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2. Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Author

Škorić-Milosavljević, D, Tadros, R, Bosada, FM, Tessadori, F, van Weerd, JH, Woudstra, OI, Tjong, FVY, Lahrouchi, N, Bajolle, F, Cordell, HJ, Agopian, AJ, Blue, GM, Barge-Schaapveld, DQCM, Gewillig, M, Preuss, C, Lodder, EM, Barnett, P, Ilgun, A, Beekman, L, van Duijvenboden, K, Bokenkamp, R, Müller-Nurasyid, M, Vliegen, HW, Konings, TC, van Melle, JP, van Dijk, APJ, van Kimmenade, RRJ, Roos-Hesselink, JW, Sieswerda, GT, Meijboom, F, Abdul-Khaliq, H, Berger, F, Dittrich, S, Hitz, M-P, Moosmann, J, Riede, F-T, Schubert, S, Galan, P, Lathrop, M, Munter, HM, Al-Chalabi, A, Shaw, CE, Shaw, PJ, Morrison, KE, Veldink, JH, van den Berg, LH, Evans, S, Nobrega, MA, Aneas, I, Radivojkov-Blagojević, M, Meitinger, T, Oechslin, E, Mondal, T, Bergin, L, Smythe, JF, Altamirano-Diaz, L, Lougheed, J, Bouma, BJ, Chaix, M-A, Kline, J, Bassett, AS, Andelfinger, G, van der Palen, RLF, Bouvagnet, P, Clur, S-AB, Breckpot, J, Kerstjens-Frederikse, WS, Winlaw, DS, Bauer, UMM, Mital, S, Goldmuntz, E, Keavney, B, Bonnet, D, Mulder, BJ, Tanck, MWT, Bakkers, J, Christoffels, VM, Boogerd, CJ, Postma, AV, Bezzina, CR, Hubrecht Institute for Developmental Biology and Stem Cell Research, Cardiology, Cardiovascular Centre (CVC), Medical Biology, ACS - Heart failure & arrhythmias, ACS - Pulmonary hypertension & thrombosis, Human Genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Cardiovascular Sciences, General Paediatrics, Paediatric Cardiology, APH - Aging & Later Life, APH - Personalized Medicine, Epidemiology and Data Science, APH - Methodology, Pediatric surgery, and Physiology

Subjects
Genome-wide association study, Multifactorial Inheritance, congenital, hereditary, and neonatal diseases and abnormalities, Cardiac & Cardiovascular Systems, Physiology, Transposition of Great Vessels, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], ZIC3 MUTATIONS, DE-NOVO, Polymorphism, Single Nucleotide, Wnt-5a Protein, Article, Mice, OF-FUNCTION MUTATIONS, Congenital Heart Disease, Genome-wide Association Study, Single Nucleotide Polymorphism, Transposition Of Great Vessels, Animals, Humans, MALFORMATIONS, Myocytes, Cardiac, GENOME-WIDE ASSOCIATION, Transposition of great vessels, Cells, Cultured, Zebrafish, Congenital heart disease, WNT5A MUTATIONS, Science & Technology, HERITABILITY, Wnt-5a protein, Hematology, DEFECTS, Single nucleotide polymorphism, CONGENITAL HEART-DISEASE, Peripheral Vascular Disease, Cardiovascular System & Cardiology, HYPOPLASTIC LEFT-HEART, T-Box Domain Proteins, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine
Abstract

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 -10 , OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10 -5 ). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A , which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A . Genomic and functional data support a causal role of WNT5A at the locus.

Published
2022

3. Activation of mitochondrial telomerase reverses relative lymphopenia post myocardial infarction: results from the randomised, double-blinded TACTIC phase IIa pilot trial

Author

Spyridopoulos, I, primary, Bawamia, B, additional, Spray, L, additional, Wangsaputra, V, additional, Stellos, K, additional, Bennaceur, K, additional, Kharatikoopaei, E, additional, Ogundimu, E, additional, Gale, C P, additional, Keavney, B, additional, Maier, R, additional, Hancock, H, additional, Richardson, G, additional, and Austin, D, additional

Published
2022
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4. Personalised Prescribing. Using pharmacogenomics to improve patient outcomes. A report from the Royal College of Physicians and British Pharmacological Society joint working party

Author

Pirmohammed, M, O’Donoghue, D, Turner, R, Magavern, E, Roebuck, D, Ross, P, Keavney, B, Shovlin, C, Popoola, J, Nasser, S, McEntagart, M, Sanghvi, S, Seller, A, Bishop, M, Caulfield, M, Sharma, R, Rafi, I, and Hayward, J

Abstract

A new report from the Royal College of Physicians and British Pharmacological Society joint working party considers the opportunities provided by increasing pharmacogenomic testing.

Published
2022
Full Text
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5. Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Author

Škorić-Milosavljević, D., Tadros, R., Bosada, F.M., Tessadori, F., Weerd, J.H. van, Woudstra, O.I., Tjong, F.V.Y., Lahrouchi, N., Bajolle, F., Cordell, H.J., Agopian, A.J., Blue, G.M., Barge-Schaapveld, D., Gewillig, M., Preuss, C., Lodder, E.M., Barnett, P., Ilgun, A., Beekman, L., Duijvenboden, K. van, Bokenkamp, R., Müller-Nurasyid, M., Vliegen, H.W., Konings, T.C., Melle, J.P. van, Dijk, A.P.J. van, Kimmenade, R.R.J. van, Roos-Hesselink, J.W., Sieswerda, G.T., Meijboom, F., Abdul-Khaliq, H., Berger, F, Dittrich, S., Hitz, M.P., Moosmann, J., Riede, F.T., Schubert, S., Galan, P., Lathrop, M., Munter, H.M., Al-Chalabi, A., Shaw, C.E., Shaw, P.J., Morrison, K.E., Veldink, J.H., Berg, L.H. van den, Evans, S., Nobrega, M.A., Aneas, I., Radivojkov-Blagojević, M., Meitinger, T., Oechslin, E., Mondal, T., Bergin, L., Smythe, J.F., Altamirano-Diaz, L., Lougheed, J., Bouma, B.J., Chaix, M.A., Kline, J., Bassett, A.S., Andelfinger, G., Palen, R.L.F. van der, Bouvagnet, P., Clur, S.B., Breckpot, J., Kerstjens-Frederikse, W.S., Winlaw, D.S., Bauer, U.M.M., Mital, S., Goldmuntz, E., Keavney, B., Bonnet, D., Mulder, B. J. M., Tanck, M.W.T., Bakkers, J., Christoffels, V.M., Boogerd, C.J., Postma, A.V., Bezzina, C.R., Škorić-Milosavljević, D., Tadros, R., Bosada, F.M., Tessadori, F., Weerd, J.H. van, Woudstra, O.I., Tjong, F.V.Y., Lahrouchi, N., Bajolle, F., Cordell, H.J., Agopian, A.J., Blue, G.M., Barge-Schaapveld, D., Gewillig, M., Preuss, C., Lodder, E.M., Barnett, P., Ilgun, A., Beekman, L., Duijvenboden, K. van, Bokenkamp, R., Müller-Nurasyid, M., Vliegen, H.W., Konings, T.C., Melle, J.P. van, Dijk, A.P.J. van, Kimmenade, R.R.J. van, Roos-Hesselink, J.W., Sieswerda, G.T., Meijboom, F., Abdul-Khaliq, H., Berger, F, Dittrich, S., Hitz, M.P., Moosmann, J., Riede, F.T., Schubert, S., Galan, P., Lathrop, M., Munter, H.M., Al-Chalabi, A., Shaw, C.E., Shaw, P.J., Morrison, K.E., Veldink, J.H., Berg, L.H. van den, Evans, S., Nobrega, M.A., Aneas, I., Radivojkov-Blagojević, M., Meitinger, T., Oechslin, E., Mondal, T., Bergin, L., Smythe, J.F., Altamirano-Diaz, L., Lougheed, J., Bouma, B.J., Chaix, M.A., Kline, J., Bassett, A.S., Andelfinger, G., Palen, R.L.F. van der, Bouvagnet, P., Clur, S.B., Breckpot, J., Kerstjens-Frederikse, W.S., Winlaw, D.S., Bauer, U.M.M., Mital, S., Goldmuntz, E., Keavney, B., Bonnet, D., Mulder, B. J. M., Tanck, M.W.T., Bakkers, J., Christoffels, V.M., Boogerd, C.J., Postma, A.V., and Bezzina, C.R.

Abstract

Item does not contain fulltext, RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10(-10), OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10(-5)). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

Published
2022

9. Response to correspondence on 'Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation'.

Author

Gurumurthy, CB, O'Brien, AR, Quadros, RM, Adams, J, Alcaide, P, Ayabe, S, Ballard, J, Batra, SK, Beauchamp, M-C, Becker, KA, Bernas, G, Brough, D, Carrillo-Salinas, F, Chan, W, Chen, H, Dawson, R, DeMambro, V, D'Hont, J, Dibb, K, Eudy, JD, Gan, L, Gao, J, Gonzales, A, Guntur, A, Guo, H, Harms, DW, Harrington, A, Hentges, KE, Humphreys, N, Imai, S, Ishii, H, Iwama, M, Jonasch, E, Karolak, M, Keavney, B, Khin, N-C, Konno, M, Kotani, Y, Kunihiro, Y, Lakshmanan, I, Larochelle, C, Lawrence, CB, Li, L, Lindner, V, Liu, X-D, Lopez-Castejon, G, Loudon, A, Lowe, J, Jerome-Majeweska, L, Matsusaka, T, Miura, H, Miyasaka, Y, Morpurgo, B, Motyl, K, Nabeshima, Y-I, Nakade, K, Nakashiba, T, Nakashima, K, Obata, Y, Ogiwara, S, Ouellet, M, Oxburgh, L, Piltz, S, Pinz, I, Ponnusamy, MP, Ray, D, Redder, RJ, Rosen, CJ, Ross, N, Ruhe, MT, Ryzhova, L, Salvador, AM, Alam, SS, Sedlacek, R, Sharma, K, Smith, C, Staes, K, Starrs, L, Sugiyama, F, Takahashi, S, Tanaka, T, Trafford, A, Uno, Y, Vanhoutte, L, Vanrockeghem, F, Willis, BJ, Wright, CS, Yamauchi, Y, Yi, X, Yoshimi, K, Zhang, X, Zhang, Y, Ohtsuka, M, Das, S, Garry, DJ, Hochepied, T, Thomas, P, Parker-Thornburg, J, Adamson, AD, Yoshiki, A, Schmouth, J-F, Golovko, A, Thompson, WR, Lloyd, KCK, Wood, JA, Cowan, M, Mashimo, T, Mizuno, S, Zhu, H, Kasparek, P, Liaw, L, Miano, JM, Burgio, G, Gurumurthy, CB, O'Brien, AR, Quadros, RM, Adams, J, Alcaide, P, Ayabe, S, Ballard, J, Batra, SK, Beauchamp, M-C, Becker, KA, Bernas, G, Brough, D, Carrillo-Salinas, F, Chan, W, Chen, H, Dawson, R, DeMambro, V, D'Hont, J, Dibb, K, Eudy, JD, Gan, L, Gao, J, Gonzales, A, Guntur, A, Guo, H, Harms, DW, Harrington, A, Hentges, KE, Humphreys, N, Imai, S, Ishii, H, Iwama, M, Jonasch, E, Karolak, M, Keavney, B, Khin, N-C, Konno, M, Kotani, Y, Kunihiro, Y, Lakshmanan, I, Larochelle, C, Lawrence, CB, Li, L, Lindner, V, Liu, X-D, Lopez-Castejon, G, Loudon, A, Lowe, J, Jerome-Majeweska, L, Matsusaka, T, Miura, H, Miyasaka, Y, Morpurgo, B, Motyl, K, Nabeshima, Y-I, Nakade, K, Nakashiba, T, Nakashima, K, Obata, Y, Ogiwara, S, Ouellet, M, Oxburgh, L, Piltz, S, Pinz, I, Ponnusamy, MP, Ray, D, Redder, RJ, Rosen, CJ, Ross, N, Ruhe, MT, Ryzhova, L, Salvador, AM, Alam, SS, Sedlacek, R, Sharma, K, Smith, C, Staes, K, Starrs, L, Sugiyama, F, Takahashi, S, Tanaka, T, Trafford, A, Uno, Y, Vanhoutte, L, Vanrockeghem, F, Willis, BJ, Wright, CS, Yamauchi, Y, Yi, X, Yoshimi, K, Zhang, X, Zhang, Y, Ohtsuka, M, Das, S, Garry, DJ, Hochepied, T, Thomas, P, Parker-Thornburg, J, Adamson, AD, Yoshiki, A, Schmouth, J-F, Golovko, A, Thompson, WR, Lloyd, KCK, Wood, JA, Cowan, M, Mashimo, T, Mizuno, S, Zhu, H, Kasparek, P, Liaw, L, Miano, JM, and Burgio, G

Published
2021

10. Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney

Author

Eales, JM, Jiang, X, Xu, X, Saluja, S, Akbarov, A, Cano-Gamez, E, McNulty, MT, Finan, C, Guo, H, Wystrychowski, W, Szulinska, M, Thomas, HB, Pramanik, S, Chopade, S, Prestes, PR, Wise, I, Evangelou, E, Salehi, M, Shakanti, Y, Ekholm, M, Denniff, M, Nazgiewicz, A, Eichinger, F, Godfrey, B, Antczak, A, Glyda, M, Krol, R, Eyre, S, Brown, J, Berzuini, C, Bowes, J, Caulfield, M, Zukowska-Szczechowska, E, Zywiec, J, Bogdanski, P, Kretzler, M, Woolf, AS, Talavera, D, Keavney, B, Maffia, P, Guzik, TJ, O'Keefe, RT, Trynka, G, Samani, NJ, Hingorani, A, Sampson, MG, Morris, AP, Charchar, FJ, Tomaszewski, M, Eales, JM, Jiang, X, Xu, X, Saluja, S, Akbarov, A, Cano-Gamez, E, McNulty, MT, Finan, C, Guo, H, Wystrychowski, W, Szulinska, M, Thomas, HB, Pramanik, S, Chopade, S, Prestes, PR, Wise, I, Evangelou, E, Salehi, M, Shakanti, Y, Ekholm, M, Denniff, M, Nazgiewicz, A, Eichinger, F, Godfrey, B, Antczak, A, Glyda, M, Krol, R, Eyre, S, Brown, J, Berzuini, C, Bowes, J, Caulfield, M, Zukowska-Szczechowska, E, Zywiec, J, Bogdanski, P, Kretzler, M, Woolf, AS, Talavera, D, Keavney, B, Maffia, P, Guzik, TJ, O'Keefe, RT, Trynka, G, Samani, NJ, Hingorani, A, Sampson, MG, Morris, AP, Charchar, FJ, and Tomaszewski, M

Abstract

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.

Published
2021

13. Human Y Chromosome Exerts Pleiotropic Effects on Susceptibility to Atherosclerosis

Author

Eales J. M., Maan A. A., Xu X., Michoel T., Hallast P., Batini C., Zadik D., Prestes P. R., Molina E., Denniff M., Schroeder J., Bjorkegren J. L. M., Thompson J., Maffia P., Guzik T. J., Keavney B., Jobling M. A., Samani N. J., Charchar F. J., Tomaszewski M., Eales, J. M., Maan, A. A., Xu, X., Michoel, T., Hallast, P., Batini, C., Zadik, D., Prestes, P. R., Molina, E., Denniff, M., Schroeder, J., Bjorkegren, J. L. M., Thompson, J., Maffia, P., Guzik, T. J., Keavney, B., Jobling, M. A., Samani, N. J., Charchar, F. J., and Tomaszewski, M.

Subjects
gene expression, risk factors, human, epigenomic, coronary artery disease
Abstract

The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis. Approach and Results: Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD-carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04-1.18; P=6.8×10-4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1-specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal.

Published
2019

15. Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney

Author

Jiang, X, Eales, JM, Scannali, D, Nazgiewicz, A, Prestes, P, Maier, M, Denniff, M, Xu, X, Saluja, S, Cano-Gamez, E, Wystrychowski, W, Szulinska, M, Antczak, A, Byars, S, Skrypnik, D, Glyda, M, Krol, R, Zywiec, J, Zukowska-Szczechowska, E, Burrell, LM, Woolf, AS, Greenstein, A, Bogdanski, P, Keavney, B, Morris, AP, Heagerty, A, Williams, B, Harrap, SB, Trynka, G, Samani, NJ, Guzik, TJ, Charchar, FJ, Tomaszewski, M, Jiang, X, Eales, JM, Scannali, D, Nazgiewicz, A, Prestes, P, Maier, M, Denniff, M, Xu, X, Saluja, S, Cano-Gamez, E, Wystrychowski, W, Szulinska, M, Antczak, A, Byars, S, Skrypnik, D, Glyda, M, Krol, R, Zywiec, J, Zukowska-Szczechowska, E, Burrell, LM, Woolf, AS, Greenstein, A, Bogdanski, P, Keavney, B, Morris, AP, Heagerty, A, Williams, B, Harrap, SB, Trynka, G, Samani, NJ, Guzik, TJ, Charchar, FJ, and Tomaszewski, M

Abstract

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Published
2020

18. Erratum to: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (Nature Genetics, (2018), 50, 10, (1412-1425), 10.1038/s41588-018-0205-x)

Author

Evangelou E., Warren H. R., Mosen-Ansorena D., Mifsud B., Pazoki R., Gao H., Ntritsos G., Dimou N., Cabrera C. P., Karaman I., Ng F. L., Evangelou M., Witkowska K., Tzanis E., Hellwege J. N., Giri A., Velez Edwards D. R., Sun Y. V., Cho K., Gaziano J. M., Wilson P. W. F., Tsao P. S., Kovesdy C. P., Esko T., Magi R., Milani L., Almgren P., Boutin T., Debette S., Ding J., Giulianini F., Holliday E. G., Jackson A. U., Li-Gao R., Lin W. -Y., Luan J., Mangino M., Oldmeadow C., Prins B. P., Qian Y., Sargurupremraj M., Shah N., Surendran P., Theriault S., Verweij N., Willems S. M., Zhao J. -H., Amouyel P., Connell J., de Mutsert R., Doney A. S. F., Farrall M., Menni C., Morris A. D., Noordam R., Pare G., Poulter N. R., Shields D. C., Stanton A., Thom S., Abecasis G., Amin N., Arking D. E., Ayers K. L., Barbieri C. M., Batini C., Bis J. C., Blake T., Bochud M., Boehnke M., Boerwinkle E., Boomsma D. I., Bottinger E. P., Braund P. S., Brumat M., Campbell A., Campbell H., Chakravarti A., Chambers J. C., Chauhan G., Ciullo M., Cocca M., Collins F., Cordell H. J., Davies G., de Borst M. H., de Geus E. J., Deary I. J., Deelen J., Del Greco M F., Demirkale C. Y., Dorr M., Ehret G. B., Elosua R., Enroth S., Erzurumluoglu A. M., Ferreira T., Franberg M., Franco O. H., Gandin I., Gasparini P., Giedraitis V., Gieger C., Girotto G., Goel A., Gow A. J., Gudnason V., Guo X., Gyllensten U., Hamsten A., Harris T. B., Harris S. E., Hartman C. A., Havulinna A. S., Hicks A. A., Hofer E., Hofman A., Hottenga J. -J., Huffman J. E., Hwang S. -J., Ingelsson E., James A., Jansen R., Jarvelin M. -R., Joehanes R., Johansson A., Johnson A. D., Joshi P. K., Jousilahti P., Jukema J. W., Jula A., Kahonen M., Kathiresan S., Keavney B. D., Khaw K. -T., Knekt P., Knight J., Kolcic I., Kooner J. S., Koskinen S., Kristiansson K., Kutalik Z., Laan M., Larson M., Launer L. J., Lehne B., Lehtimaki T., Liewald D. C. M., Lin L., Lind L., Lindgren C. M., Liu Y. M., Loos R. J. F., Lopez L. M., Lu Y., Lyytikainen L. -P., Mahajan A., Mamasoula C., Marrugat J., Marten J., Milaneschi Y., Morgan A., Morris A. P., Morrison A. C., Munson P. J., Nalls M. A., Nandakumar P., Nelson C. P., Niiranen T., Nolte I. M., Nutile T., Oldehinkel A. J., Oostra B. A., O'Reilly P. F., Org E., Padmanabhan S., Palmas W., Palotie A., Pattie A., Penninx B. W. J. H., Perola M., Peters A., Polasek O., Pramstaller P. P., Nguyen Q. T., Raitakari O. T., Ren M., Rettig R., Rice K., Ridker P. M., Ried J. S., Riese H., Ripatti S., Robino A., Rose L. M., Rotter J. I., Rudan I., Ruggiero D., Saba Y., Sala C. F., Salomaa V., Samani N. J., Sarin A. -P., Schmidt R., Schmidt H., Shrine N., Siscovick D., Smith A. V., Snieder H., Sober S., Sorice R., Starr J. M., Stott D. J., Strachan D. P., Strawbridge R. J., Sundstrom J., Swertz M. A., Taylor K. D., Teumer A., Tobin M. D., Tomaszewski M., Toniolo D., Traglia M., Trompet S., Tuomilehto J., Tzourio C., Uitterlinden A. G., Vaez A., van der Most P. J., van Duijn C. M., Vergnaud A. -C., Verwoert G. C., Vitart V., Volker U., Vollenweider P., Vuckovic D., Watkins H., Wild S. H., Willemsen G., Wilson J. F., Wright A. F., Yao J., Zemunik T., Zhang W., Attia J. R., Butterworth A. S., Chasman D. I., Conen D., Cucca F., Danesh J., Hayward C., Howson J. M. M., Laakso M., Lakatta E. G., Langenberg C., Melander O., Mook-Kanamori D. O., Palmer C. N. A., Risch L., Scott R. A., Scott R. J., Sever P., Spector T. D., van der Harst P., Wareham N. J., Zeggini E., Levy D., Munroe P. B., Newton-Cheh C., Brown M. J., Metspalu A., Hung A. M., O'Donnell C. J., Edwards T. L., Psaty B. M., Tzoulaki I., Barnes M. R., Wain L. V., Elliott P., Caulfield M. J., Evangelou, E., Warren, H. R., Mosen-Ansorena, D., Mifsud, B., Pazoki, R., Gao, H., Ntritsos, G., Dimou, N., Cabrera, C. P., Karaman, I., Ng, F. L., Evangelou, M., Witkowska, K., Tzanis, E., Hellwege, J. N., Giri, A., Velez Edwards, D. R., Sun, Y. V., Cho, K., Gaziano, J. M., Wilson, P. W. F., Tsao, P. S., Kovesdy, C. P., Esko, T., Magi, R., Milani, L., Almgren, P., Boutin, T., Debette, S., Ding, J., Giulianini, F., Holliday, E. G., Jackson, A. U., Li-Gao, R., Lin, W. -Y., Luan, J., Mangino, M., Oldmeadow, C., Prins, B. P., Qian, Y., Sargurupremraj, M., Shah, N., Surendran, P., Theriault, S., Verweij, N., Willems, S. M., Zhao, J. -H., Amouyel, P., Connell, J., de Mutsert, R., Doney, A. S. F., Farrall, M., Menni, C., Morris, A. D., Noordam, R., Pare, G., Poulter, N. R., Shields, D. C., Stanton, A., Thom, S., Abecasis, G., Amin, N., Arking, D. E., Ayers, K. L., Barbieri, C. M., Batini, C., Bis, J. C., Blake, T., Bochud, M., Boehnke, M., Boerwinkle, E., Boomsma, D. I., Bottinger, E. P., Braund, P. S., Brumat, M., Campbell, A., Campbell, H., Chakravarti, A., Chambers, J. C., Chauhan, G., Ciullo, M., Cocca, M., Collins, F., Cordell, H. J., Davies, G., de Borst, M. H., de Geus, E. J., Deary, I. J., Deelen, J., Del Greco M, F., Demirkale, C. Y., Dorr, M., Ehret, G. B., Elosua, R., Enroth, S., Erzurumluoglu, A. M., Ferreira, T., Franberg, M., Franco, O. H., Gandin, I., Gasparini, P., Giedraitis, V., Gieger, C., Girotto, G., Goel, A., Gow, A. J., Gudnason, V., Guo, X., Gyllensten, U., Hamsten, A., Harris, T. B., Harris, S. E., Hartman, C. A., Havulinna, A. S., Hicks, A. A., Hofer, E., Hofman, A., Hottenga, J. -J., Huffman, J. E., Hwang, S. -J., Ingelsson, E., James, A., Jansen, R., Jarvelin, M. -R., Joehanes, R., Johansson, A., Johnson, A. D., Joshi, P. K., Jousilahti, P., Jukema, J. W., Jula, A., Kahonen, M., Kathiresan, S., Keavney, B. D., Khaw, K. -T., Knekt, P., Knight, J., Kolcic, I., Kooner, J. S., Koskinen, S., Kristiansson, K., Kutalik, Z., Laan, M., Larson, M., Launer, L. J., Lehne, B., Lehtimaki, T., Liewald, D. C. M., Lin, L., Lind, L., Lindgren, C. M., Liu, Y. M., Loos, R. J. F., Lopez, L. M., Lu, Y., Lyytikainen, L. -P., Mahajan, A., Mamasoula, C., Marrugat, J., Marten, J., Milaneschi, Y., Morgan, A., Morris, A. P., Morrison, A. C., Munson, P. J., Nalls, M. A., Nandakumar, P., Nelson, C. P., Niiranen, T., Nolte, I. M., Nutile, T., Oldehinkel, A. J., Oostra, B. A., O'Reilly, P. F., Org, E., Padmanabhan, S., Palmas, W., Palotie, A., Pattie, A., Penninx, B. W. J. H., Perola, M., Peters, A., Polasek, O., Pramstaller, P. P., Nguyen, Q. T., Raitakari, O. T., Ren, M., Rettig, R., Rice, K., Ridker, P. M., Ried, J. S., Riese, H., Ripatti, S., Robino, A., Rose, L. M., Rotter, J. I., Rudan, I., Ruggiero, D., Saba, Y., Sala, C. F., Salomaa, V., Samani, N. J., Sarin, A. -P., Schmidt, R., Schmidt, H., Shrine, N., Siscovick, D., Smith, A. V., Snieder, H., Sober, S., Sorice, R., Starr, J. M., Stott, D. J., Strachan, D. P., Strawbridge, R. J., Sundstrom, J., Swertz, M. A., Taylor, K. D., Teumer, A., Tobin, M. D., Tomaszewski, M., Toniolo, D., Traglia, M., Trompet, S., Tuomilehto, J., Tzourio, C., Uitterlinden, A. G., Vaez, A., van der Most, P. J., van Duijn, C. M., Vergnaud, A. -C., Verwoert, G. C., Vitart, V., Volker, U., Vollenweider, P., Vuckovic, D., Watkins, H., Wild, S. H., Willemsen, G., Wilson, J. F., Wright, A. F., Yao, J., Zemunik, T., Zhang, W., Attia, J. R., Butterworth, A. S., Chasman, D. I., Conen, D., Cucca, F., Danesh, J., Hayward, C., Howson, J. M. M., Laakso, M., Lakatta, E. G., Langenberg, C., Melander, O., Mook-Kanamori, D. O., Palmer, C. N. A., Risch, L., Scott, R. A., Scott, R. J., Sever, P., Spector, T. D., van der Harst, P., Wareham, N. J., Zeggini, E., Levy, D., Munroe, P. B., Newton-Cheh, C., Brown, M. J., Metspalu, A., Hung, A. M., O'Donnell, C. J., Edwards, T. L., Psaty, B. M., Tzoulaki, I., Barnes, M. R., Wain, L. V., Elliott, P., and Caulfield, M. J.

Subjects
Blood pressure, genetic analysis
Abstract

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Published
2018

24. Scientific Business Abstracts of the 113th Annual Meeting of the Association of Physicians of Great Britain and Ireland

Author

Cacciottolo, TM, Perikari, A, van der Klaauw, A, Henning, E, Stadler, LKJ, Keogh, J, Farooqi, IS, Tenin, G, Keavney, B, Ryan, E, Budd, R, Bewley, M, Coelho, P, Rumsey, W, Sanchez, Y, McCafferty, J, Dockrell, D, Walmsley, S, Whyte, M, Liu, Y, Choy, M-K, Abraham, S, Black, G, Ford, T, Stanley, B, Good, R, Rocchiccioli, P, McEntegart, M, Watkins, S, Eteiba, H, Shaukat, A, Lindsay, M, Robertson, K, Hood, S, McGeoch, R, McDade, R, Sidik, N, McCartney, P, Corcoran, D, Collison, D, Rush, C, McConnachie, A, Touyz, R, Oldroyd, K, Berry, Colin, Gazdagh, G, Diver, L, Marshall, J, McGowan, R, Ahmed, F, Tobias, E, Curtis, E, Parsons, C, Maslin, K, D’Angelo, S, Moon, R, Crozier, S, Gossiel, F, Bishop, N, Kennedy, S, Papageorghiou, A, Fraser, R, Gandhi, S, Prentice, A, Inskip, H, Godfrey, K, Schoenmakers, I, Javaid, MK, Eastell, R, Cooper, C, Harvey, N, Watt, ER, Howden, A, Mirchandani, A, Hukelmann, JL, Sadiku, P, Plant, TM, Cantrell, DA, Whyte, MKB, Walmsley, SR, Mordi, I, Forteath, C, Wong, A, Mohan, M, Palmer, C, Doney, A, Rena, G, Lang, C, Gray, EH, Azarian, S, Riva, A, Edwards, H, McPhail, MJW, Williams, R, Chokshi, S, Patel, VC, Edwards, LA, Page, D, Miossec, M, Williams, S, Monaghan, R, Fotiou, E, Santibanez-Koref, M, Badat, M, Mettananda, S, Hua, P, Schwessinger, R, Hughes, J, Higgs, D, Davies, J, Cacciottolo, TM, Perikari, A, van der Klaauw, A, Henning, E, Stadler, LKJ, Keogh, J, Farooqi, IS, Tenin, G, Keavney, B, Ryan, E, Budd, R, Bewley, M, Coelho, P, Rumsey, W, Sanchez, Y, McCafferty, J, Dockrell, D, Walmsley, S, Whyte, M, Liu, Y, Choy, M-K, Abraham, S, Black, G, Ford, T, Stanley, B, Good, R, Rocchiccioli, P, McEntegart, M, Watkins, S, Eteiba, H, Shaukat, A, Lindsay, M, Robertson, K, Hood, S, McGeoch, R, McDade, R, Sidik, N, McCartney, P, Corcoran, D, Collison, D, Rush, C, McConnachie, A, Touyz, R, Oldroyd, K, Berry, Colin, Gazdagh, G, Diver, L, Marshall, J, McGowan, R, Ahmed, F, Tobias, E, Curtis, E, Parsons, C, Maslin, K, D’Angelo, S, Moon, R, Crozier, S, Gossiel, F, Bishop, N, Kennedy, S, Papageorghiou, A, Fraser, R, Gandhi, S, Prentice, A, Inskip, H, Godfrey, K, Schoenmakers, I, Javaid, MK, Eastell, R, Cooper, C, Harvey, N, Watt, ER, Howden, A, Mirchandani, A, Hukelmann, JL, Sadiku, P, Plant, TM, Cantrell, DA, Whyte, MKB, Walmsley, SR, Mordi, I, Forteath, C, Wong, A, Mohan, M, Palmer, C, Doney, A, Rena, G, Lang, C, Gray, EH, Azarian, S, Riva, A, Edwards, H, McPhail, MJW, Williams, R, Chokshi, S, Patel, VC, Edwards, LA, Page, D, Miossec, M, Williams, S, Monaghan, R, Fotiou, E, Santibanez-Koref, M, Badat, M, Mettananda, S, Hua, P, Schwessinger, R, Hughes, J, Higgs, D, and Davies, J

Published
2019

25. Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation.

Author

Gurumurthy, CB, O'Brien, AR, Quadros, RM, Adams, J, Alcaide, P, Ayabe, S, Ballard, J, Batra, SK, Beauchamp, M-C, Becker, KA, Bernas, G, Brough, D, Carrillo-Salinas, F, Chan, W, Chen, H, Dawson, R, DeMambro, V, D'Hont, J, Dibb, KM, Eudy, JD, Gan, L, Gao, J, Gonzales, A, Guntur, AR, Guo, H, Harms, DW, Harrington, A, Hentges, KE, Humphreys, N, Imai, S, Ishii, H, Iwama, M, Jonasch, E, Karolak, M, Keavney, B, Khin, N-C, Konno, M, Kotani, Y, Kunihiro, Y, Lakshmanan, I, Larochelle, C, Lawrence, CB, Li, L, Lindner, V, Liu, X-D, Lopez-Castejon, G, Loudon, A, Lowe, J, Jerome-Majewska, LA, Matsusaka, T, Miura, H, Miyasaka, Y, Morpurgo, B, Motyl, K, Nabeshima, Y-I, Nakade, K, Nakashiba, T, Nakashima, K, Obata, Y, Ogiwara, S, Ouellet, M, Oxburgh, L, Piltz, S, Pinz, I, Ponnusamy, MP, Ray, D, Redder, RJ, Rosen, CJ, Ross, N, Ruhe, MT, Ryzhova, L, Salvador, AM, Alam, SS, Sedlacek, R, Sharma, K, Smith, C, Staes, K, Starrs, L, Sugiyama, F, Takahashi, S, Tanaka, T, Trafford, AW, Uno, Y, Vanhoutte, L, Vanrockeghem, F, Willis, BJ, Wright, CS, Yamauchi, Y, Yi, X, Yoshimi, K, Zhang, X, Zhang, Y, Ohtsuka, M, Das, S, Garry, DJ, Hochepied, T, Thomas, P, Parker-Thornburg, J, Adamson, AD, Yoshiki, A, Schmouth, J-F, Golovko, A, Thompson, WR, Lloyd, KCK, Wood, JA, Cowan, M, Mashimo, T, Mizuno, S, Zhu, H, Kasparek, P, Liaw, L, Miano, JM, Burgio, G, Gurumurthy, CB, O'Brien, AR, Quadros, RM, Adams, J, Alcaide, P, Ayabe, S, Ballard, J, Batra, SK, Beauchamp, M-C, Becker, KA, Bernas, G, Brough, D, Carrillo-Salinas, F, Chan, W, Chen, H, Dawson, R, DeMambro, V, D'Hont, J, Dibb, KM, Eudy, JD, Gan, L, Gao, J, Gonzales, A, Guntur, AR, Guo, H, Harms, DW, Harrington, A, Hentges, KE, Humphreys, N, Imai, S, Ishii, H, Iwama, M, Jonasch, E, Karolak, M, Keavney, B, Khin, N-C, Konno, M, Kotani, Y, Kunihiro, Y, Lakshmanan, I, Larochelle, C, Lawrence, CB, Li, L, Lindner, V, Liu, X-D, Lopez-Castejon, G, Loudon, A, Lowe, J, Jerome-Majewska, LA, Matsusaka, T, Miura, H, Miyasaka, Y, Morpurgo, B, Motyl, K, Nabeshima, Y-I, Nakade, K, Nakashiba, T, Nakashima, K, Obata, Y, Ogiwara, S, Ouellet, M, Oxburgh, L, Piltz, S, Pinz, I, Ponnusamy, MP, Ray, D, Redder, RJ, Rosen, CJ, Ross, N, Ruhe, MT, Ryzhova, L, Salvador, AM, Alam, SS, Sedlacek, R, Sharma, K, Smith, C, Staes, K, Starrs, L, Sugiyama, F, Takahashi, S, Tanaka, T, Trafford, AW, Uno, Y, Vanhoutte, L, Vanrockeghem, F, Willis, BJ, Wright, CS, Yamauchi, Y, Yi, X, Yoshimi, K, Zhang, X, Zhang, Y, Ohtsuka, M, Das, S, Garry, DJ, Hochepied, T, Thomas, P, Parker-Thornburg, J, Adamson, AD, Yoshiki, A, Schmouth, J-F, Golovko, A, Thompson, WR, Lloyd, KCK, Wood, JA, Cowan, M, Mashimo, T, Mizuno, S, Zhu, H, Kasparek, P, Liaw, L, Miano, JM, and Burgio, G

Abstract

BACKGROUND: CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up to 16% efficiency in generating conditional knockout (cKO or floxed) alleles by microinjection of 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides as donors (referred herein as "two-donor floxing" method). RESULTS: We re-evaluate the two-donor method from a consortium of 20 laboratories across the world. The dataset constitutes 56 genetic loci, 17,887 zygotes, and 1718 live-born mice, of which only 15 (0.87%) mice contain cKO alleles. We subject the dataset to statistical analyses and a machine learning algorithm, which reveals that none of the factors analyzed was predictive for the success of this method. We test some of the newer methods that use one-donor DNA on 18 loci for which the two-donor approach failed to produce cKO alleles. We find that the one-donor methods are 10- to 20-fold more efficient than the two-donor approach. CONCLUSION: We propose that the two-donor method lacks efficiency because it relies on two simultaneous recombination events in cis, an outcome that is dwarfed by pervasive accompanying undesired editing events. The methods that use one-donor DNA are fairly efficient as they rely on only one recombination event, and the probability of correct insertion of the donor cassette without unanticipated mutational events is much higher. Therefore, one-donor methods offer higher efficiencies for the routine generation of cKO animal models.

Published
2019

26. Human Y Chromosome Exerts Pleiotropic Effects on Susceptibility to Atherosclerosis

Author

Eales, JM, Maan, AA, Xu, X, Michoel, T, Hallast, P, Batini, C, Zadik, D, Prestes, PR, Molina, E, Denniff, M, Schroeder, J, Bjorkegren, JLM, Thompson, J, Maffia, P, Guzik, TJ, Keavney, B, Jobling, MA, Samani, NJ, Charchar, FJ, Tomaszewski, M, Eales, JM, Maan, AA, Xu, X, Michoel, T, Hallast, P, Batini, C, Zadik, D, Prestes, PR, Molina, E, Denniff, M, Schroeder, J, Bjorkegren, JLM, Thompson, J, Maffia, P, Guzik, TJ, Keavney, B, Jobling, MA, Samani, NJ, Charchar, FJ, and Tomaszewski, M

Abstract

OBJECTIVE: The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis. Approach and Results: Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD-carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04-1.18; P=6.8×10-4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1-specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal. CONCLUSIONS: Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through proatherosclerotic reprogramming of the transcriptome, partly through UTY.

Published
2019

28. The role of the RAS pathway in iAMP21-ALL

Author

Ryan, S L, Matheson, E, Grossmann, V, Sinclair, P, Bashton, M, Schwab, C, Towers, W, Partington, M, Elliott, A, Minto, L, Richardson, S, Rahman, T, Keavney, B, Skinner, R, Bown, N, Haferlach, T, Vandenberghe, P, Haferlach, C, Santibanez-Koref, M, Moorman, A V, Kohlmann, A, Irving, J A E, and Harrison, C J

Subjects
Chromosome Aberrations, Cell Survival, Chromosomes, Human, Pair 21, MAP Kinase Signaling System, Sequence Analysis, DNA, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Mice, Mutation Rate, Journal Article, ras Proteins, Animals, Heterografts, Humans, Original Article, Benzimidazoles
Abstract

Intrachromosomal amplification of chromosome 21 (iAMP21) identifies a high-risk subtype of acute lymphoblastic leukaemia (ALL), requiring intensive treatment to reduce their relapse risk. Improved understanding of the genomic landscape of iAMP21-ALL will ascertain whether these patients may benefit from targeted therapy. We performed whole-exome sequencing of eight iAMP21-ALL samples. The mutation rate was dramatically disparate between cases (average 24.9, range 5-51) and a large number of novel variants were identified, including frequent mutation of the RAS/MEK/ERK pathway. Targeted sequencing of a larger cohort revealed that 60% (25/42) of diagnostic iAMP21-ALL samples harboured 42 distinct RAS pathway mutations. High sequencing coverage demonstrated heterogeneity in the form of multiple RAS pathway mutations within the same sample and diverse variant allele frequencies (VAFs) (2-52%), similar to other subtypes of ALL. Constitutive RAS pathway activation was observed in iAMP21 samples that harboured mutations in the predominant clone (⩾35% VAF). Viable iAMP21 cells from primary xenografts showed reduced viability in response to the MEK1/2 inhibitor, selumetinib, in vitro. As clonal (⩾35% VAF) mutations were detected in 26% (11/42) of iAMP21-ALL, this evidence of response to RAS pathway inhibitors may offer the possibility to introduce targeted therapy to improve therapeutic efficacy in these high-risk patients.Leukemia advance online publication, 10 May 2016; doi:10.1038/leu.2016.80. ispartof: Leukemia vol:30 issue:9 pages:1824-1831 ispartof: location:England status: published

Published
2016

31. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author

EVANGELOU, E., WARREN, H. R., MOSEN-ANSORENA, D., MIFSUD, B., PAZOKI, R., Gao, H., NTRITSOS, G., DIMOU, N., CABRERA, C. P., Karaman, I., NG, F. L., Evangelou, M., WITKOWSKA, K., TZANIS, E., HELLWEGE, J. N., Giri, A., VELEZ EDWARDS, D. R., Sun, Y. V., Cho, K., GAZIANO, J. M., WILSON, P. W. F., TSAO, P. S., Kovesdy, C. P., ESKO, T., MAGI, R., Milani, L., Almgren, P., Boutin, T., Debette, Stéphanie, Ding, J., GIULIANINI, F., HOLLIDAY, E. G., JACKSON, A. U., LI-GAO, R., LIN, W. Y., Luan, J., Mangino, M., OLDMEADOW, C., PRINS, B. P., Qian, Y., Sargurupremraj, Muralidharan, Shah, N., SURENDRAN, P., THERIAULT, S., VERWEIJ, N., WILLEMS, S. M., Zhao, J. H., Amouyel, P., Connell, J., DE MUTSERT, R., DONEY, A. S. F., Farrall, M., MENNI, C., NOORDAM, R., Pare, G., POULTER, N. R., SHIELDS, D. C., STANTON, A., THOM, S., ABECASIS, G., Amin, N., ARKING, D. E., Ayers, K. L., BARBIERI, C. M., Batini, C., BIS, J. C., Blake, T., Bochud, M., Boehnke, M., BOERWINKLE, E., Boomsma, D. I., BOTTINGER, E. P., BRAUND, P. S., BRUMAT, M., Campbell, A., Campbell, H., Chakravarti, A., CHAMBERS, J. C., Chauhan, Ganesh, Ciullo, M., COCCA, M., Collins, F., CORDELL, H. J., Davies, G., DE BORST, M. H., DE GEUS, E. J., DEARY, I. J., DEELEN, J., DEL GRECO, M. F., DEMIRKALE, C. Y., DORR, M., EHRET, G. B., ELOSUA, R., ENROTH, S., ERZURUMLUOGLU, A. M., Ferreira, T., Franberg, M., FRANCO, O. H., GANDIN, I., Gasparini, P., GIEDRAITIS, V., Gieger, C., GIROTTO, G., Goel, A., GOW, A. J., GUDNASON, V., Guo, X., GYLLENSTEN, U., HAMSTEN, A., HARRIS, T. B., Harris, S. E., HARTMAN, C. A., HAVULINNA, A. S., HICKS, A. A., Hofer, E., Hofman, A., HOTTENGA, J. J., HUFFMAN, J. E., Hwang, S. J., INGELSSON, E., James, A., Jansen, R., JARVELIN, M. R., JOEHANES, R., Johansson, A., JOHNSON, A. D., Joshi, P. K., JOUSILAHTI, P., JUKEMA, J. W., JULA, A., KAHONEN, M., KATHIRESAN, S., KEAVNEY, B. D., Khaw, K. T., KNEKT, P., Knight, J., KOLCIC, I., KOONER, J. S., KOSKINEN, S., KRISTIANSSON, K., KUTALIK, Z., Laan, M., Larson, M., LAUNER, L. J., LEHNE, B., LEHTIMAKI, T., LIEWALD, D. C. M., Lin, L., LIND, L., LINDGREN, C. M., Liu, Y., LOOS, R. J. F., LOPEZ, L. M., Lu, Y., LYYTIKAINEN, L. P., Mahajan, A., MAMASOULA, C., MARRUGAT, J., MARTEN, J., MILANESCHI, Y., Morgan, A., MORRIS, A. D., MORRISON, A. C., MUNSON, P. J., Nalls, M. A., NANDAKUMAR, P., NELSON, C. P., NIIRANEN, T., Nolte, I. M., Nutile, T., Oldehinkel, A. J., Oostra, B. A., O'REILLY, P. F., ORG, E., PADMANABHAN, S., PALMAS, W., Palotie, A., PATTIE, A., PENNINX, Bwjh, Perola, M., Peters, A., POLASEK, O., PRAMSTALLER, P. P., Nguyen, Q. T., RAITAKARI, O. T., REN, M., Rettig, R., Rice, K., RIDKER, P. M., RIED, J. S., RIESE, H., RIPATTI, S., ROBINO, A., ROSE, L. M., ROTTER, J. I., RUDAN, I., Ruggiero, D., SABA, Y., SALA, C. F., SALOMAA, V., SAMANI, N. J., SARIN, A. P., Schmidt, R., Schmidt, H., SHRINE, N., SISCOVICK, D., SMITH, A. V., SNIEDER, H., SOBER, S., Sorice, R., STARR, J. M., STOTT, D. J., Strachan, D. P., STRAWBRIDGE, R. J., SUNDSTROM, J., SWERTZ, M. A., TAYLOR, K. D., TEUMER, A., TOBIN, M. D., TOMASZEWSKI, M., TONIOLO, D., TRAGLIA, M., TROMPET, S., TUOMILEHTO, J., Tzourio, Christophe, UITTERLINDEN, A. G., VAEZ, A., VAN DER MOST, P. J., VAN DUIJN, C. M., VERGNAUD, A. C., VERWOERT, G. C., Vitart, V., VOLKER, U., Vollenweider, P., VUCKOVIC, D., WATKINS, H., WILD, S. H., Willemsen, G., WILSON, J. F., WRIGHT, A. F., Yao, J., ZEMUNIK, T., Zhang, W., ATTIA, J. R., BUTTERWORTH, A. S., Chasman, D. I., CONEN, D., Cucca, F., DANESH, J., Hayward, C., HOWSON, J. M. M., Laakso, M., LAKATTA, E. G., Langenberg, C., MELANDER, O., MOOK-KANAMORI, D. O., PALMER, C. N. A., Risch, L., SCOTT, R. A., SEVER, P., SPECTOR, T. D., Van Der Harst, P., Wareham, N. J., Zeggini, E., Levy, D., MUNROE, P. B., NEWTON-CHEH, C., Brown, M. J., Metspalu, A., HUNG, A. M., O'DONNELL, C. J., EDWARDS, T. L., PSATY, B. M., TZOULAKI, I., BARNES, M. R., WAIN, L. V., Elliott, P., CAULFIELD, M. 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, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, HEALTHY
Abstract

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Published
2018

32. P2427The development of a computational fluid dynamics pipeline for the study of tetralogy of Fallot and coarctation of the aorta in a developing world context

Author

Swanson, L, primary, Owen, B, additional, Revell, A, additional, Ngoepe, M, additional, Keshmiri, A, additional, Deyranlou, A, additional, Aldersley, T, additional, Lawrenson, J, additional, Human, P, additional, De Decker, R, additional, Fourie, B, additional, Comitis, G, additional, Mayosi, B, additional, Keavney, B, additional, and Zuhlke, L, additional

Published
2019
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33. Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults Implications for Primary Prevention

Author

Inouye, M, Abraham, G, Nelson, CP, Wood, AM, Sweeting, MJ, Dudbridge, F, Lai, FY, Kaptoge, S, Brozynska, M, Wang, T, Ye, S, Webb, TR, Rutter, MK, Tzoulaki, I, Patel, RS, Loos, RJF, Keavney, B, Hemingway, H, Thompson, J, Watkins, H, Deloukas, P, Di Angelantonio, E, Butterworth, AS, Danesh, J, Samani, NJ, Inouye, M, Abraham, G, Nelson, CP, Wood, AM, Sweeting, MJ, Dudbridge, F, Lai, FY, Kaptoge, S, Brozynska, M, Wang, T, Ye, S, Webb, TR, Rutter, MK, Tzoulaki, I, Patel, RS, Loos, RJF, Keavney, B, Hemingway, H, Thompson, J, Watkins, H, Deloukas, P, Di Angelantonio, E, Butterworth, AS, Danesh, J, and Samani, NJ

Abstract

BACKGROUND: Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. OBJECTIVES: This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. METHODS: Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank. RESULTS: The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. CONCLUSIONS: The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screeni

Published
2018

41. Quantitative variation in plasma angiotensin-i converting enzyme activity shows allelic heterogeneity in the ABO blood group locus

Author

Terao, C, Bayoumi, N, McKenzie, C, Zelenika, D, Muro, S, Mishima, M, Connell, J, Vickers, M, Lathrop, G, Farrall, M, Matsuda, F, and Keavney, B

Abstract

Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ̃36% lower) and Type B alleles (in whom plasma ACE activity was ̃36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects. © 2013 John Wiley and Sons Ltd.

Published
2016

46. Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E epsilon2/epsilon3/epsilon4 genotype

Author

Keavney, B, Parish, S, Palmer, A, Clark, S, Youngman, L, Danesh, J, McKenzie, C, Delépine, M, Lathrop, M, Peto, R, and Collins, R

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Results from two small studies, involving a total of only 174 cases, have suggested that the increased risk of coronary heart disease conferred by cigarette smoking is substantially affected by genotype at the apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 polymorphism. We have established APOE genotypes in 4484 patients with acute myocardial infarction diagnosed before the age of 55 years for male and 65 years for female patients, and in 5757 controls with no history of cardiovascular disease. On average, the hazard ratio for myocardial infarction was 1.17 (95% CI 1.09-1.25; p

Published
2016

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