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1. Heart failure decouples the precuneus in interaction with social cognition and executive functions

Author: Schroeter, M., Godulla, J., Thiel, F., Taskin, B., Beutner, F., Dubovoy, V., Teren, A., Camilleri, J., Eickhoff, S., Villringer, A., and Mueller, K.
Subjects: Multidisciplinary, ddc:600
Abstract: Aging increases the risk to develop Alzheimer’s disease. Cardiovascular diseases might accelerate this process. Our study aimed at investigating the impact of heart failure on brain connectivity using functional magnetic resonance imaging at resting state. Here we show brain connectivity alterations related to heart failure and cognitive performance. Heart failure decreases brain connectivity in the precuneus. Precuneus dysconnectivity was associated with biomarkers of heart failure—left ventricular ejection fraction and N-terminal prohormone of brain natriuretic peptide—and cognitive performance, predominantly executive function. Meta-analytical data-mining approaches—conducted in the BrainMap and Neurosynth databases—revealed that social and executive cognitive functions are mainly associated with those neural networks. Remarkably, the precuneus, as identified in our study in a mid-life cohort, represents one central functional hub affected by Alzheimer’s disease. A long-term follow-up investigation in our cohort after approximately nine years revealed more severe cognitive impairment in the group with heart failure than controls, where social cognition was the cognitive domain mainly affected, and not memory such as in Alzheimer’s disease. In sum, our results indicate consistently an association between heart failure and decoupling of the precuneus from other brain regions being associated with social and executive functions. Further longitudinal studies are warranted elucidating etiopathological mechanisms.
Published: 2023

2. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Author: Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), and Franke, L. (Lude)
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
Published: 2021

3. GENETIC FACTORS OF ATHEROSCLEROSIS SUSCEPTIBILITY AT HUMAN CHROMOSOME 9p21: C24

Author: Holdt, L. M., Beutner, F., Scholz, M., Gielen, S., Gäbel, G., Bergert, H., Schuler, G., Thiery, J., and Teupser, D.
Published: 2010

4. RELATIONSHIP OF INFLAMMATORY MARKER C-REACTIVE PROTEIN, LIPID MARKERS AND CONVENTIONAL CARDIOVASCULAR RISK FACTORS IN SUBJECTS WITH SUSPECTED CORONARY ARTERY DISEASE: C21

Author: Beutner, F., Teupser, D., Tennert, C., Gielen, S., Scholz, M., Schuler, G., and Thiery, J.
Published: 2010

5. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Author: Porcu, E. (Eleonora), Rueger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawusse), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A. (Anand), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M. J. (Marc Jan), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tonu), Fave, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T. (Timothy), Gharib, S. A. (Sina A.), Gibson, G. (Gregory), Heijmans, B. T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kahonen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimaki, T. (Terho), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G. W. (Grant W.), Mueler-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, B. L. (Brandon L.), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppala, I. (Ilkka), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), van Meurs, J. (Joyce), Veldink, J. H. (Jan H.), Verlouw, J. (Joost), Visscher, P. M. (Peter M.), Volker, U. (Uwe), Vosa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D. I. (Dorret I.), Bot, J. (Jan), Deelen, J. (Joris), Hofman, B. A. (Bert A.), Hottenga, J. J. (Jouke J.), Isaacs, A. (Aaron), Jhamai, P. M. (P. Mila), Kielbasa, S. M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (Rene), Mei, H. (Hailiang), Moed, M. (Matthijs), Nooren, I. (Irene), Pool, R. (Rene), Schalkwijk, C. G. (Casper G.), Slagboom, P. E. (P. Eline), Suchiman, H. E. (H. Eka D.), Swertz, M. A. (Morris A.), Tigchelaar, E. F. (Ettje F.), Uitterlinden, A. G. (Andre G.), van den Berg, L. H. (Leonard H.), van der Breggen, R. (Ruud), van der Kallen, C. J. (Carla J. H.), van Dijk, F. (Freerk), van Duijn, C. M. (Cornelia M.), van Galen, M. (Michiel), van Greevenbroek, M. M. (Marleen M. J.), van Heemst, D. (Diana), van Rooij, J. (Jeroen), Van't Hof, P. (Peter), van Zwet, E. W. (Erik. W.), Vermaat, M. (Martijn), Verbiest, M. (Michael), Verkerk, M. (Marijn), Zhernakova, D. V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F. A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltan)
Abstract: Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
Published: 2019

6. Nat Commun

Author: Franceschini, N., GIAMBARTOLOMEI, C., DE VRIES, P. S., FINAN, C., BIS, J. C., HUNTLEY, R. P., LOVERING, R. C., TAJUDDIN, S. M., WINKLER, T. W., GRAFF, M., KAVOUSI, M., Dale, C., SMITH, A. V., Hofer, E., VAN LEEUWEN, E. M., Nolte, I. M., Lu, L., Scholz, M., Sargurupremraj, Muralidharan, PITKANEN, N., FRANZEN, O., Joshi, P. K., NOORDAM, R., MARIONI, R. E., Hwang, S. J., MUSANI, S. K., SCHMINKE, U., PALMAS, W., ISAACS, A., CORREA, A., ZONDERMAN, A. B., Hofman, A., TEUMER, A., COX, A. J., UITTERLINDEN, A. G., Wong, A., SMIT, A. J., NEWMAN, A. B., Britton, A., RUUSALEPP, A., Sennblad, B., HEDBLAD, B., PASANIUC, B., PENNINX, B. W., LANGEFELD, C. D., WASSEL, C. L., Tzourio, Christophe, Fava, C., BALDASSARRE, D., O'LEARY, D. H., TEUPSER, D., Kuh, D., TREMOLI, E., MANNARINO, E., Grossi, E., BOERWINKLE, E., SCHADT, E. E., INGELSSON, E., VEGLIA, F., Rivadeneira, F., BEUTNER, F., Chauhan, Ganesh, Heiss, G., SNIEDER, H., Campbell, H., VOLZKE, H., MARKUS, H. S., DEARY, I. J., JUKEMA, J. W., de Graaf, J., Price, J., POTT, J., HOPEWELL, J. C., Liang, J., Thiery, J., Engmann, J., GERTOW, K., Rice, K., TAYLOR, K. D., DHANA, K., KIEMENEY, Lalm, LIND, L., RAFFIELD, L. M., LAUNER, L. J., HOLDT, L. M., DORR, M., DICHGANS, M., TRAYLOR, M., SITZER, M., KUMARI, M., Kivimaki, M., Nalls, M. A., MELANDER, O., RAITAKARI, O., FRANCO, O. H., RUEDA-OCHOA, O. L., ROUSSOS, P., WHINCUP, P. H., Amouyel, P., Giral, P., ANUGU, P., WONG, Q., Malik, R., RAURAMAA, R., BURKHARDT, R., Hardy, R., Schmidt, R., DE MUTSERT, R., MORRIS, R. W., STRAWBRIDGE, R. J., WANNAMETHEE, S. G., HAGG, S., Shah, S., MCLACHLAN, S., TROMPET, S., SESHADRI, S., KURL, S., HECKBERT, S. R., Ring, S., HARRIS, T. B., LEHTIMAKI, T., GALESLOOT, T. E., Shah, T., DE FAIRE, U., Plagnol, V., ROSAMOND, W. D., Post, W., Zhu, X., Zhang, X., Guo, X., SABA, Y., DEHGHAN, A., SELDENRIJK, A., MORRISON, A. C., HAMSTEN, A., PSATY, B. M., VAN DUIJN, C. M., LAWLOR, D. A., MOOK-KANAMORI, D. O., BOWDEN, D. W., Schmidt, H., WILSON, J. F., ROTTER, J. I., WARDLAW, J. M., DEANFIELD, J., HALCOX, J., LYYTIKAINEN, L. P., Loeffler, M., EVANS, M. K., Debette, Stéphanie, HUMPHRIES, S. E., VOLKER, U., GUDNASON, V., HINGORANI, A. D., BJORKEGREN, J. L. M., CASAS, J. P., O'DONNELL, C. J., Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: VINTAGE, cardiovascular system, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, cardiovascular diseases, HEALTHY
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Published: 2018

7. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Franceschini, N, Giambartolomei, C, de Vries, PS, Finan, C, Bis, JC, Huntley, RP, Lovering, RC, Tajuddin, SM, Winkler, TW, Graff, M, Kavousi, M, Dale, C, Smith, AV, Hofer, E, van Leeuwen, EM, Nolte, IM, Lu, L, Scholz, M, Sargurupremraj, M, Pitkänen, N, Franzén, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, SJ, Musani, SK, Schminke, U, Palmas, W, Isaacs, A, Correa, A, Zonderman, AB, Hofman, A, Teumer, A, Cox, AJ, Uitterlinden, AG, Wong, A, Smit, AJ, Newman, AB, Britton, A, Ruusalepp, A, Sennblad, B, Hedblad, B, Pasaniuc, B, Penninx, BW, Langefeld, CD, Wassel, CL, Tzourio, C, Fava, C, Baldassarre, D, O’Leary, DH, Teupser, D, Kuh, D, Tremoli, E, Mannarino, E, Grossi, E, Boerwinkle, E, Schadt, EE, Ingelsson, E, Veglia, F, Rivadeneira, F, Beutner, F, Chauhan, G, Heiss, G, Snieder, H, Campbell, H, Völzke, H, Markus, HS, Deary, IJ, Jukema, JW, de Graaf, J, Price, J, Pott, J, Hopewell, JC, Liang, J, Thiery, J, Engmann, J, Gertow, K, Rice, K, Taylor, KD, Dhana, K, Kiemeney, LALM, Lind, L, Raffield, LM, Launer, LJ, Holdt, LM, Dörr, M, Dichgans, M, Traylor, M, Sitzer, M, Kumari, M, Kivimaki, M, Nalls, MA, Melander, O, Raitakari, O, Franco, OH, Rueda-Ochoa, OL, Roussos, P, Whincup, PH, Amouyel, P, and Giral, P
Subjects: Aging, MEGASTROKE Consortium, Quantitative Trait Loci, ADAMTS9 Protein, Coronary Disease, Cardiovascular, Polymorphism, Single Nucleotide, Carotid Intima-Media Thickness, Protein-Lysine 6-Oxidase, Risk Factors, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Aetiology, Polymorphism, Heart Disease - Coronary Heart Disease, Plaque, Atherosclerotic, Human Genome, Single Nucleotide, Atherosclerosis, Plaque, Atherosclerotic, Brain Disorders, Stroke, Heart Disease, cardiovascular system, Amino Acid Oxidoreductases, Lod Score, Genome-Wide Association Study
Abstract: © 2018, The Author(s). Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Published: 2018

8. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Author: Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K.E., Zheng, Z., Yengo, L., Lloyd-Jones, L.R., Sidorenko, J., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.-J., Franke, L., Frayling, T., Gharib, S., Gibson, G., Hemani, G., Jansen, R., Kähönen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Metspalu, A., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Meurs, J., Verlouw, J., Völker, U., Võsa, U., Yaghootkar, H., Zeng, B., McRae, A.F., Visscher, P.M., Zeng, J., Yang, J., Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Clinicum, Complex Disease Genetics, Psychiatry, APH - Digital Health, and Internal Medicine
Subjects: 0301 basic medicine, Epigenomics, Netherlands Twin Register (NTR), endocrine system diseases, General Physics and Astronomy, Genome-wide association study, Epigenesis, Genetic, Genotype, lcsh:Science, Heat-Shock Proteins, Genetics, Multidisciplinary, Mitochondrial Proton-Translocating ATPases, 3. Good health, DNA methylation, Risk, endocrine system, Science, education, Biology, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Humans, Genetic Predisposition to Disease, Epigenetics, Gene, Genetic association, Genetic Variation, nutritional and metabolic diseases, General Chemistry, DNA Methylation, 030104 developmental biology, Calcium-Calmodulin-Dependent Protein Kinase Type 1, Diabetes Mellitus, Type 2, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, lcsh:Q, 3111 Biomedicine, Carrier Proteins, human activities, Genome-Wide Association Study
Abstract: Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants., GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
Published: 2018

9. Alteration of Multiple Leukocyte Gene Expression Networks is Linked with Magnetic Resonance Markers of Prognosis After Acute ST-Elevation Myocardial Infarction

Author: Teren, A., primary, Kirsten, H., additional, Beutner, F., additional, Scholz, M., additional, Holdt, L. M., additional, Teupser, D., additional, Gutberlet, M., additional, Thiery, J., additional, Schuler, G., additional, and Eitel, I., additional
Published: 2017
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10. A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Author: Nikpay, M. Goel, A. Won, H.-H. Hall, L.M. Willenborg, C. Kanoni, S. Saleheen, D. Kyriakou, T. Nelson, C.P. CHopewell, J. Webb, T.R. Zeng, L. Dehghan, A. Alver, M. MArmasu, S. Auro, K. Bjonnes, A. Chasman, D.I. Chen, S. Ford, I. Franceschini, N. Gieger, C. Grace, C. Gustafsson, S. Huang, J. Hwang, S.-J. Kim, Y.K. Kleber, M.E. Lau, K.W. Lu, X. Lu, Y. Lyytikäinen, L.-P. Mihailov, E. Morrison, A.C. Pervjakova, N. Qu, L. Rose, L.M. Salfati, E. Saxena, R. Scholz, M. Smith, A.V. Tikkanen, E. Uitterlinden, A. Yang, X. Zhang, W. Zhao, W. De Andrade, M. De Vries, P.S. Van Zuydam, N.R. Anand, S.S. Bertram, L. Beutner, F. Dedoussis, G. Frossard, P. Gauguier, D. Goodall, A.H. Gottesman, O. Haber, M. Han, B.-G. Huang, J. Jalilzadeh, S. Kessler, T. König, I.R. Lannfelt, L. Lieb, W. Lind, L. MLindgren, C. Lokki, M.-L. Magnusson, P.K. Mallick, N.H. Mehra, N. Meitinger, T. Memon, F.-U.-R. Morris, A.P. Nieminen, M.S. Pedersen, N.L. Peters, A. Rallidis, L.S. Rasheed, A. Samuel, M. Shah, S.H. Sinisalo, J. EStirrups, K. Trompet, S. Wang, L. Zaman, K.S. Ardissino, D. Boerwinkle, E. Borecki, I.B. Bottinger, E.P. Buring, J.E. Chambers, J.C. Collins, R. Cupples, L. Danesh, J. Demuth, I. Elosua, R. Epstein, S.E. Esko, T. Feitosa, M.F. Franco, O.H. Franzosi, M.G. Granger, C.B. Gu, D. Gudnason, V. SHall, A. Hamsten, A. Harris, T.B. LHazen, S. Hengstenberg, C. Hofman, A. Ingelsson, E. Iribarren, C. Jukema, J.W. Karhunen, P.J. Kim, B.-J. Kooner, J.S. Kullo, I.J. Lehtimäki, T. Loos, R.J.F. Melander, O. Metspalu, A. März, W. Palmer, C.N. Perola, M. Quertermous, T. Rader, D.J. Ridker, P.M. Ripatti, S. Roberts, R. Salomaa, V. Sanghera, D.K. Schwartz, S.M. Seedorf, U. Stewart, A.F. Stott, D.J. Thiery, J. Zalloua, P.A. O'Donnell, C.J. Reilly, M.P. Assimes, T.L. Thompson, J.R. Erdmann, J. Clarke, R. Watkins, H. Kathiresan, S. McPherson, R. Deloukas, P. Schunkert, H. Samani, N.J. Farrall, M.
Abstract: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. © 2015 Nature America, Inc.
Published: 2015

11. Association of peripheral-blood transcriptome with prognostic markers of myocardial damage assessed by cardiovascular magnetic resonance after reperfused ST-elevation myocardial infarction

Author: Teren, A., Eitel, I., Beutner, F., Kirsten, H., Scholz, M., Teupser, D., Gutberlet, M., Thiery, J., Schuler, G., Thiele, H., and Publica
Abstract: Purpose: Aim of the present study was to identify associations of global gene expression in peripheral blood mononuclear cells (PBMC) with established cardiovascular magnetic resonance (CMR) markers of myocardial damage and prognosis after ST-elevation myocardial infarction (STEMI). Methods: We enrolled 100 patients with STEMI (70.0% men, age 60.8±11.9 years) after primary angioplasty within 12h after symptom-onset [median pain-toballoon time 237 min (IQR 150-376)]. After reperfusion [median time interval 19.5 hrs (IQR 15-25)] whole blood was collected to perform high throughput transcriptome analysis in isolated PBMC using Illumina HumanHT-12 v4 Expression BeadChips. Subsequently, T2-weighted, SSFP-CINE, and contrast-enhanced CMR was performed within one week after infarction to assess the left ventricle ejection fraction (MR-EF), the myocardial salvage index (MSI), and to visualize late microvascular obstruction in relation to the infarct size (late MO/IS). Results: After pre-processing accounting for relevant confounders, expression levels of 9949 genes were analysed. Among these, expression of one gene involved in the regulation of protein stability correlated strongest with MR-EF [pvalue = 1.7x10-5; false discovery rate (FDR)
Published: 2014

12. Secretory phospholipase A2-IIA and cardiovascular disease: a mendelian randomization study

Author: Holmes, M.V., Simon, T., Exeter, H.J, Folkersen, L., Asselbergs, F.W., Guardiola, M., Cooper, J.A., Palmen, J., Hubacek, J.A., Carruthers, K.F., Horne, B.D., Brunisholz, K.D., Mega, J.L., Van Iperen, E.P., Li, M., Leusink, M., Trompet, S., Verschuren, J.J., Hovingh, G.K., Dehghan, A., Nelson, C.P., Kotti, S., Danchin, N., Scholz, M., Haase, C.L., Rothenbacher, D., Swerdlow, D.I., Kuchenbaecker, K.B., Staines-Urias, E., Goel, A., Van 't Hooft, F., Gertow, K., De Faire, U., Panayiotou, A.G., Tremoli, E., Baldassarre, D., Veglia, F., Holdt, L.M., Beutner, F., Gansevoort. R.T., Navis, G.J., Mateo, L.I., Breitling, L.P., Brenner, H., Thiery, J., Dallmeier, D., Franco-Cereceda, A., Boer, J.M., Stephens, J.W., Hofker, M.H., Tedgui, A., Hofman, A., Uitterlinden, A.G., Adamkova, V., Pitha, J., Onland-Moret, N.C., Cramer, M.J., Nathoe, H.M., Spiering, W., Klungel, O.H., Kumari, M., Whincup, P.H., Morrow, D.A., Braund, P.S., Hall, A.S., Olsson, A.G., Doevendans, P.A., Trip, M.D., Tobin, M.D., Hamsten, A., Watkins, H., Koenig, W., Nicolaides, A.N., Teupser, D., Day, I.N., Carlquist, J.F., Gaunt, T.R., Ford, I., Sattar, N., Tsimikas, S., Schwartz, G.G., Lawlor, D.A., Morris, R.W., Sandhu, M.S., Poledne, R., Maitland-van der Zee, A.H., Khaw, K.T., Keating, B.J., Van der Harst, P., Price, J.F., Mehta, S.R., Yusuf, S., Witteman, J.C., Franco, O.H., Jukema, J.W., De Knijff, P., Tybjaerg-Hansen, A., Rader, D.J., Farrall, M., Samani, N.J., Kivimaki, M., Fox, K.A., Humphries, S.E., Anderson, J.L., Boekholdt, S.M., Palmer, T.M., Eriksson, P., Paré, G., Hingorani, A.D., Sabatine, M.S., Mallat, Z., Casas, J.P., Talmud, P.J., Medicina i Cirurgia, and Universitat Rovira i Virgili.
Subjects: 0735-1097, Cardiovascular diseases, Drug development, Epidemiology, Genetics, Mendelian randomization, Sistema cardiovascular--Malalties, Clinical Medicine, Medical and Health Sciences
Abstract: Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2-IIA mass or sPLA 2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA 2 enzyme activity and MVE. Conclusions Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
Published: 2013

13. Genome wide meta-analysis identifies novel regulators of circulating serum progranulin

Author: Krüger, J, primary, Scholz, M, additional, Gross, A, additional, Krause, K, additional, Marzi, C, additional, Grallert, H, additional, Ladenvall, C, additional, Schleinitz, D, additional, Kirsten, H, additional, Heyne, H, additional, Laurila, E, additional, Kriebel, J, additional, Thorand, B, additional, Rathmann, W, additional, Groop, L, additional, Prokopenko, I, additional, Isomaa, B, additional, Beutner, F, additional, Kratzsch, J, additional, Thiery, J, additional, Klöting, N, additional, Fischer-Rosinský, A, additional, Pfeiffer, A, additional, Spranger, J, additional, Gieger, C, additional, Blüher, M, additional, Stumvoll, M, additional, Kovacs, P, additional, and Tönjes, A, additional
Published: 2016
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14. LB011-MON ASSOCIATION OF MICRONUTRIENT INTAKE WITH THE ANGIOGRAPHIC PREVALENCE AND SEVERITY OF CORONARY ARTERY DISEASE

Author: Vogel, A., primary, Teren, A., additional, Beutner, F., additional, Schuler, G., additional, Helmschrodt, C., additional, Ceglarek, U., additional, Scholz, M., additional, and Thiery, J., additional
Published: 2013
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15. MS342 EFFECT OF EVEROLIMUS ON PRE-EXISTING ATHEROSCLEROSIS IN LDLR−/− MICE

Author: Brendel, D., primary, Beutner, F., additional, Teupser, D., additional, Müller, M., additional, Baber, R., additional, Jeromin, F., additional, Wilfert, W., additional, Ceglarek, U., additional, and Thiery, J., additional
Published: 2010
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16. MS343 CAROTID ULTRASOUND CONTRIBUTES TO THE ASSESSMENT OF CORONARY ARTERY DISEASE

Author: Beutner, F., primary, Teupser, D., additional, Gielen, S., additional, Sandri, M., additional, Scholz, M., additional, Schuler, G., additional, and Thiery, J., additional
Published: 2010
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17. W57 INCREASED ATHEROSCLEROSIS SEVERITY AT CHROMOSOME 9P21

Author: Holdt, L., primary, Beutner, F., additional, Scholz, M., additional, Gielen, S., additional, Gäbel, G., additional, Bergert, H., additional, Schuler, G., additional, Thiery, J., additional, and Teupser, D., additional
Published: 2010
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18. MS259 RELATIONSHIP OF INFLAMMATORY MARKER C-REACTIVE PROTEIN, LIPID MARKERS AND CONVENTIONAL CARDIOVASCULAR RISK FACTORS IN SUBJECTS WITH SUSPECTED CORONARY ARTERY DISEASE

Author: Beutner, F., primary, Teupser, D., additional, Tennert, C., additional, Scholz, M., additional, Gielen, S., additional, Sandri, M., additional, Schuler, G., additional, and Thiery, J., additional
Published: 2010
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19. Abstract: P467 EFFECT OF EVEROLIMUS ON PRE-EXISTING ATHEROSCLEROSIS IN LDLR−/− MICE

Author: Brendel, D, primary, Beutner, F, additional, Müller, M, additional, Teupser, D, additional, Baber, R, additional, Ceglarek, U, additional, and Thiery, J, additional
Published: 2009
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20. Abstract: P776 SONOGRAPHIC IMAGING OF CAROTID ATHEROSCLEROSIS IS A BETTER PREDICTOR OF CORONARY ARTERY DISEASE THAN CREACTIVE PROTEIN (CRP)

Author: Beutner, F, primary, Teupser, D, additional, Scholz, M, additional, Gielen, S, additional, Schuler, G, additional, and Thiery, J, additional
Published: 2009
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21. Abstract: 1080 THE CHROMOSOME 9P21 LOCUS OF CORONARY ARTERY DISEASE AFFECTS EXPRESSION OF ADJACENT ATHEROSCLEROSIS CANDIDATE GENES

Author: Holdt, L, primary, Beutner, F, additional, Scholz, M, additional, Gielen, S, additional, Schuler, G, additional, Thiery, J, additional, and Teupser, D, additional
Published: 2009
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22. 532: The immunosuppressant everolimus significantly prevents atherosclerosis in LDLR-/- mice despite severe hypercholesterolemia

Author: Mueller, M.A., primary, Beutner, F., additional, Teupser, D., additional, Ceglarek, U., additional, Jeromin, F., additional, Wilfert, W., additional, and Thiery, J., additional
Published: 2007
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23. Th-W48:8 The immunosuppresant everolimus significantly prevents atherosclerosis in hypercholesterolemic LDLR-/- mice

Author: Mueller, M.A., primary, Beutner, F., additional, Teupser, D., additional, Ceglarek, U., additional, Jeromin, F., additional, Weise, C., additional, and Thiery, J., additional
Published: 2006
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24. MS342 EFFECT OF EVEROLIMUS ON PRE-EXISTING ATHEROSCLEROSIS IN LDLR −/− MICE

Author: Brendel, D., Beutner, F., Teupser, D., Müller, M., Baber, R., Jeromin, F., Wilfert, W., Ceglarek, U., and Thiery, J.
Published: 2010
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25. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Author: Mills, Melinda C., Tropf, Felix C., Brazel, David M., van Zuydam, Natalie, Vaez, Ahmad, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Greg, Heijmans, Bastiaan T., Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Markus, Marigorta, Urko M., Mei, Hailang, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel G., Penninx, Brenda W. J. H., Perola, Markus, Pervjakova, Natalia, Pierce, Brandon L., Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ripatti, Samuli, Rotzschke, Olaf, Rüeger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ‘t Hoen, Peter A. C., Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, van Meurs, Joyce, Veldink, Jan H., Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Wijmenga, Cisca, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Zhang, Futao, Isaacs, Aaron, Pool, René, Jan Hottenga, Jouke, van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Sasha, Tigchelaar, Ettje F., Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., van ’t Hof, Peter, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Luijk, René, van Dijk, Freerk, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., Akimova, Evelina T., Bergmann, Sven, Boardman, Jason D., Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey-Smith, George, Davies, Gail, Deary, Ian J., Franco, Oscar, Gaskins, Audrey J., de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Grabe, Hans Jörgen, Gunderson, Erica P., Harris, Kathleen Mullan, Hartwig, Fernando P., He, Chunyan, Hill, W. David, Homuth, Georg, Horta, Bernando Lessa, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M. Arfan, Johannesson, Magnus, Kamali, Zoha, Kavousi, Maryam, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, McQueen, Matthew B., Medland, Sarah E., Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Missmer, Stacey A., Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter J., de Mutsert, Renée, Nolte, Ilja M., Noordam, Raymond, Peters, Annette, Power, Chris, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Waldenberger, Melanie, Wareham, Nicholas J., Willemsen, Gonneke, Zhao, Jing Hau, Pers, Tune H., Snieder, Harold, Perry, John R. B., Ong, Ken K., den Hoed, Marcel, Barban, Nicola, Day, Felix R., Mills, M. C., Tropf, F. C., Brazel, D. M., van Zuydam, N., Vaez, A., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A. K., Arindrarto, W., Awadalla, P., Battle, A., Beutner, F., Jan Bonder, M., Boomsma, D. I., Christiansen, M. W., Claringbould, A., Deelen, P., Esko, T., Fave, M. -J., Franke, L., Frayling, T., Gharib, S. A., Gibson, G., Heijmans, B. T., Hemani, G., Jansen, R., Kahonen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimaki, T., Loeffler, M., Marigorta, U. M., Mei, H., Milani, L., Montgomery, G. W., Muller-Nurasyid, M., Nauck, M., Nivard, M. G., Penninx, B. W. J. H., Perola, M., Pervjakova, N., Pierce, B. L., Powell, J., Prokisch, H., Psaty, B. M., Raitakari, O. T., Ripatti, S., Rotzschke, O., Rueger, S., Saha, A., Scholz, M., Schramm, K., Seppala, I., Slagboom, E. P., Stehouwer, C. D. A., Stumvoll, M., Sullivan, P., 't Hoen, P. A. C., Teumer, A., Thiery, J., Tong, L., Tonjes, A., van Dongen, J., van Iterson, M., van Meurs, J., Veldink, J. H., Verlouw, J., Visscher, P. M., Volker, U., Vosa, U., Westra, H. -J., Wijmenga, C., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F., van Greevenbroek, M. M. J., Schalkwijk, C. G., Deelen, J., van Heemst, D., van Duijn, C. M., Hofman, B. A., Isaacs, A., Uitterlinden, A. G., Verbiest, M., Suchiman, H. E. D., Verkerk, M., van der Breggen, R., van Rooij, J., Lakenberg, N., Bot, J., Zhernakova, D. V., Luijk, R., Bonder, M. J., Swertz, M. A., van Zwet, E. W., Akimova, E. T., Bergmann, S., Boardman, J. D., Buring, J. E., Cesarini, D., Chasman, D. I., Chavarro, J. E., Cocca, M., Concas, M. P., Davey-Smith, G., Davies, G., Deary, I. J., Gaskins, A. J., de Geus, E. J. C., Gieger, C., Girotto, G., Grabe, H. J., Gunderson, E. P., Harris, K. M., Hartwig, F. P., He, C., Homuth, G., Horta, B. L., Jan Hottenga, J., Huang, H., Hyppӧnen, E., Ikram, M. A., Johannesson, M., Kamali, Z., Kavousi, M., Kraft, P., Kuhnel, B., Langenberg, C., Study, L. C., Lind, P. A., Luan, J., Magi, R., Magnusson, P. K. E., Mahajan, A., Martin, N. G., Mbarek, H., Mccarthy, M. I., Mcmahon, G., Mcqueen, M. B., Medland, S. E., Meitinger, T., Metspalu, A., Mihailov, E., Missmer, S. A., Mollegaard, S., Mook-Kanamori, D. O., Morgan, A., van der Most, P. J., de Mutsert, R., Noordam, R., Power, C., Redmond, P., Rich-Edwards, J. W., Ridker, P. M., Rietveld, C. A., Ring, S. M., Rose, L. M., Rueedi, R., Stefansson, K., Stockl, D., Strauch, K., Thurik, A. R., Timpson, N. J., Turman, C., Wareham, N. J., Willemsen, G., Zhao, J. H., Pers, T. H., Snieder, H., Perry, J. R. B., Ong, K. K., den Hoed, M., Barban, N., Day, F. R., Mills, Melinda C, Tropf, Felix C, Brazel, David M, van Zuydam, Natalie, Vaez, Ahmad, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, den Hoed, Marcel, Barban, Nicola, Day, Felix R, Hyppӧnen, Elina, eQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Consortium, eQTLGen, Consortium, BIOS, Consortium, Human Reproductive Behaviour, Mahajan, A, McCarthy, MI, Mills, Melinda C., Tropf, Felix C., Brazel, David M., Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Battle, Alexi, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Greg, Heijmans, Bastiaan T., Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johanne, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Marku, Marigorta, Urko M., Mei, Hailang, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthia, Nivard, Michel G., Penninx, Brenda W. J. H., Perola, Marku, Pervjakova, Natalia, Pierce, Brandon L., Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ripatti, Samuli, Rotzschke, Olaf, Rüeger, Sina, Saha, Ashi, Scholz, Marku, Schramm, Katharina, Seppälä, Ilkka, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ‘t Hoen, Peter A. C., Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, van Meurs, Joyce, Veldink, Jan H., Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Wijmenga, Cisca, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Zhang, Futao, Isaacs, Aaron, Pool, René, Jan Hottenga, Jouke, van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Sasha, Tigchelaar, Ettje F., Beekman, Marian, Deelen, Jori, van Heemst, Diana, van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., van ’t Hof, Peter, Nooren, Irene, Moed, Matthij, Vermaat, Martijn, Luijk, René, van Dijk, Freerk, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., Akimova, Evelina T., Bergmann, Sven, Boardman, Jason D., Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey-Smith, George, Davies, Gail, Deary, Ian J., Franco, Oscar, Gaskins, Audrey J., de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Grabe, Hans Jörgen, Gunderson, Erica P., Harris, Kathleen Mullan, Hartwig, Fernando P., He, Chunyan, Hill, W. David, Homuth, Georg, Horta, Bernando Lessa, Huang, Hongyang, Ikram, M. Arfan, Johannesson, Magnu, Kamali, Zoha, Kavousi, Maryam, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, McQueen, Matthew B., Medland, Sarah E., Meitinger, Thoma, Metspalu, Andre, Mihailov, Evelin, Missmer, Stacey A., Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter J., de Mutsert, Renée, Nolte, Ilja M., Noordam, Raymond, Peters, Annette, Power, Chri, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Stefánsson, Kári, Stöckl, Dori, Strauch, Konstantin, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Waldenberger, Melanie, Wareham, Nicholas J., Willemsen, Gonneke, Zhao, Jing Hau, Pers, Tune H., Perry, John R. B., Ong, Ken K., Day, Felix R., Sociology [until 2010], Biological Psychology, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Management and Organisation, Urology, Medical Informatics, Department of Marketing Management, Epidemiology, Internal Medicine, Radiology & Nuclear Medicine, Neurology, Applied Economics, and Life Course Epidemiology (LCE)
Subjects: Male, demography, genetic variants, reproductive biology, externalising behavior, environmental effects, Disease, Genome-wide association studies, Behavioral Neuroscience, 0302 clinical medicine, genetics, media_common, fertility, 0303 health sciences, Reproduction, Incidence (epidemiology), Coitus, Age Factors, Longevity, sexual intercourse, health, Spermatid differentiation, Single Nucleotide, Reproduction/genetics, 3. Good health, Behavioural genetics, Parturition/genetics, Female, infertility, Infertility, genetic variant, Adolescent, Social Psychology, media_common.quotation_subject, Experimental and Cognitive Psychology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Reproductive biology, medicine, Humans, Polymorphism, behavioural genetics, first sexual intercourse, Genetic Association Studies, Demography, 030304 developmental biology, Parturition, Coitus/physiology, medicine.disease, externalising behaviour, Sexual intercourse, Fertility, age, 030217 neurology & neurosurgery, first birth
Abstract: Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.
Published: 2021

26. C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis

Author: Zoltán Kutalik, Joyce Van Meurs, Urmo Võsa, Martina Müller-Nurasyid, Marc Jan Bonder, Michael Stumvoll, Joseph Powell, Kaido Lepik, Michel Nivard, Peter Kovacs, Holger Prokisch, Pärt Peterson, Jenny Van Dongen, Silva Kasela, Kai Kisand, Annique Claringbould, Tarmo Annilo, Joost Verlouw, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Digital Health, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Personalized Medicine, eQTLGen Consortium, Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.J., Franke, L., Frayling, T., Gharib, S., Gibson, G., Hemani, G., Jansen, R., Kähönen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Metspalu, A., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Meurs, J., Verlouw, J., Visscher, P., Völker, U., Võsa, U., Yaghootkar, H., Yang, J., Zeng, B., and Zhang, F.
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Physiology, Economics, Economic Models, Complement System, Gene Expression, Social Sciences, Adult, Antigens, CD59/blood, Antigens, CD59/metabolism, C-Reactive Protein/metabolism, Cohort Studies, Estonia, Humans, Inflammation/metabolism, Up-Regulation/physiology, Bioinformatics, Biochemistry, Sequencing techniques, Immune Physiology, Gene expression, Medicine and Health Sciences, Biology (General), Whole blood, Regulation of gene expression, Immune System Proteins, Ecology, RNA sequencing, Mendelian Randomization Analysis, C-Reactive Proteins, Body Fluids, Up-Regulation, 3. Good health, Blood, C-Reactive Protein, Computational Theory and Mathematics, Modeling and Simulation, Biological Cultures, Anatomy, medicine.symptom, Research Article, QH301-705.5, Inflammatory Diseases, Immunology, CD59 Antigens, Inflammation, CD59, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Genetics, medicine, Journal Article, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, C-reactive protein, Biology and Life Sciences, Proteins, Cell Cultures, ta3121, Research and analysis methods, Molecular biology techniques, 030104 developmental biology, Immune System, biology.protein
Abstract: Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits., Author summary Chronic inflammation is associated with chronic diseases, morbidity and mortality while lower base inflammation levels are thought to be predictive of healthy aging. Thus, to pursue a long and healthy lifespan, it is essential to understand the inflammatory regulatory mechanisms. To that end, we studied the functional role of C-reactive protein (CRP)–an inflammatory biomarker that is used to measure cardiovascular risk in clinical practice. There is evidence for a strong genetic component of elevated CRP levels but it is still unclear if it has a direct impact on the processes that lead to inflammatory diseases. In order to elucidate the function of CRP in the blood, we used statistical methods for causal inference to infer causal relationships between changes in CRP and gene expression levels. Our statistical analysis and cell culture experiments suggest that CRP drives the expression of complement regulatory protein CD59. Thus, CRP can have a functional role in protecting human blood cells from the adverse effects of the immune defence system.
Published: 2017

27. Brain dysconnectivity with heart failure.

Author: Mueller K, Thiel F, Taskin B, Beutner F, Teren A, Dubovoy VK, Möller HE, Villringer A, and Schroeter ML
Abstract: Structural brain damage associated with heart failure is well described; however, little is known about associated changes in various specific brain functions that bear immediate clinical relevance. A satisfactory pathophysiological link between heart failure and decline in cognitive function is still missing. In the present study, we aim to detect functional correlates of heart failure in terms of alterations in functional brain connectivity (quantified by functional magnetic resonance imaging) related to cognitive performance assessed by neuropsychological testing. Eighty patients were post hoc grouped into subjects with and without coronary artery disease. The coronary artery disease patients were further grouped as presenting with or without heart failure according to the guidelines of the European Society of Cardiology. On the basis of resting-state functional magnetic resonance imaging, brain connectivity was investigated using network centrality as well as seed-based correlation. Statistical analysis aimed at specifying centrality group differences and potential correlations between centrality and heart failure-related measures including left ventricular ejection fraction and serum concentrations of N-terminal fragment of the pro-hormone brain-type natriuretic peptide. The resulting correlation maps were then analysed using a flexible factorial model with the factors 'heart failure' and 'cognitive performance'. Our core findings are: (i) A statistically significant network centrality decrease was found to be associated with heart failure primarily in the precuneus, i.e. we show a positive correlation between centrality and left ventricular ejection fraction as well as a negative correlation between centrality and N-terminal fragment of the pro-hormone brain-type natriuretic peptide. (ii) Seed-based correlation analysis showed a significant interaction between heart failure and cognitive performance related to a significant decrease of precuneus connectivity to other brain regions. We obtained these results by different analysis approaches indicating the robustness of the findings we report here. Our results suggest that the precuneus is a brain region involved in connectivity decline in patients with heart failure, possibly primarily or already at an early stage. Current models of Alzheimer's disease-having pathophysiological risk factors in common with cerebrovascular disorders-also consider reduced precuneus connectivity as a marker of brain degeneration. Consequently, we propose that heart failure and Alzheimer's disease exhibit partly overlapping pathophysiological paths or have common endpoints associated with a more or less severe decrease in brain connectivity. This is further supported by specific functional connectivity alterations between the precuneus and widely distributed cortical regions, particularly in patients showing reduced cognitive performance., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Published: 2023
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28. Heart failure decouples the precuneus in interaction with social cognition and executive functions.

Author: Schroeter ML, Godulla J, Thiel F, Taskin B, Beutner F, Dubovoy VK, Teren A, Camilleri J, Eickhoff S, Villringer A, and Mueller K
Subjects: Humans, Executive Function, Social Cognition, Stroke Volume, Ventricular Function, Left, Brain, Cognition, Brain Mapping, Parietal Lobe, Magnetic Resonance Imaging, Alzheimer Disease, Cognitive Dysfunction, Heart Failure
Abstract: Aging increases the risk to develop Alzheimer's disease. Cardiovascular diseases might accelerate this process. Our study aimed at investigating the impact of heart failure on brain connectivity using functional magnetic resonance imaging at resting state. Here we show brain connectivity alterations related to heart failure and cognitive performance. Heart failure decreases brain connectivity in the precuneus. Precuneus dysconnectivity was associated with biomarkers of heart failure-left ventricular ejection fraction and N-terminal prohormone of brain natriuretic peptide-and cognitive performance, predominantly executive function. Meta-analytical data-mining approaches-conducted in the BrainMap and Neurosynth databases-revealed that social and executive cognitive functions are mainly associated with those neural networks. Remarkably, the precuneus, as identified in our study in a mid-life cohort, represents one central functional hub affected by Alzheimer's disease. A long-term follow-up investigation in our cohort after approximately nine years revealed more severe cognitive impairment in the group with heart failure than controls, where social cognition was the cognitive domain mainly affected, and not memory such as in Alzheimer's disease. In sum, our results indicate consistently an association between heart failure and decoupling of the precuneus from other brain regions being associated with social and executive functions. Further longitudinal studies are warranted elucidating etiopathological mechanisms., (© 2023. The Author(s).)
Published: 2023
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29. Biomarkers for Non-Invasive Stratification of Coronary Artery Disease and Prognostic Impact on Long-Term Survival in Patients with Stable Coronary Heart Disease.

Author: Netto J, Teren A, Burkhardt R, Willenberg A, Beutner F, Henger S, Schuler G, Thiele H, Isermann B, Thiery J, Scholz M, and Kaiser T
Subjects: Biomarkers, C-Reactive Protein, Constriction, Pathologic, Female, Humans, Interleukin-6, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prognosis, Coronary Artery Disease
Abstract: Knowledge about cardiac and inflammatory biomarkers in patients with stable coronary artery disease (CAD) is limited. To address this, we analyzed 3072 patients (36% female) with a median follow-up of 10 years in the Leipzig LIFE Heart Study with suspected CAD with coronary angiography. Selected biomarkers included troponin T (hsTNT), N-terminal pro B-type natriuretic peptide (NT-proBNP), copeptin, C-reactive protein (hsCRP), and interleukin-6 (IL-6). Patients were stratified by CAD severity: CAD0 (no sclerosis), CAD1 (non-obstructive, i.e., stenosis < 50%), and CAD2 (≥one stenosis ≥ 50%). Group comparison (GC) included GC1: CAD0 + 1 vs. CAD2; GC2: CAD0 vs. CAD1 + 2. CAD0, CAD1, and CAD2 were apparent in 1271, 631, and 1170 patients, respectively. Adjusted for classical risk factors, hs-cTnT, NT-proBNP, and IL-6 differed significantly in both GC and hsCRP only in GC2. After multivariate analysis, hs-cTnT, NT-proBNP, and IL-6 remained significant in GC1. In GC2, hs-cTnT (p < 0.001) and copeptin (p = 0.014) reached significance. Ten-year survival in groups CAD0, CAD1, and CAD2 was 88.3%, 77.3%, and 72.4%. Incorporation of hs-cTnT, NT-proBNP, copeptin, and IL-6 improved risk prediction (p < 0.001). The studied cardiac and inflammatory biomarkers enable fast and precise non-invasive identification of mortality risk in CAD patients, allowing the tailoring of primary and secondary CAD prevention.
Published: 2022
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30. Simultaneous Mass Spectrometry-Based Apolipoprotein Profiling and Apolipoprotein E Phenotyping in Patients with ASCVD and Mild Cognitive Impairment.

Author: Begcevic Brkovic I, Zöhrer B, Scholz M, Reinicke M, Dittrich J, Kamalsada S, Baber R, Beutner F, Teren A, Engel C, Wirkner K, Thiele H, Löffler M, Riedel-Heller SG, and Ceglarek U
Subjects: Apolipoprotein B-100, Apolipoprotein E2 genetics, Apolipoprotein E3 genetics, Apolipoprotein E4, Apolipoproteins E metabolism, Humans, Mass Spectrometry, Protein Isoforms, Cardiovascular Diseases, Cognitive Dysfunction
Abstract: Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8−12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.
Published: 2022
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31. Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues.

Author: Castaneda AB, Petty LE, Scholz M, Jansen R, Weiss S, Zhang X, Schramm K, Beutner F, Kirsten H, Schminke U, Hwang SJ, Marzi C, Dhana K, Seldenrijk A, Krohn K, Homuth G, Wolf P, Peters MJ, Dörr M, Peters A, van Meurs JBJ, Uitterlinden AG, Kavousi M, Levy D, Herder C, van Grootheest G, Waldenberger M, Meisinger C, Rathmann W, Thiery J, Polak J, Koenig W, Seissler J, Bis JC, Franceshini N, Giambartolomei C, Hofman A, Franco OH, Penninx BWJH, Prokisch H, Völzke H, Loeffler M, O'Donnell CJ, Below JE, Dehghan A, and de Vries PS
Subjects: Gene Expression, Genome-Wide Association Study, Humans, Risk Factors, Atherosclerosis, Carotid Intima-Media Thickness
Abstract: Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT., (Published by Oxford University Press 2021.)
Published: 2022
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32. A metabolomic approach to identify the link between sports activity and atheroprotection.

Author: Beutner F, Ritter C, Scholz M, Teren A, Holdt LM, Teupser D, Becker S, Thiele H, Gielen S, Thiery J, and Ceglarek U
Subjects: Biomarkers, Exercise, Humans, Mass Spectrometry, Amino Acids, Metabolomics methods
Abstract: Aims: Physical activity (PA) is a mainstay of cardiovascular prevention. This study aimed to identify metabolic mediators of PA that protect against the development of atherosclerosis., Methods and Results: A total of 2160 participants in the LIFE heart study were analysed with data on PA and vascular phenotyping. In a targeted metabolomic approach, 61 metabolites (amino acids and acylcarnitines) were measured using liquid chromatography-tandem mass spectrometry. We investigated the interactions between PA, metabolites and markers of atherosclerosis in order to uncover possible mediation effects. Intended sports activity, but no daily PA, was associated with a lower degree of atherosclerosis, odds ratio (OR) for total atherosclerotic burden of 0.76 (95% confidence interval 0.62-0.94), carotid artery plaque OR 0.79 (0.66-0.96), and peripheral artery disease OR 0.74 (0.56-0.98). Twelve amino acids, free carnitine, five acylcarnitines were associated with sports activity. Of these, eight metabolites were also associated with the degree of atherosclerosis. In the mediation analyses, a cluster of amino acids (arginine, glutamine, pipecolic acid, taurine) were considered as possible mediators of atheroprotection. In contrast, a group of members of the carnitine metabolism (free carnitine, acetyl carnitine, octadecenoyl carnitine) were associated with inactivity and higher atherosclerotic burden., Conclusion: Our metabolomic approach, which is integrated into a mediation model, provides transformative insights into the complex metabolic processes involved in atheroprotection. Metabolites with antioxidant and endothelial active properties are believed to be possible mediators of atheroprotection. The metabolomic mediation approach can support the understanding of complex diseases in order to identify targets for prevention and therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Published: 2022
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33. Whole Blood Metabolite Profiles Reflect Changes in Energy Metabolism in Heart Failure.

Author: Beuchel C, Dittrich J, Pott J, Henger S, Beutner F, Isermann B, Loeffler M, Thiery J, Ceglarek U, and Scholz M
Abstract: A variety of atherosclerosis and cardiovascular disease (ASCVD) phenotypes are tightly linked to changes in the cardiac energy metabolism that can lead to a loss of metabolic flexibility and to unfavorable clinical outcomes. We conducted an association analysis of 31 ASCVD phenotypes and 97 whole blood amino acids, acylcarnitines and derived ratios in the LIFE-Adult ( n = 9646) and LIFE-Heart ( n = 5860) studies, respectively. In addition to hundreds of significant associations, a total of 62 associations of six phenotypes were found in both studies. Positive associations of various amino acids and a range of acylcarnitines with decreasing cardiovascular health indicate disruptions in mitochondrial, as well as peroxisomal fatty acid oxidation. We complemented our metabolite association analyses with whole blood and peripheral blood mononuclear cell (PBMC) gene-expression analyses of fatty acid oxidation and ketone-body metabolism related genes. This revealed several differential expressions for the heart failure biomarker N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in peripheral blood mononuclear cell (PBMC) gene expression. Finally, we constructed and compared three prediction models of significant stenosis in the LIFE-Heart study using (1) traditional risk factors only, (2) the metabolite panel only and (3) a combined model. Area under the receiver operating characteristic curve (AUC) comparison of these three models shows an improved prediction accuracy for the combined metabolite and classical risk factor model (AUC = 0.78, 95%-CI: 0.76-0.80). In conclusion, we improved our understanding of metabolic implications of ASCVD phenotypes by observing associations with metabolite concentrations and gene expression of the mitochondrial and peroxisomal fatty acid oxidation. Additionally, we demonstrated the predictive potential of the metabolite profile to improve classification of patients with significant stenosis.
Published: 2022
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34. Association of plasma trimethylamine N-oxide levels with atherosclerotic cardiovascular disease and factors of the metabolic syndrome.

Author: Ringel C, Dittrich J, Gaudl A, Schellong P, Beuchel CF, Baber R, Beutner F, Teren A, Engel C, Wirkner K, Thiele H, Büttner P, Löffler M, Scholz M, Thiery J, and Ceglarek U
Subjects: Adult, Biomarkers, Humans, Methylamines, Risk Factors, Atherosclerosis diagnosis, Cardiovascular Diseases, Metabolic Syndrome diagnosis, Percutaneous Coronary Intervention
Abstract: Background and Aims: The association of plasma trimethylamine N-oxide (TMAO) with atherosclerotic cardiovascular disease (ASCVD), diabetes mellitus (DM) and its determinants, as well as the role of TMAO as a predictor for short and long-term mortality, is still under discussion. We investigated associations between four plasma metabolites of the TMAO pathway and different clinical manifestations of atherosclerosis, diabetes determinants, and risk of short and long-term mortality in patients with stable ASCVD, acute myocardial infarction (AMI), cardiogenic shock (CS), and DM in three independent cohorts., Methods: TMAO and its dietary precursors were simultaneously quantified by liquid chromatography-tandem mass spectrometry in a total of 2655 participants of the German Leipzig Research Center for Civilization Diseases (LIFE)-Heart study, LIFE-Adult study, and the European Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) multicenter trial. Associations with ASCVD manifestations, metabolic syndrome, 30-day mortality of patients with AMI and CS, and long-term mortality of subjects with suspected coronary artery disease (CAD) were analyzed., Results: TMAO plasma levels were not independently associated with stable ASCVD. Elevated TMAO plasma concentrations were independently associated with obesity (odds ratio, 1.23; p < 0.01) and DM (odds ratio, 1.37; p < 0.001) in LIFE-Heart. The latter association was confirmed in LIFE-Adult. We found no association of TMAO plasma levels with short-term mortality in patients with AMI and CS. However, TMAO plasma levels were independent predictors of long-term mortality in patients with suspected CAD (hazard ratio, 1.24; p < 0.05)., Conclusions: Potential proatherogenic mechanisms of TMAO seem to have no short-term effect in AMI. Presented associations with diabetes mellitus and obesity suggest that TMAO might have a functional role in metabolic syndrome., (Copyright © 2021 Elsevier B.V. All rights reserved.)
Published: 2021
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35. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Author: Võsa U, Claringbould A, Westra HJ, Bonder MJ, Deelen P, Zeng B, Kirsten H, Saha A, Kreuzhuber R, Yazar S, Brugge H, Oelen R, de Vries DH, van der Wijst MGP, Kasela S, Pervjakova N, Alves I, Favé MJ, Agbessi M, Christiansen MW, Jansen R, Seppälä I, Tong L, Teumer A, Schramm K, Hemani G, Verlouw J, Yaghootkar H, Sönmez Flitman R, Brown A, Kukushkina V, Kalnapenkis A, Rüeger S, Porcu E, Kronberg J, Kettunen J, Lee B, Zhang F, Qi T, Hernandez JA, Arindrarto W, Beutner F, Dmitrieva J, Elansary M, Fairfax BP, Georges M, Heijmans BT, Hewitt AW, Kähönen M, Kim Y, Knight JC, Kovacs P, Krohn K, Li S, Loeffler M, Marigorta UM, Mei H, Momozawa Y, Müller-Nurasyid M, Nauck M, Nivard MG, Penninx BWJH, Pritchard JK, Raitakari OT, Rotzschke O, Slagboom EP, Stehouwer CDA, Stumvoll M, Sullivan P, 't Hoen PAC, Thiery J, Tönjes A, van Dongen J, van Iterson M, Veldink JH, Völker U, Warmerdam R, Wijmenga C, Swertz M, Andiappan A, Montgomery GW, Ripatti S, Perola M, Kutalik Z, Dermitzakis E, Bergmann S, Frayling T, van Meurs J, Prokisch H, Ahsan H, Pierce BL, Lehtimäki T, Boomsma DI, Psaty BM, Gharib SA, Awadalla P, Milani L, Ouwehand WH, Downes K, Stegle O, Battle A, Visscher PM, Yang J, Scholz M, Powell J, Gibson G, Esko T, and Franke L
Subjects: Genome-Wide Association Study, Humans, Multifactorial Inheritance genetics, Polymorphism, Single Nucleotide genetics, Transcriptome genetics, Blood Proteins genetics, Gene Expression Regulation genetics, Quantitative Trait Loci genetics
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2021
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36. Cohort Profile: The Leipzig Research Center for Civilization Diseases-Heart Study (LIFE-Heart).

Author: Scholz M, Henger S, Beutner F, Teren A, Baber R, Willenberg A, Ceglarek U, Pott J, Burkhardt R, and Thiery J
Subjects: Cohort Studies, Humans, Civilization, Heart Diseases epidemiology
Published: 2020
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37. Relationship between fermented dairy consumption, circulating short-chain acylcarnitines and angiographic severity of coronary artery disease.

Author: Teren A, Vogel A, Beutner F, Gielen S, Burkhardt R, Scholz M, Thiery J, and Ceglarek U
Subjects: Aged, Biomarkers blood, Carnitine blood, Coronary Artery Disease blood, Coronary Artery Disease epidemiology, Coronary Artery Disease prevention & control, Coronary Stenosis blood, Coronary Stenosis epidemiology, Coronary Stenosis prevention & control, Cross-Sectional Studies, Female, Germany epidemiology, Humans, Male, Middle Aged, Predictive Value of Tests, Prevalence, Protective Factors, Risk Factors, Severity of Illness Index, Carnitine analogs & derivatives, Coronary Angiography, Coronary Artery Disease diagnostic imaging, Coronary Stenosis diagnostic imaging, Cultured Milk Products
Abstract: Background and Aims: Current epidemiologic data suggest beneficial cardiovascular effects of fermented dairy products (FDP). However, the relationship between FDP consumption and angiographic coronary status has not been previously studied. Furthermore, the role of novel metabolomic biomarkers of cardiovascular risk in this context is unclear. We hypothesize that short-chain acylcarnitines (SCA) reflect the link between FDP intake and angiographic extent of stable coronary artery disease (CAD)., Methods and Results: We recruited 1185 patients admitted for suspected CAD [median age 62 years (interquartile range: 54-69); 714 men (60.3%)]. Prior to coronary angiography, each patient completed a validated Food Frequency Questionnaire. In addition, venous blood was collected from each patient for whole blood metabolomic analysis, using targeted mass-spectrometry. CAD was defined by the presence of ≥1 coronary stenosis ≥50%. Patients with CAD (n = 441) reported lower median FDP intake [86.8 g/day (IQR: 53.4-127.6)] than patients without CAD [n = 744; 103.9 g/day (IQR: 62.9-152.7); p < 0.001]. Upon adjustment for relevant confounders, increased circulating SCA, particularly level of acetylcarnitine (C2) associated with both higher CAD probability [SCA:β(SE) = 0.584 (0.235), p = 0.013; C2:β(SE) = 0.575 (0.242), p = 0.017] and decreased FDP consumption [SCA:β/100 g FDP-increment/day (SE) = -0.785 (0.242), p = 0.001; C2:β(SE) = -0.560 (0.230), p = 0.015]. By mediation analysis, neither SCA nor C2 showed relevant mediator effect linking FDP consumption to the risk of CAD., Conclusion: Increased consumption of fermented milk was associated with lower prevalence of CAD and correlated inversely with circulating SCA, in particular with acetylcarnitine. No substantial mediator effect of SCA linking fermented milk intake with risk of CAD was found., Clinical Trial Registry: NCT00497887., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)
Published: 2020
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38. Genome-wide analysis of carotid plaque burden suggests a role of IL5 in men.

Author: Pott J, Beutner F, Horn K, Kirsten H, Olischer K, Wirkner K, Loeffler M, and Scholz M
Subjects: Aged, Carotid Artery, External diagnostic imaging, Carotid Artery, External pathology, Carotid Artery, Internal diagnostic imaging, Carotid Artery, Internal pathology, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Sex Factors, Arteriosclerosis genetics, Carotid Artery Diseases genetics, Genetic Predisposition to Disease genetics, Interleukin-5 genetics, Interleukin-5 physiology, Plaque, Atherosclerotic genetics, Sex Characteristics
Abstract: Background: Carotid artery plaque is an established marker of subclinical atherosclerosis with pronounced sex-dimorphism. Here, we aimed to identify genetic variants associated with carotid plaque burden (CPB) and to examine potential sex-specific genetic effects on plaque sizes., Methods and Results: We defined six operationalizations of CPB considering plaques in common carotid arteries, carotid bulb, and internal carotid arteries. We performed sex-specific genome-wide association analyses for all traits in the LIFE-Adult cohort (n = 727 men and n = 550 women) and tested significantly associated loci for sex-specific effects. In order to identify causal genes, we analyzed candidate gene expression data for correlation with CPB traits and corresponding sex-specific effects. Further, we tested if previously reported SNP associations with CAD and plaque prevalence are also associated with CBP. We found seven loci with suggestive significance for CPB (p<3.33x10-7), explaining together between 6 and 13% of the CPB variance. Sex-specific analysis showed a genome-wide significant hit for men at 5q31.1 (rs201629990, β = -0.401, p = 5.22x10-9), which was not associated in women (β = -0.127, p = 0.093) with a significant difference in effect size (p = 0.008). Analyses of gene expression data suggested IL5 as the most plausible candidate, as it reflected the same sex-specific association with CPBs (p = 0.037). Known plaque prevalence or CAD loci showed no enrichment in the association with CPB., Conclusions: We showed that CPB is a complementary trait in analyzing genetics of subclinical atherosclerosis. We detected a novel locus for plaque size in men only suggesting a role of IL5. Several estrogen response elements in this locus point towards a functional explanation of the observed sex-specific effect., Competing Interests: The authors have declared that no competing interests exist.
Published: 2020
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39. Brain Damage With Heart Failure: Cardiac Biomarker Alterations and Gray Matter Decline.

Author: Mueller K, Thiel F, Beutner F, Teren A, Frisch S, Ballarini T, Möller HE, Ihle K, Thiery J, Schuler G, Villringer A, and Schroeter ML
Subjects: Aged, Biomarkers blood, Brain Damage, Chronic etiology, Cardiac Output, Female, Heart Failure blood, Humans, Male, Middle Aged, Natriuretic Peptide, Brain blood, Brain Damage, Chronic diagnostic imaging, Gray Matter diagnostic imaging, Heart Failure complications, Parietal Lobe diagnostic imaging
Abstract: Rationale: Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea, and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF; however, the underlying mechanisms leading to the observed brain changes remain unclear., Objective: To study the relationship between impaired heart function, hampered blood circulation, and structural brain change in a case-control study., Methods and Results: Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain's gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain's gray matter. Moreover, we also obtained a relationship between GMD and the NT-proBNP (N-terminal prohormone of brain natriuretic peptide)-a biomarker that is used for screening, diagnosis, and prognosis of HF. Here, we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia., Conclusions: We obtained significant correlations between brain structure and markers of heart failure including ejection fraction and NT-proBNP. A diminished GMD was found with decreased ejection fraction and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition; however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.
Published: 2020
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40. Clinical and lifestyle related factors influencing whole blood metabolite levels - A comparative analysis of three large cohorts.

Author: Beuchel C, Becker S, Dittrich J, Kirsten H, Toenjes A, Stumvoll M, Loeffler M, Thiele H, Beutner F, Thiery J, Ceglarek U, and Scholz M
Subjects: Adult, Aged, Carnitine blood, Chromatography, High Pressure Liquid, Cohort Studies, Coronary Artery Disease metabolism, Coronary Artery Disease pathology, Female, Humans, Linear Models, Male, Metabolic Networks and Pathways, Metabolome, Middle Aged, Tandem Mass Spectrometry, Amino Acids blood, Carnitine analogs & derivatives, Life Style
Abstract: Objective: Human blood metabolites are influenced by a number of lifestyle and environmental factors. Identification of these factors and the proper quantification of their relevance provides insights into human biological and metabolic disease processes, is key for standardized translation of metabolite biomarkers into clinical applications, and is a prerequisite for comparability of data between studies. However, so far only limited data exist from large and well-phenotyped human cohorts and current methods for analysis do not fully account for the characteristics of these data. The primary aim of this study was to identify, quantify and compare the impact of a comprehensive set of clinical and lifestyle related factors on metabolite levels in three large human cohorts. To achieve this goal, we improve current methodology by developing a principled analysis approach, which could be translated to other cohorts and metabolite panels., Methods: 63 Metabolites (amino acids, acylcarnitines) were quantified by liquid chromatography tandem mass spectrometry in three cohorts (total N = 16,222). Supported by a simulation study evaluating various analytical approaches, we developed an analysis pipeline including preprocessing, identification, and quantification of factors affecting metabolite levels. We comprehensively identified uni- and multivariable metabolite associations considering 29 environmental and clinical factors and performed metabolic pathway enrichment and network analyses., Results: Inverse normal transformation of batch corrected and outlier removed metabolite levels accompanied by linear regression analysis proved to be the best suited method to deal with the metabolite data. Association analyses revealed numerous uni- and multivariable significant associations. 15 of the analyzed 29 factors explained >1% of variance for at least one of the metabolites. Strongest factors are application of steroid hormones, reticulocytes, waist-to-hip ratio, sex, haematocrit, and age. Effect sizes of factors are comparable across studies., Conclusions: We introduced a principled approach for the analysis of MS data allowing identification, and quantification of effects of clinical and lifestyle factors with metabolite levels. We detected a number of known and novel associations broadening our understanding of the regulation of the human metabolome. The large heterogeneity observed between cohorts could almost completely be explained by differences in the distribution of influencing factors emphasizing the necessity of a proper confounder analysis when interpreting metabolite associations., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Published: 2019
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41. Plasma levels of apolipoproteins C-III, A-IV, and E are independently associated with stable atherosclerotic cardiovascular disease.

Author: Dittrich J, Beutner F, Teren A, Thiery J, Burkhardt R, Scholz M, and Ceglarek U
Subjects: Aged, Biomarkers blood, Carotid Stenosis diagnosis, Carotid Stenosis drug therapy, Carotid Stenosis epidemiology, Case-Control Studies, Coronary Stenosis diagnosis, Coronary Stenosis drug therapy, Coronary Stenosis epidemiology, Dyslipidemias diagnosis, Dyslipidemias drug therapy, Dyslipidemias epidemiology, Germany epidemiology, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Middle Aged, Peripheral Arterial Disease diagnosis, Peripheral Arterial Disease drug therapy, Peripheral Arterial Disease epidemiology, Prognosis, Protective Factors, Risk Assessment, Risk Factors, Apolipoprotein C-III blood, Apolipoproteins A blood, Apolipoproteins E blood, Carotid Stenosis blood, Coronary Stenosis blood, Dyslipidemias blood, Peripheral Arterial Disease blood
Abstract: Background and Aims: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). As key regulators of lipoprotein metabolism, apolipoproteins (apos) are discussed as vascular risk factors. This study aimed to analyze associations of major plasma apos with coronary artery disease (CAD), peripheral artery disease (PAD) and carotid artery plaque (CAP) to elucidate their diagnostic potential in risk assessment., Methods: ApoA-I, apoA-II, apoA-IV, apoB-100, apoC-I, apoC-III, apoE, and apoJ were simultaneously quantified in 3 μL EDTA-plasma by LC-MS/MS in a case-control subgroup of the Leipziger LIFE-Heart Study (N = 911). Confounder analysis with demographic, clinical covariates and serum lipids, cardiac, inflammatory, and hepatic markers were performed. Apos were associated with CAD, CAP, and PAD in a multivariate regression model., Results: Fasting and statin therapy showed strongest effects on apo concentrations. Inverse correlations of HDL-related apos A-I, A-II, A-IV, and C-I were observed for troponin T and interleukin 6. Concentrations of apos A-II, B-100, C-I, and E were decreased under statin therapy. After adjustment for influencing factors and related lipids, only apoB-100 (odds ratio per one SD [OR], 1.39; 95% confidence interval [CI], 1.05-1.84) was independently associated with CAD while apoA-IV (OR, 0.74; 95% CI 0.58-0.95) indicated PAD. ApoB-100 (OR, 1.55; 95% CI, 1.18-2.04), apoC-III (OR, 1.30; 95% CI, 1.06-1.58), and apoE (OR, 1.34; 95% CI, 1.13-1.58) were associated with CAP., Conclusions: Triglyceride rich lipoproteins (TRLs) associated apos A-IV, B-100, C-III, and E are independently associated with stable ASCVD, providing further evidence for a potential role of TRLs in atherogenesis., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2019
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42. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Author: Franceschini N, Giambartolomei C, de Vries PS, Finan C, Bis JC, Huntley RP, Lovering RC, Tajuddin SM, Winkler TW, Graff M, Kavousi M, Dale C, Smith AV, Hofer E, van Leeuwen EM, Nolte IM, Lu L, Scholz M, Sargurupremraj M, Pitkänen N, Franzén O, Joshi PK, Noordam R, Marioni RE, Hwang SJ, Musani SK, Schminke U, Palmas W, Isaacs A, Correa A, Zonderman AB, Hofman A, Teumer A, Cox AJ, Uitterlinden AG, Wong A, Smit AJ, Newman AB, Britton A, Ruusalepp A, Sennblad B, Hedblad B, Pasaniuc B, Penninx BW, Langefeld CD, Wassel CL, Tzourio C, Fava C, Baldassarre D, O'Leary DH, Teupser D, Kuh D, Tremoli E, Mannarino E, Grossi E, Boerwinkle E, Schadt EE, Ingelsson E, Veglia F, Rivadeneira F, Beutner F, Chauhan G, Heiss G, Snieder H, Campbell H, Völzke H, Markus HS, Deary IJ, Jukema JW, de Graaf J, Price J, Pott J, Hopewell JC, Liang J, Thiery J, Engmann J, Gertow K, Rice K, Taylor KD, Dhana K, Kiemeney LALM, Lind L, Raffield LM, Launer LJ, Holdt LM, Dörr M, Dichgans M, Traylor M, Sitzer M, Kumari M, Kivimaki M, Nalls MA, Melander O, Raitakari O, Franco OH, Rueda-Ochoa OL, Roussos P, Whincup PH, Amouyel P, Giral P, Anugu P, Wong Q, Malik R, Rauramaa R, Burkhardt R, Hardy R, Schmidt R, de Mutsert R, Morris RW, Strawbridge RJ, Wannamethee SG, Hägg S, Shah S, McLachlan S, Trompet S, Seshadri S, Kurl S, Heckbert SR, Ring S, Harris TB, Lehtimäki T, Galesloot TE, Shah T, de Faire U, Plagnol V, Rosamond WD, Post W, Zhu X, Zhang X, Guo X, Saba Y, Dehghan A, Seldenrijk A, Morrison AC, Hamsten A, Psaty BM, van Duijn CM, Lawlor DA, Mook-Kanamori DO, Bowden DW, Schmidt H, Wilson JF, Wilson JG, Rotter JI, Wardlaw JM, Deanfield J, Halcox J, Lyytikäinen LP, Loeffler M, Evans MK, Debette S, Humphries SE, Völker U, Gudnason V, Hingorani AD, Björkegren JLM, Casas JP, and O'Donnell CJ
Subjects: ADAMTS9 Protein genetics, Amino Acid Oxidoreductases genetics, Coronary Disease pathology, Humans, Lod Score, Plaque, Atherosclerotic pathology, Polymorphism, Single Nucleotide, Protein-Lysine 6-Oxidase, Quantitative Trait Loci genetics, Risk Factors, Carotid Intima-Media Thickness, Coronary Disease genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Plaque, Atherosclerotic genetics
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Published: 2018
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43. Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.

Author: Tönjes A, Scholz M, Krüger J, Krause K, Schleinitz D, Kirsten H, Gebhardt C, Marzi C, Grallert H, Ladenvall C, Heyne H, Laurila E, Kriebel J, Meisinger C, Rathmann W, Gieger C, Groop L, Prokopenko I, Isomaa B, Beutner F, Kratzsch J, Fischer-Rosinsky A, Pfeiffer A, Krohn K, Spranger J, Thiery J, Blüher M, Stumvoll M, and Kovacs P
Subjects: Animals, Genotype, Humans, Leukocytes, Mononuclear metabolism, Mice, Phosphoproteins genetics, Phosphoproteins metabolism, Polymorphism, Single Nucleotide genetics, RNA, Messenger metabolism, Genome-Wide Association Study methods, Progranulins blood
Abstract: Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 × 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 × 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion., (© The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2018
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44. Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

Author: Zewinger S, Kleber ME, Tragante V, McCubrey RO, Schmidt AF, Direk K, Laufs U, Werner C, Koenig W, Rothenbacher D, Mons U, Breitling LP, Brenner H, Jennings RT, Petrakis I, Triem S, Klug M, Filips A, Blankenberg S, Waldeyer C, Sinning C, Schnabel RB, Lackner KJ, Vlachopoulou E, Nygård O, Svingen GFT, Pedersen ER, Tell GS, Sinisalo J, Nieminen MS, Laaksonen R, Trompet S, Smit RAJ, Sattar N, Jukema JW, Groesdonk HV, Delgado G, Stojakovic T, Pilbrow AP, Cameron VA, Richards AM, Doughty RN, Gong Y, Cooper-DeHoff R, Johnson J, Scholz M, Beutner F, Thiery J, Smith JG, Vilmundarson RO, McPherson R, Stewart AFR, Cresci S, Lenzini PA, Spertus JA, Olivieri O, Girelli D, Martinelli NI, Leiherer A, Saely CH, Drexel H, Mündlein A, Braund PS, Nelson CP, Samani NJ, Kofink D, Hoefer IE, Pasterkamp G, Quyyumi AA, Ko YA, Hartiala JA, Allayee H, Tang WHW, Hazen SL, Eriksson N, Held C, Hagström E, Wallentin L, Åkerblom A, Siegbahn A, Karp I, Labos C, Pilote L, Engert JC, Brophy JM, Thanassoulis G, Bogaty P, Szczeklik W, Kaczor M, Sanak M, Virani SS, Ballantyne CM, Lee VV, Boerwinkle E, Holmes MV, Horne BD, Hingorani A, Asselbergs FW, Patel RS, Krämer BK, Scharnagl H, Fliser D, März W, and Speer T
Subjects: Cohort Studies, Coronary Disease blood, Coronary Disease epidemiology, Coronary Disease genetics, Europe epidemiology, Female, Humans, Male, Middle Aged, Prognosis, Risk Factors, Survival Rate, Biomarkers blood, Coronary Disease mortality, Genetic Association Studies, Lipoprotein(a) blood, Lipoprotein(a) genetics, Polymorphism, Single Nucleotide
Abstract: Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear., Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts., Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies., Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established., Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
Published: 2017
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45. Genome-wide meta-analysis identifies novel loci of plaque burden in carotid artery.

Author: Pott J, Burkhardt R, Beutner F, Horn K, Teren A, Kirsten H, Holdt LM, Schuler G, Teupser D, Loeffler M, Thiery J, and Scholz M
Subjects: Aged, Carotid Arteries diagnostic imaging, Carotid Artery Diseases diagnostic imaging, Carotid Artery Diseases pathology, Carotid Intima-Media Thickness, Cation Transport Proteins genetics, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 9, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Severity of Illness Index, Stroke diagnostic imaging, Stroke pathology, Carotid Arteries pathology, Carotid Artery Diseases genetics, Genetic Loci, Plaque, Atherosclerotic, Stroke genetics
Abstract: Background and Aims: Carotid artery plaque is an established marker of subclinical atherosclerosis and common patho-mechanisms with coronary artery disease (CAD) are hypothesized. We aimed to identify genetic variants associated with carotid plaque and to examine the potential shared genetic basis with CAD., Methods: After investigating the reliability of plaque detection, we performed a genome-wide meta-association study in two independent cohorts (LIFE-Adult, n = 4037 and LIFE-Heart, n = 3152) for carotid plaque score (PS), defined as the sum of the plaque load of common carotid artery and carotid bulb. Further, we analyzed whether previously reported CAD and stroke loci were also associated with PS., Results: We identified two loci with genome-wide significance for PS. One locus is the known CAD-locus at chromosome 9p21 (lead SNP rs9644862, p = 8.73 × 10 -12 ). We also describe a novel locus on chromosome 10q24 within the SFXN2 gene as the most probable candidate (lead SNP rs2902548, p = 1.97 × 10 -8 ). In addition, 17 out of 58 known CAD loci and six of 17 known stroke loci were associated with PS at a nominal level of significance., Conclusions: We showed that PS is a reliable trait to analyze genetics of atherosclerosis. Two new loci of genome-wide significant association with PS were found. The observed non-random overlap of CAD and PS associations strengthens the hypothesis of a shared genetic basis for these atherosclerotic manifestations., (Copyright © 2017 Elsevier B.V. All rights reserved.)
Published: 2017
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46. No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

Author: Loley C, Alver M, Assimes TL, Bjonnes A, Goel A, Gustafsson S, Hernesniemi J, Hopewell JC, Kanoni S, Kleber ME, Lau KW, Lu Y, Lyytikäinen LP, Nelson CP, Nikpay M, Qu L, Salfati E, Scholz M, Tukiainen T, Willenborg C, Won HH, Zeng L, Zhang W, Anand SS, Beutner F, Bottinger EP, Clarke R, Dedoussis G, Do R, Esko T, Eskola M, Farrall M, Gauguier D, Giedraitis V, Granger CB, Hall AS, Hamsten A, Hazen SL, Huang J, Kähönen M, Kyriakou T, Laaksonen R, Lind L, Lindgren C, Magnusson PK, Marouli E, Mihailov E, Morris AP, Nikus K, Pedersen N, Rallidis L, Salomaa V, Shah SH, Stewart AF, Thompson JR, Zalloua PA, Chambers JC, Collins R, Ingelsson E, Iribarren C, Karhunen PJ, Kooner JS, Lehtimäki T, Loos RJ, März W, McPherson R, Metspalu A, Reilly MP, Ripatti S, Sanghera DK, Thiery J, Watkins H, Deloukas P, Kathiresan S, Samani NJ, Schunkert H, Erdmann J, and König IR
Subjects: Cohort Studies, Female, Humans, Internationality, Male, Chromosomes, Human, X, Coronary Artery Disease genetics
Abstract: In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
Published: 2016
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47. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans.

Author: Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, Kohlmaier A, Herbst A, Northoff BH, Nicolaou A, Gäbel G, Beutner F, Scholz M, Thiery J, Musunuru K, Krohn K, Mann M, and Teupser D
Subjects: Apoptosis, Atherosclerosis pathology, Cell Nucleolus metabolism, Cell Proliferation, Chromosomes, Human, Pair 9, Clustered Regularly Interspaced Short Palindromic Repeats, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p15 metabolism, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p18 genetics, Cyclin-Dependent Kinase Inhibitor p18 metabolism, Gene Expression Profiling, HEK293 Cells, Humans, Macrophages pathology, Muscle, Smooth, Vascular metabolism, Proteins metabolism, RNA Processing, Post-Transcriptional, RNA, Long Noncoding genetics, RNA, Ribosomal genetics, RNA-Binding Proteins, Atherosclerosis genetics, Atherosclerosis metabolism, RNA, Long Noncoding metabolism, RNA, Ribosomal metabolism
Abstract: Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.
Published: 2016
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48. Incremental value of Veterans Specific Activity Questionnaire and the YMCA-step test for the assessment of cardiorespiratory fitness in population-based studies.

Author: Teren A, Zachariae S, Beutner F, Ubrich R, Sandri M, Engel C, Löffler M, and Gielen S
Subjects: Adult, Aged, Body Mass Index, Cardiovascular Diseases epidemiology, Electrocardiography, Exercise Test, Female, Follow-Up Studies, Germany epidemiology, Humans, Male, Middle Aged, Morbidity trends, Oxygen Consumption, Retrospective Studies, Time Factors, Young Adult, Cardiorespiratory Fitness, Cardiovascular Diseases prevention & control, Exercise physiology, Population Surveillance, Surveys and Questionnaires, Veterans
Abstract: Background: Cardiorespiratory fitness is a well-established independent predictor of cardiovascular health. However, the relevance of alternative exercise and non-exercise tests for cardiorespiratory fitness assessment in large cohorts has not been studied in detail. We aimed to evaluate the YMCA-step test and the Veterans Specific Activity Questionnaire (VSAQ) for the estimation of cardiorespiratory fitness in the general population., Methods: One hundred and five subjects answered the VSAQ, performed the YMCA-step test and a maximal cardiopulmonary exercise test (CPX) and gave BORG ratings for both exercise tests (BORGSTEP, BORGCPX). Correlations of peak oxygen uptake on a treadmill (VO2_PEAK) with VSAQ, BORGSTEP, one-minute, post-exercise heartbeat count, and peak oxygen uptake during the step test (VO2_STEP) were determined. Moreover, the incremental values of the questionnaire and the step test in addition to other fitness-related parameters were evaluated using block-wise hierarchical regression analysis., Results: Eighty-six subjects completed the step test according to the protocol. For completers, correlations of VO2_PEAK with the age- and gender-adjusted VSAQ, heartbeat count and VO2_STEP were 0.67, 0.63 and 0.49, respectively. However, using hierarchical regression analysis, age, gender and body mass index already explained 68.8% of the variance of VO2_PEAK, while the additional benefit of VSAQ was rather low (3.4%). The inclusion of BORGSTEP, heartbeat count and VO2_STEP increased R(2) by a further 2.2%, 3.3% and 5.6%, respectively, yielding a total R(2) of 83.3%., Conclusions: Neither VSAQ nor the YMCA-step test contributes sufficiently to the assessment of cardiorespiratory fitness in population-based studies., (© The European Society of Cardiology 2015.)
Published: 2016
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49. Relationship Between Determinants of Arterial Stiffness Assessed by Diastolic and Suprasystolic Pulse Oscillometry: Comparison of Vicorder and Vascular Explorer.

Author: Teren A, Beutner F, Wirkner K, Löffler M, and Scholz M
Subjects: Diastole, Feasibility Studies, Female, Humans, Male, Middle Aged, Observer Variation, Reproducibility of Results, Diagnostic Techniques, Cardiovascular instrumentation, Oscillometry instrumentation, Vascular Stiffness
Abstract: Pulse wave velocity (PWV) and augmentation index (AI) are independent predictors of cardiovascular health. However, the comparability of multiple oscillometric modalities currently available for their assessment was not studied in detail. In the present study, we aimed to evaluate the relationship between indices of arterial stiffness assessed by diastolic and suprasystolic oscillometry.In total, 56 volunteers from the general population (23 males; median age 70 years [interquartile range: 65-72 years]) were recruited into observational feasibility study to evaluate the carotid-femoral/aortic PWV (cf/aoPWV), brachial-ankle PWV (baPWV), and AI assessed by 2 devices: Vicorder (VI) applying diastolic, right-sided oscillometry for the determination of all 3 indices, and Vascular explorer (VE) implementing single-point, suprasystolic brachial oscillometry (SSBO) pulse wave analysis for the assessment of cfPWV and AI. Within- and between-device correlations of measured parameters were analyzed. Furthermore, agreement of repeated measurements, intra- and inter-observer concordances were determined and compared for both devices.In VI, both baPWV and cfPWV inter-correlated well and showed good level of agreement with bilateral baPWV measured by VE (baPWV[VI]-baPWV[VE]R: overall concordance correlation coefficient [OCCC] = 0.484, mean difference = 1.94 m/s; cfPWV[VI]-baPWV[VE]R: OCCC = 0.493, mean difference = 1.0 m/s). In contrast, SSBO-derived aortic PWA (cf/aoPWA[VE]) displayed only weak correlation with cfPWV(VI) (r = 0.196; P = 0.04) and ipsilateral baPWV (cf/aoPWV[VE]R-baPWV[VE]R: r = 0.166; P = 0.08). cf/aoPWA(VE) correlated strongly with AI(VE) (right-sided: r = 0.725, P < 0.001). AI exhibited marginal between-device agreement (right-sided: OCCC = 0.298, mean difference: 6.12%). All considered parameters showed good-to-excellent repeatability giving OCCC > 0.9 for 2-point-PWV modes and right-sided AI(VE). Intra- and inter-observer concordances were similarly high except for AI yielding a trend toward better reproducibility in VE (interobserver-OCCC[VI] vs [VE] = 0.774 vs 0.844; intraobserver-OCCC[VI] vs [VE] = 0.613 vs 0.769).Both diastolic oscillometry-derived PWV modes, and AI measured either with VI or VE, are comparable and reliable alternatives for the assessment of arterial stiffness. Aortic PWV assessed by SSBO in VE is not related to the corresponding indices determined by traditional diastolic oscillometry., Competing Interests: The authors have no conflicts of interest to disclose.
Published: 2016
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50. The value of noncoronary atherosclerosis for identifying coronary artery disease: results of the Leipzig LIFE Heart Study.

Author: Weissgerber A, Scholz M, Teren A, Sandri M, Teupser D, Gielen S, Thiery J, Schuler G, and Beutner F
Subjects: Aged, Ankle Brachial Index methods, Atherosclerosis diagnostic imaging, Carotid Intima-Media Thickness, Carotid Stenosis pathology, Coronary Artery Disease diagnostic imaging, Female, Humans, Logistic Models, Male, Middle Aged, Predictive Value of Tests, Risk Factors, Atherosclerosis diagnosis, Carotid Stenosis diagnostic imaging, Coronary Angiography methods, Coronary Artery Disease diagnosis
Abstract: Background: Despite the widespread use of noninvasive testing prior to invasive coronary diagnostic the diagnostic yield of elective coronary angiography has been reported low in subjects with suspected obstructive CAD., Objective: To determine the predictive value of noncoronary atherosclerosis (NCA) in subjects with suspected stable coronary artery disease (CAD) intended to invasive coronary angiography., Methods: Ultrasound-based assessment of carotid artery plaque (CAP), carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) was performed in 2216 subjects with suspected CAD prior to coronary angiography. Logistic regression and c-statistics were used to analyze the diagnostic value of NCA for the presence of obstructive CAD and the intention to revascularization., Results: Percentage of positive results of elective coronary angiography was low but comparable to other studies (41% obstructive CAD). We identified 1323 subjects (60%) with NCA, most of them were characterized by CAP (93%). CAP independently predicted obstructive CAD in addition to traditional risk factors and clinical factors while CIMT and ABI failed to improve the prediction. The presence of NCA and typical angina were the strongest predictors for obstructive CAD (OR 4.0 and 2.4, respectively). A large subgroup of patients (n = 703, 32%) with atypical clinical presentation and lack of NCA revealed a low indication for revascularization <15% indicating a large proportion of subjects with non-obstructive CAD in this subgroup., Conclusion: The evaluation of noncoronary atherosclerosis has the potential to impact clinical decision making and to direct subsequent diagnostic procedures in subjects with suspected coronary artery disease., Clinical Trial Registration: NCT00497887.
Published: 2016
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