabetes, 030204 cardiovascular system & hematology, Inbred C57BL, Cardiovascular, HAN CHINESE, Whole Exome Sequencing, Mice, 0302 clinical medicine, Risk Factors, ANGPTL4, Homeostasis, Glucose homeostasis, lcsh:Science, Mice, Knockout, Lipoprotein lipase, Multidisciplinary, Diabetes, Lipoprotein Lipase/metabolism, REMNANT CHOLESTEROL, ADIPOSE-TISSUE, Female, Type 2, Heterozygote, medicine.medical_specialty, Knockout, Science, LIPOPROTEIN-LIPASE, HEART-DISEASE, Diabetes Mellitus, Type 2/etiology, Article, General Biochemistry, Genetics and Molecular Biology, Angiopoietin-like 4 Protein/deficiency, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Exome Sequencing, Diabetes Mellitus, Genetics, medicine, Angiopoietin-Like Protein 4, Animals, Humans, Gene Silencing, GENOME-WIDE ASSOCIATION, Metabolic and endocrine, Genetic Association Studies, CHINESE POPULATION, Blood Glucose/metabolism, PLASMA-LIPIDS, business.industry, Case-control study, Genetic Variation, General Chemistry, Odds ratio, Atherosclerosis, medicine.disease, Mice, Inbred C57BL, Lipoprotein Lipase, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Amino Acid Substitution, Case-Control Studies, lcsh:Q, 3111 Biomedicine, ANGIOPOIETIN-LIKE PROTEIN-4, Insulin Resistance, business
Abstract

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D., Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.

Published
2018
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8. A NEW GENETIC RISK SCORE FOR BLOOD PRESSURE STRONGLY ASSOCIATES WITH THE INCIDENCE OF HYPERTENSION AND CARDIOVASCULAR ENDPOINTS IN TWO SWEDISH COHORTS

Author

Alice Giontella, Marketa Sjögren, Luca Lotta, John Overton, Aris Baras, Regeneron Genetics Center, Fava Cristiano, and Olle Melander

Subjects
medicine.medical_specialty, Blood pressure, Physiology, business.industry, Incidence (epidemiology), Internal medicine, Internal Medicine, Medicine, Genetic risk, Cardiology and Cardiovascular Medicine, business
Published
2021
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9. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Author

Tom Palmer, Lars Lind, George Davey Smith, Ting Qi, Michael W. Nagle, Paul W. Franks, Bram P. Prins, Julie Lee, Jingyuan Fu, Niclas Eriksson, Peter K. Joshi, Chris Haley, Ljubica Perisic Matic, Jeremy D. Gale, Mika Ala-Korpela, Michael V. Holmes, Urmo Võsa, Adam S. Butterworth, Eric B. Fauman, Anette Kalnapenkis, Reedik Mägi, Åsa Johansson, James F. Wilson, Mikael Landén, Gunnar Engström, Johan Ärnlöv, Anders Hamsten, Ozren Polasek, Andres Ingason, Andrew J. Schork, Agneta Siegbahn, Lasse Folkersen, Qin Wang, Andrew P. Morris, Johan Sundström, Daria V. Zhernakova, Olle Melander, Erik Ingelsson, Federico De Masi, Lude Franke, James E. Peters, Alexandra Zhernakova, Seung Hoan Choi, Rasmus Wernersson, Thibaud Boutin, Karl Michaëlsson, Stefan Gustafsson, Bianca E. Suur, Karen Page, Yang Wu, Caroline Hayward, Marketa Sjögren, Cecilia M. Lindgren, Stefan Enroth, Tõnu Esko, Amira Quazi, John Danesh, Anders Mälarstig, Daniel Hvidberg Hansen, Åsa K Hedman, Jan Nilsson, Ulf Gyllensten, Vilmantas Giedraitis, J. Gustav Smith, Martin Magnusson, Marju Orho-Melander, Steven A. Lubitz, Erin Macdonald-Dunlop, Thomas Werge, Praveen Surendran, Yan Chen, Céline Fernandez, Weidong Zhang, Lars Wallentin, Andrew D. Bretherick, Jian Yang, Peter M. Nilsson, Jesper R. Gådin, Annique Claringbould, Sölve Elmståhl, Sarah E Bergen, Harm-Jan Westra, Erik Pålsson, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), United Kingdom Research and Innovation, Folkersen, Lasse [0000-0003-0708-9530], Hansen, Daniel Hvidberg [0000-0003-3285-605X], Wu, Yang [0000-0002-0128-7280], Eriksson, Niclas [0000-0002-2152-4343], Bretherick, Andrew D [0000-0001-9258-3140], Enroth, Stefan [0000-0002-5056-9137], Lee, Julie [0000-0001-6090-6718], Ala-Korpela, Mika [0000-0001-5905-1206], Claringbould, Annique [0000-0002-9201-6557], Davey Smith, George [0000-0002-1407-8314], Fauman, Eric [0000-0002-9739-0249], Fernandez, Celine [0000-0003-1290-4982], Franke, Lude [0000-0002-5159-8802], Franks, Paul W [0000-0002-0520-7604], Giedraitis, Vilmantas [0000-0003-3423-2021], Haley, Chris [0000-0002-9811-0210], Johansson, Åsa [0000-0002-2915-4498], Lubitz, Steven [0000-0002-9599-4866], Palmer, Tom [0000-0003-4655-4511], Macdonald-Dunlop, Erin [0000-0001-6569-6086], Magnusson, Martin [0000-0003-1710-5936], Michaelsson, Karl [0000-0003-2815-1217], Nagle, Michael W [0000-0002-4677-7582], Nilsson, Peter M [0000-0002-5652-8459], Nilsson, Jan [0000-0002-9752-7479], Prins, Bram [0000-0001-5774-034X], Sundström, Johan [0000-0003-2247-8454], Werge, Thomas [0000-0003-1829-0766], Westra, Harm-Jan [0000-0001-7038-567X], Fu, Jingyuan [0000-0001-5578-1236], Esko, Tõnu [0000-0003-1982-6569], Hayward, Caroline [0000-0002-9405-9550], Landen, Mikael [0000-0002-4496-6451], Butterworth, Adam S [0000-0002-6915-9015], Holmes, Michael V [0000-0001-6617-0879], Ingelsson, Erik [0000-0003-2256-6972], Mälarstig, Anders [0000-0003-2608-1358], Apollo - University of Cambridge Repository, and 30387078 - Magnusson, P. Martin

Subjects
Proteomics, Proteome, Endocrinology, Diabetes and Metabolism, Asthma, ATP Binding Cassette Transporter 1, Cardiovascular System, Chromosome Mapping, Drug Delivery Systems, Gene Knockdown Techniques, Genome-Wide Association Study, Genomics, Humans, Inflammatory Bowel Diseases, Interleukin-1 Receptor-Like 1 Protein, Intracellular Signaling Peptides and Proteins, Linkage Disequilibrium, Mendelian Randomization Analysis, Protein-Serine-Threonine Kinases, Quantitative Trait Loci, Receptors, CCR2, Receptors, CCR5, Genome-wide association study, 030204 cardiovascular system & hematology, Chemokine receptor, 0302 clinical medicine, RECEPTOR ANTAGONIST, GWAS, Cardiac and Cardiovascular Systems, 0303 health sciences, Molecular medicine, 3. Good health, Medical genetics, Medical Genetics, Life Sciences & Biomedicine, medicine.medical_specialty, Computational biology, Biology, Protein Serine-Threonine Kinases, Article, 03 medical and health sciences, Endocrinology & Metabolism, Physiology (medical), Mendelian randomization, Internal Medicine, medicine, 030304 developmental biology, Science & Technology, Cell Biology, GENE, ANTIBODY
Abstract

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.

Published
2020
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10. Orthostatic Hypotension and Novel Blood Pressure Associated Gene Variants in Older Adults: Data From the TILDA Study

Author

Olle Melander, Marketa Sjögren, Aisling M O'Halloran, Daniel Carey, Eamon Laird, Artur Fedorowski, Ann Hever, and Rose Anne Kenny

Subjects
Male, Aging, Candidate gene, medicine.medical_specialty, Genotype, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Orthostatic vital signs, Hypotension, Orthostatic, Risk Factors, Internal medicine, Surveys and Questionnaires, Medicine, SNP, Humans, Longitudinal Studies, Allele, education, Alleles, Aged, education.field_of_study, business.industry, Genetic Variation, Blood Pressure Determination, Middle Aged, Minor allele frequency, Endocrinology, Blood pressure, Female, Geriatrics and Gerontology, business, Ireland
Abstract

Orthostatic hypotension (OH) is associated with increased risk of trauma and cardiovascular events. Recent studies have identified new genetic variants that influence orthostatic blood pressure (BP). The aim of this study was to investigate the associations of candidate gene loci with orthostatic BP responses in older adults. A total of 3,430 participants aged ≥50 years from The Irish Longitudinal Study on Ageing (TILDA) with BP measures and genetic data from 12 single-nucleotide polymorphism (SNP) linked to BP responses were analyzed. Orthostatic BP responses were recorded at each 10 s interval and were defined as OH (SBP drop ≥20 mmHg or DBP drop ≥10 mmHg) at the time-points 40, 90, and 110 s. We defined sustained OH (SOH) as a drop that exceeded consensus BP thresholds for OH at 40, 90, and 110 s after standing. Logistic regression analyses modeled associations between the candidate SNP alleles and OH. We report no significant associations between OH and measured SNPs after correction for multiple comparisons apart from the SNP rs5068 where proportion of the minor allele was significantly different between cases and controls for SOH 40 (p = .002). After adjustment for covariates in a logistic regression, those with the minor G allele (compared to the A allele) had a decreased incidence rate ratio (IRR) for SOH 40 (IRR 0.45, p = .001, 95% CI 0.29–0.72). Only one SNP linked with increased natriuretic peptide concentrations was associated with OH. These results suggest that genetic variants may have a weak impact on OH but needs verification in other population studies.

Published
2019

11. Polygenetic risk for coronary artery disease increases hospitalization burden and mortality

Author

Peter Almgren, Olle Melander, and Marketa Sjögren

Subjects
lcsh:Diseases of the circulatory (Cardiovascular) system, medicine.medical_specialty, Genome-wide association study, 030204 cardiovascular system & hematology, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Diet and cancer, Internal medicine, Genetic predisposition, Risk of mortality, Medicine, 030212 general & internal medicine, Mortality, Prospective cohort study, Cause of death, Original Paper, Genetic risk score (GRS), business.industry, fungi, medicine.disease, 3. Good health, Coronary artery disease (CAD), Hospitalization, lcsh:RC666-701, Population study, Cardiology and Cardiovascular Medicine, business
Abstract

Background: Coronary artery disease (CAD) is a leading cause of death worldwide and increasing cost for society. Genome wide association studies (GWAS) have identified common variants associated with CAD. Combining single nucleotide polymorphisms (SNPs) into a genetic risk score (GRS) can estimate an individual's genetic burden. Objectives: To investigate whether GRS for CAD can predict hospitalization and mortality. Methods: 23,594 individuals without CAD at baseline and with full data for all covariates from the population based prospective study Malmö diet and cancer study were investigated. The association between hospitalizations was calculated by negative binomial regression and risk of mortality was calculated by Cox proportional hazards regression. The GRS was constructed from 50 SNPs. Results: The study population was divided into quintiles according to the value of GRS. During the mean follow-up time of 17.8 years, 17,254 individuals were hospitalized at least once. Individuals in the highest quintile of GRS were hospitalized 10% more often than individuals in the lowest quintile (IRR: 1.10 [95% CI 1.04–1.16], p = 0.001), mainly for cardiovascular reasons (IRR: 1.31 [95% CI 1.20–1.43], p = 5.17 × 10−10). These individuals had highly increased risk of CVD mortality (HR: 1.44 [1.25–1.66], p = 6.56 × 10−7) but not the risk of mortality due to other causes. Conclusion: Our results suggest that genetic predisposition for CAD can predict hospitalization burden and mortality, especially due to cardiovascular causes, independently of traditional risk factors. As the risk conferred by the GRS is partially modifiable, our results may help to reduce societal costs, individual suffering and prolong life. Keywords: Genetic risk score (GRS), Coronary artery disease (CAD), Hospitalization, Mortality

Published
2019
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12. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Author

Bo Isomaa, Anne U. Jackson, Richard N. Bergman, A Sandbaek, Yun Li, Oluf Pedersen, Thomas Edward Hughes, Mike Erdos, Christine Meisinger, Kari Kubalanza, Felicity Payne, Mark Walker, E Pettersen, William L. Duren, Kristin Ardlie, Palmer Cna., Michael Boehnke, Peter M. Nilsson, Graham A. Hitman, Rachel M. Freathy, Matthew G. Rees, Johanna Kuusisto, Finny G Kuruvilla, Kari Stefansson, P Deodhar, Knut Borch-Johnsen, Perry Jrb., Inês Barroso, Hana Lango, Richa Saxena, Augustine Kong, Gonçalo R. Abecasis, Katherine S. Elliott, Jonathan Marchini, Richard M. Watanabe, Christopher J. Groves, Niels Grarup, Unnur Thorsteinsdottir, Doney Asf., Kristina Bengtsson Boström, Peter Almgren, Cristen J. Willer, Torben Jørgensen, Lauren Gianniny, Beverley M. Shields, Christian Herder, Mario A. Morken, Lu Qi, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Nigel W. Rayner, Benjamin F. Voight, H Chen, J J Roix, Karen L. Mohlke, Heather M. Stringham, Andrew D. Morris, Mark I. McCarthy, Gudmar Thorleifsson, Frank B. Hu, Narisu Narisu, Mark J. Daly, Amanda F. Marvelle, Markku Laakso, Leif Groop, Laura J. Scott, Ding C-J., L Qin, Lori L. Bonnycastle, Thomas Illig, Noël P. Burtt, Michael N. Weedon, Valeriya Lyssenko, Amy J. Swift, Timothy M. Frayling, Nicholas J. Wareham, de Bakker Piw., Tiinamaija Tuomi, Kristian Hveem, Candace Guiducci, T Hu, Andrew T. Hattersley, David Altshuler, Harald Grallert, Peter S. Chines, Inga Prokopenko, Torsten Lauritzen, Katharine R. Owen, Eleftheria Zeggini, Carl Platou, Marketa Sjögren, Jaakko Tuomilehto, Nicholas J. Timpson, Francis S. Collins, Kristian Midthjell, Gregers S. Andersen, Claudia Langenberg, and Torben Hansen

Subjects
Genetics, 0303 health sciences, endocrine system, SLC30A8, Genome, Human, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Diabetes Mellitus, Type 2, Meta-analysis, biology.protein, Humans, Genetic Predisposition to Disease, Human genome, CDKAL1, 030304 developmental biology
Abstract

Udgivelsesdato: 2008-May Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

Published
2016
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13. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Author

Jemma B. Wilk, Xiaoyin Shan, Christine S. Moravec, Christopher Newton-Cheh, Stella Trompet, Eric Boerwinkle, Javed Butler, Julius S. Ngwa, Laurie A. Boyer, Michael Morley, Nona Sotoodehnia, Nicholas L. Smith, Howard D. Sesso, David J. Stott, David Aguilar, Ying A. Wang, Ian Ford, Kenneth B. Margulies, Kent D. Taylor, André G. Uitterlinden, Jeffrey Brandimarto, Xinchen Wang, Joshua C. Bis, J. Michael Gaziano, Manolis Kellis, Janine F. Felix, Chunyu Liu, Symen Ligthart, Björn Olde, Luc Djoussé, Abbas Dehghan, Serkalem Demissie, Michael M. Mendelson, Roby Joehanes, J. Wouter Jukema, Bruce M. Psaty, Brendan M. Buckley, Marketa Sjögren, Ramachandran S. Vasan, J. Gustav Smith, Stephen B. Kritchevsky, Bruno H. Stricker, Daniel Levy, Andreas P. Kalogeropoulos, Olof Gidlöf, Alanna C. Morrison, Albert Hofman, Kenneth Rice, Oscar H. Franco, Yongmei Liu, L. Adrienne Cupples, Pim van der Harst, Chen Yao, Joyce B. J. van Meurs, Thomas P. Cappola, Cardiovascular Centre (CVC), Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Wang, Xinchen, Kellis, Manolis, Boyer, Laurie Ann, Epidemiology, Internal Medicine, and Medical Informatics

Subjects
0301 basic medicine, Male, Cancer Research, Physiology, Genome-wide association study, 030204 cardiovascular system & hematology, VARIANTS, Bioinformatics, Biochemistry, Genome-wide association studies, 0302 clinical medicine, AFRICAN ANCESTRY, HUMAN-POPULATIONS, Basic Helix-Loop-Helix Transcription Factors, Medicine and Health Sciences, Genetics (clinical), AGING RESEARCH, RISK, Hematology, DNA methylation, Death rates, Genomics, Middle Aged, Chromatin, 3. Good health, Body Fluids, Nucleic acids, Blood, PRESERVED EJECTION FRACTION, Gene Knockdown Techniques, SURVIVAL, Chromosomes, Human, Pair 5, Female, Epigenetics, Anatomy, DNA modification, Chromatin modification, Research Article, Chromosome biology, medicine.medical_specialty, Cell biology, Genotype, lcsh:QH426-470, Death Rates, Genetic loci, Cardiology, Heart failure, Biology, Polymorphism, Single Nucleotide, Chromosomes, 03 medical and health sciences, Population Metrics, Molecular genetics, Internal medicine, Genetic variation, medicine, Genetics, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Receptors, Cytokine, GENOME-WIDE ASSOCIATION, Enhancer, Molecular Biology, Genotyping, Ecology, Evolution, Behavior and Systematics, Alleles, METAANALYSIS, Genetic association, Demography, Heart Failure, Biology and life sciences, Population Biology, Genetic Variation, Computational Biology, Human Genetics, DNA, medicine.disease, Genome Analysis, Black or African American, lcsh:Genetics, 030104 developmental biology, HEK293 Cells, Gene Expression Regulation, Genetic Loci, People and Places, Gene expression, Genome-Wide Association Study, EPIDEMIOLOGY CHARGE CONSORTIUM
Abstract

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10⁻⁹. We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10⁻⁴⁰) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10⁻⁴). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure., National Heart, Lung, and Blood Institute (HHSN268201100005C), National Heart, Lung, and Blood Institute (HHSN268201100006C), National Heart, Lung, and Blood Institute (HHSN268201100007C), National Heart, Lung, and Blood Institute (HHSN268201100008C), National Heart, Lung, and Blood Institute (HHSN268201100009C), National Heart, Lung, and Blood Institute (HHSN268201100010C), National Heart, Lung, and Blood Institute (HHSN268201100011C), National Heart, Lung, and Blood Institute (HHSN268201100012C), National Heart, Lung, and Blood Institute (N01-HC-55015), National Heart, Lung, and Blood Institute (N01-HC-55016), National Heart, Lung, and Blood Institute (N01-HC-55018), National Heart, Lung, and Blood Institute (N01-HC-55019), National Heart, Lung, and Blood Institute (N01-HC-55020), National Heart, Lung, and Blood Institute (N01-HC-55021), National Heart, Lung, and Blood Institute (N01-HC-55022), National Heart, Lung, and Blood Institute (R01HL087641), National Heart, Lung, and Blood Institute (R01HL59367), National Heart, Lung, and Blood Institute (R01HL086694), National Human Genome Research Institute (U.S.) (U01HG004402), United States. National Institutes of Health (HHSN268200625226C), United States. National Institutes of Health (UL1RR025005), National Heart, Lung, and Blood Institute (HHSN268201200036C), National Heart, Lung, and Blood Institute (N01HC55222), National Heart, Lung, and Blood Institute (HHSN268200800007C), National Heart, Lung, and Blood Institute (N01HC85079), National Heart, Lung, and Blood Institute (N01HC85080), National Heart, Lung, and Blood Institute (N01HC85081), National Heart, Lung, and Blood Institute (N01HC85082), National Heart, Lung, and Blood Institute (N01HC85083), National Heart, Lung, and Blood Institute (N01HC85086), National Heart, Lung, and Blood Institute (U01HL080295), National Science Foundation (U.S.) (R01HL087652), National Heart, Lung, and Blood Institute (R01HL105756), National Heart, Lung, and Blood Institute (R01HL103612), National Heart, Lung, and Blood Institute (R01HL120393), National Institute on Aging (R01AG023629), National Center for Advancing Translational Sciences (U.S.) (UL1TR000124), National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (DK063491), National Heart, Lung, and Blood Institute (N01-HC-25195), National Heart, Lung, and Blood Institute (2K24HL04334), National Heart, Lung, and Blood Institute (R01HL077477), National Heart, Lung, and Blood Institute (R01HL093328), National Heart, Lung, and Blood Institute (NIH R01HL105993), National Institute on Aging (N01AG62101), National Heart, Lung, and Blood Institute (N01AG62103), National Heart, Lung, and Blood Institute (N01AG62106), National Institute on Aging (1R01AG032098-01A1), United States. National Institutes of Health (HHSN268200782096C), National Cancer Institute (U.S.) (CA-34944), National Cancer Institute (U.S.) (CA-40360), National Cancer Institute (U.S.) (CA-097193), National Heart, Lung, and Blood Institute (HL-26490), National Heart, Lung, and Blood Institute (HL-34595)

Published
2016

15. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. 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L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.

Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016
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16. Genetic vasopressin 1b receptor variance in overweight and diabetes mellitus

Author

Peter M. Nilsson, Bo Hedblad, Sofia Enhörning, Olle Melander, Joachim Struck, and Marketa Sjögren

Subjects
Male, medicine.medical_specialty, Receptors, Vasopressin, endocrine system, Genotype, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Overweight, Endocrinology and Diabetes, Polymorphism, Single Nucleotide, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Copeptin, Internal medicine, medicine, Diabetes Mellitus, Humans, Obesity, Prospective Studies, Prospective cohort study, education, Abdominal obesity, Aged, Sweden, education.field_of_study, business.industry, urogenital system, Glycopeptides, Genetic Variation, General Medicine, Middle Aged, 3. Good health, nervous system, Obesity, Abdominal, Cohort, Clinical Study, Female, medicine.symptom, business, hormones, hormone substitutes, and hormone antagonists, Cohort study
Abstract

ObjectiveRecently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM.DesignMalmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991–1996.MethodsFour tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort).ResultsIn MDC-CC, the major allele of rs35810727 was associated with elevated BMI (β-coefficient±s.e.m.; 0.30±0.14, P=0.03) and waist (0.78±0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21±0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00–1.20), P=0.04).ConclusionsGenetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation.

Published
2016

18. [OP.2A.08] RELATIONSHIP BETWEEN SELECTED DNA POLYMORPHISMS AND CORONARY ARTERY DISEASE COMPLICATIONS

Author

Marcin Wirtwein, Wojciech Sobiczewski, Olle Melander, Marcin Gruchała, Marketa Sjögren, and K. Narkiewicz

Subjects
medicine.medical_specialty, Physiology, business.industry, Dna polymorphism, 030204 cardiovascular system & hematology, medicine.disease, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, Cardiology, medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business
Published
2017
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19. ISH NIA PS 03-06 Genetic risk score determines cardiovascular complications in patients with stable coronary artery disease

Author

Michal Hoffmann, Krzysztof Narkiewicz, Olle Melander, Marcin Wirtwein, Wojciech Sobiczewski, Marketa Sjögren, and Marcin Gruchała

Subjects
medicine.medical_specialty, Physiology, business.industry, medicine.disease, Coronary artery disease, Internal medicine, Internal Medicine, Cardiology, Medicine, In patient, Medical emergency, Genetic risk, Cardiology and Cardiovascular Medicine, business
Published
2016
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20. [PP.07.02] AMBULATORY SYSTOLIC-DIASTOLIC PRESSURE REGRESSION INDEX IS GENETICALLY DETERMINED IN HYPERTENSIVE PATIENTS WITH CORONARY HEART DISEASE

Author

Marcin Gruchała, Marketa Sjögren, K. Narkiewicz, Olle Melander, Michal Hoffmann, and Marcin Wirtwein

Subjects
medicine.medical_specialty, Index (economics), Blood pressure, Physiology, business.industry, Internal medicine, Ambulatory, Internal Medicine, medicine, Cardiology, Cardiology and Cardiovascular Medicine, business, Coronary heart disease
Published
2016
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21. [PS 03-25] ELEVATED AMBULATORY SYSTOLIC-DIASTOLIC PRESSURE REGRESSION INDEX IS GENETICALLY DETERMINED IN PATIENTS WITH CORONARY HEART DISEASE

Author

Michal Hoffmann, Marcin Wirtwein, Wojciech Sobiczewski, Krzysztof Narkiewicz, Marcin Gruchała, Olle Melander, and Marketa Sjögren

Subjects
medicine.medical_specialty, Index (economics), Physiology, business.industry, Coronary heart disease, Regression, Blood pressure, Internal medicine, Ambulatory, Internal Medicine, medicine, Cardiology, In patient, Cardiology and Cardiovascular Medicine, business
Published
2016
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22. [PP.07.03] GENETIC RISK SCORE AND DIPPING PROFILE IN HYPERTENSIVE PATIENTS WITH CORONARY HEART DISEASE

Author

Olle Melander, Michal Hoffmann, Marcin Wirtwein, Wojciech Sobiczewski, K. Narkiewicz, Marcin Gruchała, and Marketa Sjögren

Subjects
medicine.medical_specialty, Framingham Risk Score, Physiology, business.industry, Internal medicine, Internal Medicine, medicine, Cardiology, Genetic risk, Cardiology and Cardiovascular Medicine, business, Coronary heart disease
Published
2016
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23. OS 30-05 GENETIC RISK SCORE DETERMINES DIPPING PROFILE IN PATIENTS WITH CORONARY HEART DISEASE

Author

Marcin Gruchała, Marketa Sjögren, Michal Hoffmann, Olle Melander, Wojciech Sobiczewski, and Marcin Wirtwein

Subjects
medicine.medical_specialty, Framingham Risk Score, Physiology, business.industry, Internal medicine, Internal Medicine, Cardiology, Medicine, In patient, Genetic risk, Cardiology and Cardiovascular Medicine, business, Coronary heart disease
Published
2016
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24. 1A.10

Author

Katarzyna Polonis, K. Narkiewicz, Marcin Wirtwein, Marketa Sjögren, M. Hoffman, D. Jarosz, Marcin Gruchała, Wojciech Sobiczewski, Olle Melander, and Thomas Hedner

Subjects
medicine.medical_specialty, Framingham Risk Score, Physiology, business.industry, Coronary heart disease, stomatognathic diseases, Internal medicine, Internal Medicine, medicine, Cardiology, In patient, Cardiology and Cardiovascular Medicine, business, Gene
Abstract

Coronary heart disease (CHD) development is associated to a combination of lifestyle and genetic factors. A number of lifestyle risk factors is well defined, while genetic factors have not yet been well determined.

Published
2015
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25. Elevated ambulatory systolic-diastolic pressure regression index is genetically determined in hypertensive patients with coronary heart disease

Author

Marcin Wirtwein, Olle Melander, Marketa Sjőgren, Michal Hoffmann, Krzysztof Narkiewicz, Marcin Gruchala, and Wojciech Sobiczewski

Subjects
dna polymorphism, coronary artery disease, hypertension, dipping, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Objectives: Ambulatory systolic-diastolic pressure regression index (ASDPRI) as a composite marker of cardiovascular (CV) properties is related to CV complications. However, genetic determinants of ASDPRI are not known. The aim of this study is to report the relationship between certain single nucleotide polymorphisms (SNP) and ASDPRI in hypertensive patients with CAD confirmed by coronary angiography. Methods: A total of 1345 hypertensive subjects with CAD were included. SNPs were selected from genome-wide association studies. SNPs were reported to be associated with coronary artery disease risk. There were significant differences in 24 h and daytime and nighttime ASDPRIs for PHCTR1, LPA and ADAMTS7 polymorphisms. Genetic risk score (GRS18) was constructed to evaluate additive effect of 18 SNPs for ASDPRI. Results: Analysis of covariance revealed a significant relationship between the PPAB2B (β − 0.85; 95 CI −1.85–−0.16, p

Published
2017
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