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6. Counselor Competence Gender Identity Scale: Measuring Bias, Knowledge, and Skills among School Counselors

Author

Simons, Jack D., Bahr, Michael W., and Ramdas, S. Melissa

Abstract

The measures presently available to examine the effectiveness of school counselors to provide counseling services to youth and emerging adults who identify as gender diverse are limited. This mixed-methods research study aimed to validate the psychometric properties of the Counselor Competence Gender Identity Scale (CCGIS) with a sample of school counselors. The CCGIS is a competency-based assessment that measures the effectiveness of counselors who provide services to gender diverse individuals in schools. We also examined school counselors' levels of gender identity counselor competence in relation to region of practice. Considering requests by many gender diverse individuals to have gender-inclusive curriculum in the schools and the negative impact of the COVID-19 pandemic on gender minority youth, we recruited school counselors in the United States to take the CCGIS so its factor structure and validity could be examined. Exploratory factor analysis retained 25 items that formed four subscales with good internal consistency. Criterion and concurrent validity tests indicated that the CCGIS is psychometrically sound. The CCGIS was able to discriminate between groups of school counselors based on region. The CCGIS is a valid tool that can be self-administered by school counselors to assess their effectiveness with gender diverse students.

Published
2022
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9. Pressure Swing Distillation: Heat Integration and Economics.

Author

Kadam, Ramdas S. and Yadav, Ganapati D.

Subjects
*SEPARATION (Technology), *THERMODYNAMIC equilibrium, *MATHEMATICAL optimization, *PROCESS optimization, *RESEARCH personnel
Abstract

This review article explores the azeotropic mixtures and investigates the application of Pressure Swing Distillation (PSD) as an effective separation method. Azeotropic mixtures have compositions that result in vapor and liquid phases with the same composition, making them challenging to separate using simple distillation. The content offers a structured approach to design, optimize, and execute separation processes, emphasizing the importance of heat integration, process optimization, control strategies, economic considerations, and environmental impacts within the context of PSD. Furthermore, these findings provide valuable insights for practitioners in the selection of appropriate heat-integration, optimization methods, and balancing the trade-off between economy and controllability when selecting an appropriate separation technique by balancing the economic benefits and controllable performance of different methods. PSD is reviewed detailing thermodynamic equilibrium, selection of pressure and column sequence, heat integration, optimization techniques, control strategy, and economics. The recent progresses of PSD are evaluated to determine how different heat integration techniques are useful in achieving cost and energy savings. The review provides valuable guidance to researchers and engineers navigating the complexities of azeotropic mixture separation, with a specific focus on PSD practical applications. [ABSTRACT FROM AUTHOR]

Published
2024
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10. The emerging spectrum of neurodevelopmental comorbidities in early-onset Spinal Muscular Atrophy

Author

Baranello, Giovanni, Roy, S. Q., Servais, L., Munell, F., Molinero, M. A., Natera de Benito, D., Nascimento, A., Gomez-Andres, D., Comellas, L. C., Exposito, J., Tizzano, E. F., Cuppen, I., Van der Pol, L., Aleman, A., Lochmuller, H., Mcmillan, H., Kirschner, J., Muller, C., Oskoui, M., Masson, R., Bruno, C., Gonorazky, H. D., Tesi-Rocha, C., Yaworski, A. M., Zanoteli, E., Mendonca, R., D'Amico, A., Cumbo, F., Tosi, Clelia Maria, Pane, Marika, Mercuri, Eugenio Maria, Nardes, F., Prufer, A., Arci, B. K., Pascual, S. I., Fattal-Valevski, A., De Waele, L., Deconinck, N., Farrar, M., Haberlova, J., Gomez-Garcia de la Banda, M., Childs, A. -M., Martos, C., Wraige, E., Gowda, V., Illingworth, M., Ong, M., Majundar, A., Hughes, I., Torne, K., Willis, T., Ramdas, S., De Goede, C., Erbas, Y., Brusa, C., Scoto, M., Muntoni, F., Baranello G., Tosi M., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Baranello, Giovanni, Roy, S. Q., Servais, L., Munell, F., Molinero, M. A., Natera de Benito, D., Nascimento, A., Gomez-Andres, D., Comellas, L. C., Exposito, J., Tizzano, E. F., Cuppen, I., Van der Pol, L., Aleman, A., Lochmuller, H., Mcmillan, H., Kirschner, J., Muller, C., Oskoui, M., Masson, R., Bruno, C., Gonorazky, H. D., Tesi-Rocha, C., Yaworski, A. M., Zanoteli, E., Mendonca, R., D'Amico, A., Cumbo, F., Tosi, Clelia Maria, Pane, Marika, Mercuri, Eugenio Maria, Nardes, F., Prufer, A., Arci, B. K., Pascual, S. I., Fattal-Valevski, A., De Waele, L., Deconinck, N., Farrar, M., Haberlova, J., Gomez-Garcia de la Banda, M., Childs, A. -M., Martos, C., Wraige, E., Gowda, V., Illingworth, M., Ong, M., Majundar, A., Hughes, I., Torne, K., Willis, T., Ramdas, S., De Goede, C., Erbas, Y., Brusa, C., Scoto, M., Muntoni, F., Baranello G., Tosi M., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

n/a

Published
2024

11. Computer-assisted vaccine design

Author

Zhou, Rao, Pophale, Ramdas S., and Deem, Michael W.

Subjects
Quantitative Biology - Populations and Evolution
Abstract

We define a new parameter to quantify the antigenic distance between two H3N2 influenza strains: we use this parameter to measure antigenic distance between circulating H3N2 strains and the closest vaccine component of the influenza vaccine. For the data between 1971 and 2004, the measure of antigenic distance correlates better with efficacy in humans of the H3N2 influenza A annual vaccine than do current state of the art measures of antigenic distance such as phylogenetic sequence analysis or ferret antisera inhibition assays. We suggest that this measure of antigenic distance could be used to guide the design of the annual flu vaccine. We combine the measure of antigenic distance with a multiple-strain avian influenza transmission model to study the threat of simultaneous introduction of multiple avian influenza strains. For H3N2 influenza, the model is validated against observed viral fixation rates and epidemic progression rates from the World Health Organization FluNet - Global Influenza Surveillance Network. We find that a multiple-component avian influenza vaccine is helpful to control a simultaneous multiple introduction of bird-flu strains. We introduce Population at Risk (PaR) to quantify the risk of a flu pandemic, and calculate by this metric the improvement that a multiple vaccine offers., Comment: 25 pages; 5 figures; 1 table; to appear in Influenza: Molecular Virology, Horizon Scientific Press, edited by Qinghua Wang and Yizhi Jane Tao, 2009

Published
2009

14. Emojifying youth mental health research -- Leveraging digital expressions in South Asia.

Author

Philip, Sharad, Datta, Anirban, Jamir, Limalemla, Marri, Anushka R., and Ransing, Ramdas S.

Subjects
MENTAL health, MEDICAL care, EMOTICONS & emojis, MEDICAL research, TELECOMMUNICATION, HEALTH promotion, FACIAL expression, CULTURAL pluralism
Abstract

The article discusses research by Sharad Philip and colleagues, reported in the April 2024 issue of the Indian Journal of Psychiatry, focusing on the utilization of emojis in youth mental health research in South Asia. Topics include the varied purposes of emojis in mental health assessment, their potential advantages and limitations, and the need for their integration into psychometric research methodologies to address cultural and linguistic challenges.

Published
2024
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16. Author Correction: The power of genetic diversity in genome-wide association studies of lipids (Nature, (2021), 600, 7890, (675-679), 10.1038/s41586-021-04064-3)

Author

Graham, S.E. Clarke, S.L. Wu, K.-H.H. Kanoni, S. Zajac, G.J.M. Ramdas, S. Surakka, I. Ntalla, I. Vedantam, S. Winkler, T.W. Locke, A.E. Marouli, E. Hwang, M.Y. Han, S. Narita, A. Choudhury, A. Bentley, A.R. Ekoru, K. Verma, A. Trivedi, B. Martin, H.C. Hunt, K.A. Hui, Q. Klarin, D. Zhu, X. Thorleifsson, G. Helgadottir, A. Gudbjartsson, D.F. Holm, H. Olafsson, I. Akiyama, M. Sakaue, S. Terao, C. Kanai, M. Zhou, W. Brumpton, B.M. Rasheed, H. Ruotsalainen, S.E. Havulinna, A.S. Veturi, Y. Feng, Q.P. Rosenthal, E.A. Lingren, T. Pacheco, J.A. Pendergrass, S.A. Haessler, J. Giulianini, F. Bradford, Y. Miller, J.E. Campbell, A. Lin, K. Millwood, I.Y. Hindy, G. Rasheed, A. Faul, J.D. Zhao, W. Weir, D.R. Turman, C. Huang, H. Graff, M. Mahajan, A. Brown, M.R. Zhang, W. Yu, K. Schmidt, E.M. Pandit, A. Gustafsson, S. Yin, X. Luan, J. Zhao, J.-H. Matsuda, F. Jang, H.-M. Yoon, K. Medina-Gomez, C. Pitsillides, A. Hottenga, J.J. Willemsen, G. Wood, A.R. Ji, Y. Gao, Z. Haworth, S. Mitchell, R.E. Chai, J.F. Aadahl, M. Yao, J. Manichaikul, A. Warren, H.R. Ramirez, J. Bork-Jensen, J. Kårhus, L.L. Goel, A. Sabater-Lleal, M. Noordam, R. Sidore, C. Fiorillo, E. McDaid, A.F. Marques-Vidal, P. Wielscher, M. Trompet, S. Sattar, N. Møllehave, L.T. Thuesen, B.H. Munz, M. Zeng, L. Huang, J. Yang, B. Poveda, A. Kurbasic, A. Lamina, C. Forer, L. Scholz, M. Galesloot, T.E. Bradfield, J.P. Daw, E.W. Zmuda, J.M. Mitchell, J.S. Fuchsberger, C. Christensen, H. Brody, J.A. Feitosa, M.F. Wojczynski, M.K. Preuss, M. Mangino, M. Christofidou, P. Verweij, N. Benjamins, J.W. Engmann, J. Kember, R.L. Slieker, R.C. Lo, K.S. Zilhao, N.R. Le, P. Kleber, M.E. Delgado, G.E. Huo, S. Ikeda, D.D. Iha, H. Yang, J. Liu, J. Leonard, H.L. Marten, J. Schmidt, B. Arendt, M. Smyth, L.J. Cañadas-Garre, M. Wang, C. Nakatochi, M. Wong, A. Hutri-Kähönen, N. Sim, X. Xia, R. Huerta-Chagoya, A. Fernandez-Lopez, J.C. Lyssenko, V. Ahmed, M. Jackson, A.U. Yousri, N.A. Irvin, M.R. Oldmeadow, C. Kim, H.-N. Ryu, S. Timmers, P.R.H.J. Arbe and Graham, S.E. Clarke, S.L. Wu, K.-H.H. Kanoni, S. Zajac, G.J.M. Ramdas, S. Surakka, I. Ntalla, I. Vedantam, S. Winkler, T.W. Locke, A.E. Marouli, E. Hwang, M.Y. Han, S. Narita, A. Choudhury, A. Bentley, A.R. Ekoru, K. Verma, A. Trivedi, B. Martin, H.C. Hunt, K.A. Hui, Q. Klarin, D. Zhu, X. Thorleifsson, G. Helgadottir, A. Gudbjartsson, D.F. Holm, H. Olafsson, I. Akiyama, M. Sakaue, S. Terao, C. Kanai, M. Zhou, W. Brumpton, B.M. Rasheed, H. Ruotsalainen, S.E. Havulinna, A.S. Veturi, Y. Feng, Q.P. Rosenthal, E.A. Lingren, T. Pacheco, J.A. Pendergrass, S.A. Haessler, J. Giulianini, F. Bradford, Y. Miller, J.E. Campbell, A. Lin, K. Millwood, I.Y. Hindy, G. Rasheed, A. Faul, J.D. Zhao, W. Weir, D.R. Turman, C. Huang, H. Graff, M. Mahajan, A. Brown, M.R. Zhang, W. Yu, K. Schmidt, E.M. Pandit, A. Gustafsson, S. Yin, X. Luan, J. Zhao, J.-H. Matsuda, F. Jang, H.-M. Yoon, K. Medina-Gomez, C. Pitsillides, A. Hottenga, J.J. Willemsen, G. Wood, A.R. Ji, Y. Gao, Z. Haworth, S. Mitchell, R.E. Chai, J.F. Aadahl, M. Yao, J. Manichaikul, A. Warren, H.R. Ramirez, J. Bork-Jensen, J. Kårhus, L.L. Goel, A. Sabater-Lleal, M. Noordam, R. Sidore, C. Fiorillo, E. McDaid, A.F. Marques-Vidal, P. Wielscher, M. Trompet, S. Sattar, N. Møllehave, L.T. Thuesen, B.H. Munz, M. Zeng, L. Huang, J. Yang, B. Poveda, A. Kurbasic, A. Lamina, C. Forer, L. Scholz, M. Galesloot, T.E. Bradfield, J.P. Daw, E.W. Zmuda, J.M. Mitchell, J.S. Fuchsberger, C. Christensen, H. Brody, J.A. Feitosa, M.F. Wojczynski, M.K. Preuss, M. Mangino, M. Christofidou, P. Verweij, N. Benjamins, J.W. Engmann, J. Kember, R.L. Slieker, R.C. Lo, K.S. Zilhao, N.R. Le, P. Kleber, M.E. Delgado, G.E. Huo, S. Ikeda, D.D. Iha, H. Yang, J. Liu, J. Leonard, H.L. Marten, J. Schmidt, B. Arendt, M. Smyth, L.J. Cañadas-Garre, M. Wang, C. Nakatochi, M. Wong, A. Hutri-Kähönen, N. Sim, X. Xia, R. Huerta-Chagoya, A. Fernandez-Lopez, J.C. Lyssenko, V. Ahmed, M. Jackson, A.U. Yousri, N.A. Irvin, M.R. Oldmeadow, C. Kim, H.-N. Ryu, S. Timmers, P.R.H.J. Arbe

Abstract

Correction to: Nature Published online 9 December 2021 In the version of this article initially published, Noha A. Yousri (Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar and Department of Computer and Systems Engineering, Alexandria University, Egypt) and Steven C. Hunt (Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA and Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar) were not included in the author list. In addition, Hieab H. H. Adams (Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands and Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands) was shown with an incorrect second affiliation in the HTML and PDF versions of the article. Finally, in the HTML version, Cristen J. Willer was mistakenly listed with an extra affiliation (Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia). The authors and affiliations have been corrected in the HTML and PDF versions of the article. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

Published
2023

17. Muscle cramps and contractures: causes and treatment.

Author

Dijkstra, J.N., Boon, E., Kruijt, N., Brusse, E., Ramdas, S., Jungbluth, H., Engelen, B.G.M. van, Walters, J., Voermans, N.C., Dijkstra, J.N., Boon, E., Kruijt, N., Brusse, E., Ramdas, S., Jungbluth, H., Engelen, B.G.M. van, Walters, J., and Voermans, N.C.

Abstract

01 februari 2023, Item does not contain fulltext, Muscle cramps are painful, sudden, involuntary muscle contractions that are generally self-limiting. They are often part of the spectrum of normal human physiology and can be associated with a wide range of acquired and inherited causes. Cramps are only infrequently due to progressive systemic or neuromuscular diseases. Contractures can mimic cramps and are defined as shortenings of the muscle resulting in an inability of the muscle to relax normally, and are generally myogenic. General practitioners and neurologists frequently encounter patients with muscle cramps but more rarely those with contractures. The main questions for clinicians are: (1) Is this a muscle cramp, a contracture or a mimic? (2) Are the cramps exercise induced, idiopathic or symptomatic? (3) What is/are the presumed cause(s) of symptomatic muscle cramps or contractures? (4) What should be the diagnostic approach? and (5) How should we advise and treat patients with muscle cramps or contractures? We consider these questions and present a practical approach to muscle cramps and contractures, including their causes, pathophysiology and treatment options.

Published
2023

18. Process integration of hydrolysis and hydrogen generation processes in the six-step Cu-Cl cycle for green hydrogen production.

Author

Kadam, Ramdas S. and Yadav, Ganapati D.

Subjects
*COPPER chlorides, *INTERSTITIAL hydrogen generation, *WASTE heat boilers, *HYDROGEN production, *PRODUCT life cycle assessment
Abstract

The ICT-OEC six-step Cu-Cl cycle dissociates water thermochemically to produce hydrogen and oxygen. In the Cu-Cl cycle integrating the hydrolysis and hydrogen processes poses a crucial engineering challenge. Hydrolysis at 350-400 °C requires extra steam, resulting in the generation of dilute HCl instead of dry HCl gas, which must be recycled for hydrogen production. To address this, pressure swing distillation (PSD) is integrated into the hydrolysis and hydrogen generation reactions to separate HCl and water. The study examines operating parameters in PSD processes. A simulated process integration model includes an intermediate heat recovery steam generator (HRSG) with PSD to complete the overall conceptual design. The nuclear-based Cu-Cl cycle without PSD demonstrates a lower environmental impact when compared to the Cu-Cl cycle with PSD. The Cu-Cl cycle with a higher HCl concentration in PSD feed exhibits a minimum global warming potential (GWP) value of 2.53 kg of CO 2 eq for 1 kmol/h hydrogen production. [Display omitted] • Analysis of the ICT-OEC six-step Cu-Cl closed loop thermochemical cycle. • Integration of pressure swing distillation of hydrolysis and hydrogen generation processes. • Separation of HCl-water enhances the efficiency of the Cu-Cl cycle. • Molar ratio of CuCl 2 to water has a significant impact on the Cu-Cl cycle. • Life cycle assessment of Cu-Cl cycle with and without pressure swing distillation. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Impact of adavertisement on buying behaviour of youths in Madha city

Author

Rupesh A. Pawar, Rushikesh B. Mandlik, Ambadas L. Bhasake, Vivek V. Jadhav, and Ramdas S. Shelake

Subjects
ComputingMilieux_MISCELLANEOUS, General Nursing, Education
Abstract

Advertisement plays an important and very significant role in sale of any goods and services in the market. It is one of the best way of communication with the consumers. Advertisement helps to inform about the availability of various brands in the market. It helps to provides detail information about the products to everyone including the kids, women, men, youth and senior citizens in the nation. There are having various modes of advertisement such as display advertisement, native advertising, print advertisement, direct mail advertisement, television advertisement, radio advertisement, social media advertisement, outdoor advertisement and public services advertisement. Advertisement is very powerful tool of marketing which directly and indirectly increasing the sale of various products in the market. Advertising plays an important role in introduction of new of product, introduction of new brand of products, creation of awareness, acquiring the customers, increasing the sale, profits and recognition in the market.

Published
2022
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24. Advances in Total Synthesis of Some 2,3,5‐Trisubstituted Tetrahydrofuran Natural Products

Author

Dnyaneshwar A Gorve, Ramdas S. Pathare, and Rodney A. Fernandes

Subjects
Biological Products, 010405 organic chemistry, media_common.quotation_subject, Fatty Acids, Organic Chemistry, Total synthesis, Stereoisomerism, General Chemistry, 010402 general chemistry, Lipids, 01 natural sciences, Biochemistry, Natural (archaeology), 0104 chemical sciences, Lactones, chemistry.chemical_compound, Ingenuity, chemistry, Biochemical engineering, Furans, Sesquiterpenes, Tetrahydrofuran, media_common
Abstract

2,3,5-Trisubstituted tetrahydrofuran moiety is ubiquitous in natural products. These have served as appealing candidates for total synthesis due to their varied bio- and pharmaceutical activities. This tutorial review delineates the ingenious efforts by many researchers in the total synthesis of selected natural products based on a common 2,3,5-trisubstituted tetrahydrofuran core structure. Many of the syntheses display nuanced interplay between new methods and the ingenuity of planned strategies achieved through catalysis or cascade chemistry. In some cases, the chiron approach has come quite handy, wherein the structural features and the stereochemistry in select molecules could map well with naturally available starting materials. This compilation also aims to enhance the diversity space based on these natural products and further interest in sustainable total synthesis.

Published
2020
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25. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Author

Ramdas, S. Judd, J. Graham, S.E. Kanoni, S. Wang, Y. Surakka, I. Wenz, B. Clarke, S.L. Chesi, A. Wells, A. Bhatti, K.F. Vedantam, S. Winkler, T.W. Locke, A.E. Marouli, E. Zajac, G.J.M. Wu, K.-H.H. Ntalla, I. Hui, Q. Klarin, D. Hilliard, A.T. Wang, Z. Xue, C. Thorleifsson, G. Helgadottir, A. Gudbjartsson, D.F. Holm, H. Olafsson, I. Hwang, M.Y. Han, S. Akiyama, M. Sakaue, S. Terao, C. Kanai, M. Zhou, W. Brumpton, B.M. Rasheed, H. Havulinna, A.S. Veturi, Y. Pacheco, J.A. Rosenthal, E.A. Lingren, T. Feng, Q. Kullo, I.J. Narita, A. Takayama, J. Martin, H.C. Hunt, K.A. Trivedi, B. Haessler, J. Giulianini, F. Bradford, Y. Miller, J.E. Campbell, A. Lin, K. Millwood, I.Y. Rasheed, A. Hindy, G. Faul, J.D. Zhao, W. Weir, D.R. Turman, C. Huang, H. Graff, M. Choudhury, A. Sengupta, D. Mahajan, A. Brown, M.R. Zhang, W. Yu, K. Schmidt, E.M. Pandit, A. Gustafsson, S. Yin, X. Luan, J. Zhao, J.-H. Matsuda, F. Jang, H.-M. Yoon, K. Medina-Gomez, C. Pitsillides, A. Hottenga, J.J. Wood, A.R. Ji, Y. Gao, Z. Haworth, S. Mitchell, R.E. Chai, J.F. Aadahl, M. Bjerregaard, A.A. Yao, J. Manichaikul, A. Lee, W.-J. Hsiung, C.A. Warren, H.R. Ramirez, J. Bork-Jensen, J. Kårhus, L.L. Goel, A. Sabater-Lleal, M. Noordam, R. Mauro, P. Matteo, F. McDaid, A.F. Marques-Vidal, P. Wielscher, M. Trompet, S. Sattar, N. Møllehave, L.T. Munz, M. Zeng, L. Huang, J. Yang, B. Poveda, A. Kurbasic, A. Schönherr, S. Forer, L. Scholz, M. Galesloot, T.E. Bradfield, J.P. Ruotsalainen, S.E. Daw, E.W. Zmuda, J.M. Mitchell, J.S. Fuchsberger, C. Christensen, H. Brody, J.A. Le, P. Feitosa, M.F. Wojczynski, M.K. Hemerich, D. Preuss, M. Mangino, M. Christofidou, P. Verweij, N. Benjamins, J.W. Engmann, J. Noah, T.L. Verma, A. Slieker, R.C. Lo, K.S. Zilhao, N.R. Kleber, M.E. Delgado, G.E. Huo, S. Ikeda, D.D. Iha, H. Yang, J. Liu, J. Demirkan, A. Leonard, H.L. Marten, J. Emmel, C. Schmidt, B. Smyth, L.J. Cañadas-Garre, M. Wang, C. Nakatochi, M. Wong, A. Hutri-Kähönen, N. Sim, X. Xia, R. Huerta-Chagoya, A. Fernandez-Lopez, J.C. Ly and Ramdas, S. Judd, J. Graham, S.E. Kanoni, S. Wang, Y. Surakka, I. Wenz, B. Clarke, S.L. Chesi, A. Wells, A. Bhatti, K.F. Vedantam, S. Winkler, T.W. Locke, A.E. Marouli, E. Zajac, G.J.M. Wu, K.-H.H. Ntalla, I. Hui, Q. Klarin, D. Hilliard, A.T. Wang, Z. Xue, C. Thorleifsson, G. Helgadottir, A. Gudbjartsson, D.F. Holm, H. Olafsson, I. Hwang, M.Y. Han, S. Akiyama, M. Sakaue, S. Terao, C. Kanai, M. Zhou, W. Brumpton, B.M. Rasheed, H. Havulinna, A.S. Veturi, Y. Pacheco, J.A. Rosenthal, E.A. Lingren, T. Feng, Q. Kullo, I.J. Narita, A. Takayama, J. Martin, H.C. Hunt, K.A. Trivedi, B. Haessler, J. Giulianini, F. Bradford, Y. Miller, J.E. Campbell, A. Lin, K. Millwood, I.Y. Rasheed, A. Hindy, G. Faul, J.D. Zhao, W. Weir, D.R. Turman, C. Huang, H. Graff, M. Choudhury, A. Sengupta, D. Mahajan, A. Brown, M.R. Zhang, W. Yu, K. Schmidt, E.M. Pandit, A. Gustafsson, S. Yin, X. Luan, J. Zhao, J.-H. Matsuda, F. Jang, H.-M. Yoon, K. Medina-Gomez, C. Pitsillides, A. Hottenga, J.J. Wood, A.R. Ji, Y. Gao, Z. Haworth, S. Mitchell, R.E. Chai, J.F. Aadahl, M. Bjerregaard, A.A. Yao, J. Manichaikul, A. Lee, W.-J. Hsiung, C.A. Warren, H.R. Ramirez, J. Bork-Jensen, J. Kårhus, L.L. Goel, A. Sabater-Lleal, M. Noordam, R. Mauro, P. Matteo, F. McDaid, A.F. Marques-Vidal, P. Wielscher, M. Trompet, S. Sattar, N. Møllehave, L.T. Munz, M. Zeng, L. Huang, J. Yang, B. Poveda, A. Kurbasic, A. Schönherr, S. Forer, L. Scholz, M. Galesloot, T.E. Bradfield, J.P. Ruotsalainen, S.E. Daw, E.W. Zmuda, J.M. Mitchell, J.S. Fuchsberger, C. Christensen, H. Brody, J.A. Le, P. Feitosa, M.F. Wojczynski, M.K. Hemerich, D. Preuss, M. Mangino, M. Christofidou, P. Verweij, N. Benjamins, J.W. Engmann, J. Noah, T.L. Verma, A. Slieker, R.C. Lo, K.S. Zilhao, N.R. Kleber, M.E. Delgado, G.E. Huo, S. Ikeda, D.D. Iha, H. Yang, J. Liu, J. Demirkan, A. Leonard, H.L. Marten, J. Emmel, C. Schmidt, B. Smyth, L.J. Cañadas-Garre, M. Wang, C. Nakatochi, M. Wong, A. Hutri-Kähönen, N. Sim, X. Xia, R. Huerta-Chagoya, A. Fernandez-Lopez, J.C. Ly

Abstract

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. © 2022 American Society of Human Genetics

Published
2022

26. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Kanoni, S. Graham, S.E. Wang, Y. Surakka, I. Ramdas, S. Zhu, X. Clarke, S.L. Bhatti, K.F. Vedantam, S. Winkler, T.W. Locke, A.E. Marouli, E. Zajac, G.J.M. Wu, K.-H.H. Ntalla, I. Hui, Q. Klarin, D. Hilliard, A.T. Wang, Z. Xue, C. Thorleifsson, G. Helgadottir, A. Gudbjartsson, D.F. Holm, H. Olafsson, I. Hwang, M.Y. Han, S. Akiyama, M. Sakaue, S. Terao, C. Kanai, M. Zhou, W. Brumpton, B.M. Rasheed, H. Havulinna, A.S. Veturi, Y. Pacheco, J.A. Rosenthal, E.A. Lingren, T. Feng, Q.P. Kullo, I.J. Narita, A. Takayama, J. Martin, H.C. Hunt, K.A. Trivedi, B. Haessler, J. Giulianini, F. Bradford, Y. Miller, J.E. Campbell, A. Lin, K. Millwood, I.Y. Rasheed, A. Hindy, G. Faul, J.D. Zhao, W. Weir, D.R. Turman, C. Huang, H. Graff, M. Choudhury, A. Sengupta, D. Mahajan, A. Brown, M.R. Zhang, W. Yu, K. Schmidt, E.M. Pandit, A. Gustafsson, S. Yin, X. Luan, J. Zhao, J.-H. Matsuda, F. Jang, H.-M. Yoon, K. Medina-Gomez, C. Pitsillides, A. Hottenga, J.J. Wood, A.R. Ji, Y. Gao, Z. Haworth, S. Yousri, N.A. Mitchell, R.E. Chai, J.F. Aadahl, M. Bjerregaard, A.A. Yao, J. Manichaikul, A. Hwu, C.-M. Hung, Y.-J. Warren, H.R. Ramirez, J. Bork-Jensen, J. Kårhus, L.L. Goel, A. Sabater-Lleal, M. Noordam, R. Mauro, P. Matteo, F. McDaid, A.F. Marques-Vidal, P. Wielscher, M. Trompet, S. Sattar, N. Møllehave, L.T. Munz, M. Zeng, L. Huang, J. Yang, B. Poveda, A. Kurbasic, A. Lamina, C. Forer, L. Scholz, M. Galesloot, T.E. Bradfield, J.P. Ruotsalainen, S.E. Daw, E.W. Zmuda, J.M. Mitchell, J.S. Fuchsberger, C. Christensen, H. Brody, J.A. Vazquez-Moreno, M. Feitosa, M.F. Wojczynski, M.K. Wang, Z. Preuss, M.H. Mangino, M. Christofidou, P. Verweij, N. Benjamins, J.W. Engmann, J. Tsao, N.L. Verma, A. Slieker, R.C. Lo, K.S. Zilhao, N.R. Le, P. Kleber, M.E. Delgado, G.E. Huo, S. Ikeda, D.D. Iha, H. Yang, J. Liu, J. Demirkan, A. Leonard, H.L. Marten, J. Frank, M. Schmidt, B. Smyth, L.J. Cañadas-Garre, M. Wang, C. Nakatochi, M. Wong, A. Hutri-Kähönen, N. Sim, X. Xia, R. Huerta-Chagoya, A. Fernandez-Lopez, J.C. Lyss and Kanoni, S. Graham, S.E. Wang, Y. Surakka, I. Ramdas, S. Zhu, X. Clarke, S.L. Bhatti, K.F. Vedantam, S. Winkler, T.W. Locke, A.E. Marouli, E. Zajac, G.J.M. Wu, K.-H.H. Ntalla, I. Hui, Q. Klarin, D. Hilliard, A.T. Wang, Z. Xue, C. Thorleifsson, G. Helgadottir, A. Gudbjartsson, D.F. Holm, H. Olafsson, I. Hwang, M.Y. Han, S. Akiyama, M. Sakaue, S. Terao, C. Kanai, M. Zhou, W. Brumpton, B.M. Rasheed, H. Havulinna, A.S. Veturi, Y. Pacheco, J.A. Rosenthal, E.A. Lingren, T. Feng, Q.P. Kullo, I.J. Narita, A. Takayama, J. Martin, H.C. Hunt, K.A. Trivedi, B. Haessler, J. Giulianini, F. Bradford, Y. Miller, J.E. Campbell, A. Lin, K. Millwood, I.Y. Rasheed, A. Hindy, G. Faul, J.D. Zhao, W. Weir, D.R. Turman, C. Huang, H. Graff, M. Choudhury, A. Sengupta, D. Mahajan, A. Brown, M.R. Zhang, W. Yu, K. Schmidt, E.M. Pandit, A. Gustafsson, S. Yin, X. Luan, J. Zhao, J.-H. Matsuda, F. Jang, H.-M. Yoon, K. Medina-Gomez, C. Pitsillides, A. Hottenga, J.J. Wood, A.R. Ji, Y. Gao, Z. Haworth, S. Yousri, N.A. Mitchell, R.E. Chai, J.F. Aadahl, M. Bjerregaard, A.A. Yao, J. Manichaikul, A. Hwu, C.-M. Hung, Y.-J. Warren, H.R. Ramirez, J. Bork-Jensen, J. Kårhus, L.L. Goel, A. Sabater-Lleal, M. Noordam, R. Mauro, P. Matteo, F. McDaid, A.F. Marques-Vidal, P. Wielscher, M. Trompet, S. Sattar, N. Møllehave, L.T. Munz, M. Zeng, L. Huang, J. Yang, B. Poveda, A. Kurbasic, A. Lamina, C. Forer, L. Scholz, M. Galesloot, T.E. Bradfield, J.P. Ruotsalainen, S.E. Daw, E.W. Zmuda, J.M. Mitchell, J.S. Fuchsberger, C. Christensen, H. Brody, J.A. Vazquez-Moreno, M. Feitosa, M.F. Wojczynski, M.K. Wang, Z. Preuss, M.H. Mangino, M. Christofidou, P. Verweij, N. Benjamins, J.W. Engmann, J. Tsao, N.L. Verma, A. Slieker, R.C. Lo, K.S. Zilhao, N.R. Le, P. Kleber, M.E. Delgado, G.E. Huo, S. Ikeda, D.D. Iha, H. Yang, J. Liu, J. Demirkan, A. Leonard, H.L. Marten, J. Frank, M. Schmidt, B. Smyth, L.J. Cañadas-Garre, M. Wang, C. Nakatochi, M. Wong, A. Hutri-Kähönen, N. Sim, X. Xia, R. Huerta-Chagoya, A. Fernandez-Lopez, J.C. Lyss

Abstract

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk. © 2022, The Author(s).

Published
2022

27. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Kanoni, S., Graham, S.E., Wang, Yuxuan, Surakka, I., Ramdas, S., Zhu, X, Clarke, S.L., Bhatti, K.F., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Zeyuan, Xue, C., Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, Wei, Weir, D.R., Turman, C., Huang, H., Graff, M, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Zhang, W, Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Yousri, N.A., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Hwu, C.M., Hung, Y.J., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Mauro, P., Galesloot, T.E., Lores-Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Graaf, J. de, Assimes, T.L., Peloso, G.M., Kanoni, S., Graham, S.E., Wang, Yuxuan, Surakka, I., Ramdas, S., Zhu, X, Clarke, S.L., Bhatti, K.F., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Zeyuan, Xue, C., Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, Wei, Weir, D.R., Turman, C., Huang, H., Graff, M, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Zhang, W, Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Yousri, N.A., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Hwu, C.M., Hung, Y.J., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Mauro, P., Galesloot, T.E., Lores-Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Graaf, J. de, Assimes, T.L., and Peloso, G.M.

Abstract

Item does not contain fulltext, BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022

28. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Author

Ramdas, S., Judd, J., Graham, S.E., Kanoni, S., Wang, Y, Surakka, I., Wenz, B., Clarke, S.L., Chesi, A., Wells, A., Bhatti, K.F., Vedantam, S., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Z, Xue, C., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, W, Weir, D.R., Turman, C., Huang, H., Graff, Mariaelisa, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Lee, W.J., Hsiung, C.A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Galesloot, T.E., Lores de Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Zhu, Xiang, Brown, C.D., Ramdas, S., Judd, J., Graham, S.E., Kanoni, S., Wang, Y, Surakka, I., Wenz, B., Clarke, S.L., Chesi, A., Wells, A., Bhatti, K.F., Vedantam, S., Locke, A.E., Marouli, E., Zajac, G.J.M., Wu, K.H., Ntalla, I., Hui, Q., Klarin, D., Hilliard, A.T., Wang, Z, Xue, C., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Hwang, M.Y., Han, S., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W, Brumpton, B.M., Rasheed, H., Havulinna, A.S., Veturi, Y., Pacheco, J.A., Rosenthal, E.A., Lingren, T., Feng, Q., Kullo, I.J., Narita, A., Takayama, J., Martin, H.C., Hunt, K.A., Trivedi, B., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Rasheed, A., Hindy, G., Faul, J.D., Zhao, W, Weir, D.R., Turman, C., Huang, H., Graff, Mariaelisa, Choudhury, A., Sengupta, D., Mahajan, A., Brown, M.R., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J, Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Bjerregaard, A.A., Yao, J., Manichaikul, A., Lee, W.J., Hsiung, C.A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Galesloot, T.E., Lores de Motta, L., Pauper, M., Hollander, A.I. den, Kiemeney, L.A.L.M., Zhu, Xiang, and Brown, C.D.

Abstract

Item does not contain fulltext, A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Published
2022

30. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Author

Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, He J, Gindin Y, Chung C, Myers R, Schneider C, Park J, Lee K, Serper M, Carr R, Kaplan D, Haas M, MacLean M, Witschey W, Zhu X, Tcheandjieu C, Kember R, Kranzler H, Verma A, Giri A, Klarin D, Sun Y, Huang J, Huffman J, TownsendCreasy K, Hand N, Liu C, Long M, Yao J, Budoff M, Tan J, Li X, Lin H, Chen Y, Taylor K, Chang R, Krauss R, Vilarinho S, Brancale J, Nielsen J, Locke A, Jones M, Verweij N, Baras A, Reddy K, NeuschwanderTetri B, Schwimmer J, Sanyal A, Chalasani N, Ryan K, Mitchell B, Gill D, Wells A, Manduchi E, Saiman Y, Mahmud N, Miller D, Reaven P, Phillips L, Muralidhar S, DuVall S, Lee J, Assimes T, Pyarajan S, Cho K, Edwards T, Damrauer S, Wilson P, Gaziano J, ODonnell C, Khera A, Grant S, Brown C, Tsao P, Saleheen D, Lotta L, Bastarache L, Anstee QM, Daly A, Meigs J, Rotter JI, Lynch JA, Rader DJ, Voight BF, Chang KM

Published
2022
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35. A Decade with Dötz Benzannulation in the Synthesis of Natural Products

Author

Anupama Kumari, Ramdas S. Pathare, and Rodney A. Fernandes

Subjects
chemistry.chemical_classification, chemistry.chemical_compound, Annulation, Natural product, chemistry, 010405 organic chemistry, Organic Chemistry, Alkyne, 010402 general chemistry, 01 natural sciences, Combinatorial chemistry, Cycloaddition, 0104 chemical sciences
Abstract

The Dötz benzannulation is a named reaction that utilizes Fischer chromium carbenes in a formal [3+2+1] cycloaddition with an alkyne and CO to produce the corresponding benzannulated product. Since its development in the 1970s, this reaction has been extensively used in the synthesis of natural products and various molecular architectures. Although the reaction sometimes suffers from the formation of other competing side products, the rapid construction of naphthol structures with a 1,4-dihydroxy unit makes it the most appropriate reaction for the synthesis of p-naphthoquinones. This review focuses on our group’s efforts over the past decade on the extensive use of this annulation reaction along with the contributions of others on the synthesis of different natural products.1 Introduction2 General Description and Mechanism of the Dötz Benzannulation Reaction3 Applications of the Dötz Benzannulation in Natural Product Synthesis over the Last Decade4 Conclusion

Published
2020
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36. Emergence of 2,3,5-trisubstituted tetrahydrofuran natural products and their synthesis

Author

Dnyaneshwar A Gorve, Ramdas S. Pathare, and Rodney A. Fernandes

Subjects
chemistry.chemical_compound, chemistry, Organic Chemistry, Physical and Theoretical Chemistry, Biochemistry, Combinatorial chemistry, Tetrahydrofuran
Abstract

The emergence of various 2,3,5-trisubstituted tetrahydrofuran natural products in the recent literature and their synthesis is the focus of this review. These molecules exhibit varied bioactivities and have garnered the interest of several synthetic chemists owing to their efficient synthesis. A few of them have been synthesized and their absolute stereo structure has been confirmed for the first time. These will be appealing candidates in future synthetic investigations along with the untouched molecules. Thus, this compilation will reveal these molecules for expansion of their diversity within the realm of both synthesis and bioactivity studies.

Published
2020
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37. Incidental Presentation of Dandy Walker Variant in 66 Year Male Patient

Author

Rakesh S, Shinde, Pradip Pai, Dhungat, Jayant S, Kulkarni, Dilip P, Bhoge, Ramdas S, Joshi, and Amey A, Bedekar

Subjects
Adult, Male, Paresis, Stroke, Humans, Hypertrophy, Dandy-Walker Syndrome
Abstract

Dandy-Walker variant consists of vermian hypoplasia and cystic dilatation of the fourth ventricle, without enlargement of the posterior fossa is a distinctive entity believed to represent a mild subtype of Dandy-Walker complex. We report a case of 66 year male presented with right sided hemiparesis due to ischemic stroke whose imaging showed incidental findings Dandy walker variant. This Incidental Dandy Walker malformation finding in adult is rare with only a few cases reported till date.

Published
2021

40. A diversity-oriented synthesis of polyheterocycles via the cyclocondensation of azomethine imine

Author

Antim K. Maurya, Arshad J. Ansari, Anita Kumawat, Ramdas S. Pathare, Ram T. Pardasani, Vijai K. Agnihotri, Devesh M. Sawant, Ramesh K. Metre, Ashoke Sharon, Sarika Verma, and Rahul Joshi

Subjects
Drug discovery, Imine, 02 engineering and technology, General Chemistry, respiratory system, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, Combinatorial chemistry, Catalysis, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Electrophile, Materials Chemistry, 0210 nano-technology, human activities, Diversity (business)
Abstract

Pd-Catalyzed sequential reactions to afford skeletally diverse molecules are described. The reaction involved azomethine imine formation and a cyclocondensation reaction as individual steps. The methodology provides excellent regio- and stereocontrol. Skeletal diversity was ensured by changing the electrophilic counterpart of azomethine imine. Due to its broader diversity and complexity, the DOS methodology is likely to benefit drug discovery and development in the future.

Published
2019
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41. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S.E., Clarke, S.L., Wu, K.H., Kanoni, S., Zajac, G.J.M., Ramdas, S., Surakka, I., Ntalla, I., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Hwang, M.Y., Han, S., Narita, A., Choudhury, A., Bentley, A.R., Ekoru, K., Verma, A., Trivedi, B., Martin, H.C., Hunt, K.A., Hui, Q., Klarin, D., Zhu, X, Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W., Brumpton, B.M., Rasheed, H., Ruotsalainen, S.E., Havulinna, A.S., Veturi, Y., Feng, Q., Rosenthal, E.A., Lingren, T., Pacheco, J.A., Pendergrass, S.A., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Hindy, G., Rasheed, A., Faul, J.D., Zhao, W., Weir, D.R., Turman, C., Huang, H., Graff, M, Mahajan, A., Brown, M.R., Zhang, W., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J., Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Willemsen, G., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Yao, J., Manichaikul, A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Sidore, C., Fiorillo, E., McDaid, A.F., Marques-Vidal, P., Wielscher, M., Trompet, S., Sattar, N., Galesloot, T.E., Kiemeney, B., Graaf, J. de, Lores de Motta, L., Pauper, M., Hollander, A.I. den, Sun, Y.V., Willer, C.J., Graham, S.E., Clarke, S.L., Wu, K.H., Kanoni, S., Zajac, G.J.M., Ramdas, S., Surakka, I., Ntalla, I., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Hwang, M.Y., Han, S., Narita, A., Choudhury, A., Bentley, A.R., Ekoru, K., Verma, A., Trivedi, B., Martin, H.C., Hunt, K.A., Hui, Q., Klarin, D., Zhu, X, Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W., Brumpton, B.M., Rasheed, H., Ruotsalainen, S.E., Havulinna, A.S., Veturi, Y., Feng, Q., Rosenthal, E.A., Lingren, T., Pacheco, J.A., Pendergrass, S.A., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Hindy, G., Rasheed, A., Faul, J.D., Zhao, W., Weir, D.R., Turman, C., Huang, H., Graff, M, Mahajan, A., Brown, M.R., Zhang, W., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J., Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Willemsen, G., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Yao, J., Manichaikul, A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Sidore, C., Fiorillo, E., McDaid, A.F., Marques-Vidal, P., Wielscher, M., Trompet, S., Sattar, N., Galesloot, T.E., Kiemeney, B., Graaf, J. de, Lores de Motta, L., Pauper, M., Hollander, A.I. den, Sun, Y.V., and Willer, C.J.

Abstract

Item does not contain fulltext, Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use(1). Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels(2), heart disease remains the leading cause of death worldwide(3). Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS(4-23) have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns(24). Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine(25), we anticipate that increased diversity of participants will lead to more accurate and equitable(26) application of polygenic scores in clinical practice.

Published
2021

42. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), Willer, C. J. (Cristen J.), Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), and Willer, C. J. (Cristen J.)

Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4‐23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

43. Sequential Pd(0)/Fe(III) Catalyzed Azide–Isocyanide Coupling/Cyclization Reaction: One-Pot Synthesis of Aminotetrazoles

Author

Arshad J. Ansari, Ram T. Pardasani, Sarika Verma, Vijai K. Agnihotri, Ramdas S. Pathare, Ashoke Sharon, Anand Maurya, Devesh M. Sawant, and Antim K. Maurya

Subjects
010405 organic chemistry, Isocyanide, Aryl, Organic Chemistry, One-pot synthesis, 010402 general chemistry, 01 natural sciences, Coupling reaction, 0104 chemical sciences, Catalysis, chemistry.chemical_compound, chemistry, Polymer chemistry, Azide, Stoichiometry, Carbodiimide
Abstract

A rapid and efficient synthesis of aminotetrazole from aryl azides, isocyanides, and TMSN3 is developed. The reaction is promoted by sequential Pd(0)/Fe(III) catalysis. The reaction sequence utilizes the Pd-catalyzed azide-isocyanide denitrogenative coupling reaction to generate unsymmetric carbodiimide in situ, which reacts with TMSN3 in the presence of FeCl3 in a single pot. The methodology has distinct advantages over traditional synthetic approaches where toxic Hg and Pb salts are employed at stoichiometric scale.

Published
2018
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44. 235P Cross sectional study of 187 patients with congenital myasthenia syndrome, describing the clinical phenotypes, genetic mutations, and single point standardised assessment scores.

Author

Ramdas, S., Ramjattan, H., Hennehan, L., Natera De Benito, D., Nascimiento, A., Della Marina, A., Schara-Schmidt, U., Munot, P., Simmons, E., Maggi, L., Gallone, A., Nadaj Pakleza, A., Chanson, J., Marini-Bettolo, C., Moat, D., Paz Guerrero-Molina, M., Dominguez-González, C., Jungbluth, H., Sheehan, J., and Palace, J.

Subjects
*CONGENITAL myasthenic syndromes, *NEUROMUSCULAR transmission, *GENETIC disorders, *NEUROMUSCULAR diseases, *GENETIC mutation
Abstract

Congenital myasthenic syndromes (CMS) are inherited disorders of defective neuromuscular transmission. The clinical phenotype and treatment response vary between the over 30 genetic subtypes. Currently, there is limited published large cohort data in this population. A multicentre international study was undertaken to identify the genetic spectrum, clinical data, treatments, and standardised outcome measures in genetically confirmed CMS patients. Cross sectional data was collected at the time of routine clinic appointment within the last 12-months. Clinical, genetic information and three outcome measures (Myasthenia Gravis Quantitative Score - QMG, Myasthenia Gravis Activities of Daily Living - MG-ADL and Sit to stand in 1 minute - STS1M) were collected. Cohort data analysis was performed on complete data sets, with sub analysis of common subtypes. 187 patients were included, with AChR deficiency 29%, DOK7 20%, RAPSN 17%, COLQ 7%, and Slow Channel 6%. Median age at clinic was 25 years (range 1-83 years). Mean age at symptom onset (n=172) was 2.8 years. Median age at genetic diagnosis (n=174) was 8.4 years. Median age at treatment initiation (n=169) was 5 years. Total QMG score (n=132) was median 12/39 (range 0-34), in AChR deficiency-13 (range 3-34), DOK7-10 (range 0-29), RAPSN-8 (range 2-17). MG-ADL score (n=174), median 5/24 (range 0-20), in AChR deficiency-5 (range 0-18), DOK7-7 (range 0-14), RAPSN-3.5 (range 0-10) and STS1M (n=146), median-22 (range 0-50), AChR deficiency-21.5(range 0-38), DOK7-17.5 (range 4-45) and RAPSN-25 (range 9-50). This is the largest reported CMS cohort including genetics, clinical data, and standardised outcome measures. Significant variability in the outcome measures was noted within individual CMS subtypes. This highlights the wide spectrum but also provides pivotal information for clinical trial designs. STS1M was identified as a robust easy deliverable outcome measure of fatigable weakness across all ages. [ABSTRACT FROM AUTHOR]

Published
2024
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45. 04INV Acquired muscle disorders - a paediatric perspective.

Author

Ramdas, S.

Subjects
*YOUNG adults, *DELAYED diagnosis, *SYMPTOMS, *TREATMENT delay (Medicine), *DERMATOMYOSITIS, *POLYMYOSITIS
Abstract

Acquired muscle disorders comprise of a heterogenous group of treatable infectious or inflammatory disorders. Outside the benign self-limiting viral myositis, the most common acquired muscle disorders are Immune mediated myopathies (IIMs) which include juvenile dermatomyositis, juvenile polymyositis and immune-mediated necrotising myopathy. IIMs are rare in paediatric cohorts with an annual incidence of 1.6- 4 cases/million children compared to adult incidence of 0.2-2/100,000 person years, leading to diagnostic delay including misdiagnosis as genetic or para-infectious muscle disorders and consequently morbidity and mortality due to treatment delay. The talk will cover the pathophysiology mechanisms, clinical presentations, current and emerging treatment strategies in management of paediatric acquired muscle disorders focusing particularly on the nuances of the issues which are pertinent to children and young people compared to adults. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Author

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, Novo S, Krum H, Varigos J, Siostrzonek P, Sinnaeve P, Gotcheva N, Yong H, Urina-Triana M, Milicic D, Vettus R, Manolis AJ, Wyss F, Sigurdsson A, Fucili A, Veze I, Petrauskiene B, Salvador L, Klemsdal TO, Medina F, Budaj A, Otasevic P, Lainscak M, Seung KB, Commerford P, Donath M, Hwang JJ, Kultursay H, Bilazarian S, East C, Forgosh L, Harris B, Ligueros M, Bohula E, Charmarthi B, Cheng S, Chou S, Danik J, McMahon G, Maron B, Ning M, Olenchock B, Pande R, Perlstein T, Pradhan A, Rost N, Singhal A, Taqueti V, Wei N, Burris H, Cioffi A, Dalseg AM, Ghosh N, Gralow J, Mayer T, Rugo H, Fowler V, Limaye AP, Cosgrove S, Levine D, Lopes R, Scott J, Hilkert R, Tamesby G, Mickel C, Manning B, Woelcke J, Tan M, Manfreda S, Ponce T, Kam J, Saini R, Banker K, Salko T, Nandy P, Tawfik R, O’Neil G, Manne S, Jirvankar P, Lal S, Nema D, Jose J, Collins R, Bailey K, Blumenthal R, Colhoun H, Gersh B, Abreu M, Actis MV, Aiub J, Aiub F, Albisu J, Alvarisqueta A, Avalos V, Barreto M, Berli MA, Blumberg C, Bocanera M, Botta C, Bowen L, Budassi N, Buhlman S, Westberg JC, Carabajal T, Caruso G, Casala J, Cendali G, Coloma G, Berra FC, Cuneo C, Degennaro N, Dellasa M, Diaz M, Dos Santos P, Espinosa V, Facello A, Facello M, Farias E, Fernandez AA, Ferrari V, Pacora FF, Flores GS, Franco M, Gabito A, Viola HG, Garcia F, Garcia Duran R, Garcia Pinna J, Glenny J, Godoy Sanchez M, Grosse A, Guzman P, Hasbani E, Hominal M, Ibañez J, Jure H, Jure D, Vico ML, Liniado G, Luciardi H, Luquez H, Maehara G, Maffei L, Majul C, Mallagray M, Marinaro S, Martinez J, Massaccesi R, De Los Milagros Had M, Azize GM, Montana O, Montenegro E, Morell Y, Muntaner J, Navarrete S, Olmedo M, Paganini M, Paz S, Perez Manghi F, Piskorz D, Polato C, Recoaro R, Romano A, Salinger M, Sanchez A, Saravia MA, Sarjanovich R, Scaro G, Schiavi LB, Soler J, Tinnirello V, Tomassi A, Valle M, Vallejo MA, Venturini C, Marcela Wenetz LM, Yossen M, Zaidman C, Zalazar L, Zangroniz P, Amerena J, Brady L, Colquhoun D, Eccleston D, Ferreira-Jardim A, French J, Jayasinghe R, Mcintosh C, Ord M, Plotz M, Purnell P, Roberts-Thomson P, Schultz C, Shanahan T, Tan R, Taverner P, Turner F, Vibert J, Vorster M, William M, Youssef G, Bergler-Klein J, Brath H, Brodmann M, Fliesser-Goerzer E, Haider K, Heeren G, Hiden C, Mandic L, Paulweber B, Ploechl A, Prenner A, Steringer-Mascherbauer R, Strohner-Kaestenbauer H, Barbato E, Bouvy C, Briké C, Charlier F, Cools F, De Knijf K, De Wolf L, Delforge M, Deweerdt N, Gits F, Goffinet C, Hermans K, Hollanders G, Mestdagh I, Pirenne B, Servaes V, Simons N, Tahon S, Theunissen E, Van Genechten G, Vervoort G, Vissers C, Vranckx P, Vrolix M, Abib E Jr, Abrantes J, Araujo Fonseca M, Barbosa E, Barroso W, Barroso A, Bodanese L, Botelho R, Costa Amorim R, Da Costa F, Da Silva A, Da Silva O Jr, Da Silva D Jr, Ferreira Dos Santos T, Dos Santos F, Dos Santos A, Duda N, Feitosa G, Felario Junior GA, Ferraz R, Filho P, Fonseca A, Wanderley FF, Freitas E, Fucci F, Marengo Garcia De Carvalho L, Hernandez M, Hettwer Magedanz E, Julião K, Kormann A, Lameira A, Lima F, Lino E, Maia L, Manenti E, Marchi AL, Fischer SM, Michalaros Y, Moraes J Jr, Moreira L, Pagnan M, Pesce F, Pinheiro L, Rassi S, Reis G, Reis H, Resende I, Roel A, Ruschel K, Saporito W, Saraiva JF, Seroqui M, Silva R, Unterkircher B, Vicente C, Vieira N, Xavier JP, Zucchetti C, Angelova I, Dimitrov G, Genova D, Gospodinov K, Goudev A, Grigorova V, Hristova K, Makedonska JJ, Katova T, Kostov K, Lazov P, Manov E, Manukov I, Manukov D, Milanova M, Kabakchieva VM, Petrov D, Petrusheva T, Pramatarova I, Raev D, Runev N, Sirakova-Taseva A, Tisheva-Gospodinova S, Todorova A, Tzekova M, Yakovova S, Yanev T, Abulencia K, Arora S, Baker A, Bata IR, Beaudry M, Belle Isle J, Bilodeau N, Boivin MC, Bolduc H, Bourgeois S, Brons S, Cantor W, Chaussé I, Chhabra A, Chouinard G, Cleveland T, Dattani D, Deslongchamps F, Diodati J, Drouin K, Duchesne L, Fontaine S, d'Amours DG, Gervais B, Gosselin G, Graham J, Grover A, Gupta A, Haldane H, Hartleib M, Hickey L, Huynh T, Johnston J, Julien VE, Lachance P, Lake J, Lamontagne C, Lauzon C, Lepage S, Maheux K, Manyari D, Martin E, McPherson C, Mehta S, Michaud N, Kouz SM, Murphy G, OKeefe D, Otis R, Ouimet F, Pandey S, Peck C, Perkins L, Richert L, Robbins K, Robinson S, Cabau JR, Ross B, Roy C, Roy M, Roy A, Rupka D, Affaki GS, Saunders K, Savard D, Soucy D, St Amour E, Thiessen S, Vertes G, Vezina M, Vincelli G, Weisnagel SJ, Zadra R, Chen J, Chen Y, Dong X, Feng Y, Feng Z, Fu G, Han B, Hao Y, He Y, He Z, Hong T, Jia Z, Jiang T, Jiang J, Jiang X, Ke Y, Li Y, Li Z, Li W, Li X, Liu P, Liu Y, Liu B, Liu S, Liu L, Lu Z, Lv Y, Ma C, Ma G, Peng L, Qing L, Ren L, Sang X, Song M, Sun Z, Wang J, Wang Y, Wei J, Wu W, Wu J, Xu H, Yan J, Yang P, Yang K, Yao Z, Yaoqing H, Yuan Z, Zhai Z, Zhang J, Zhang Y, Zhao R, Zhou H, Accini Mendoza JL, Aparicio CV, Castillo T, Chaverra I, Conrado Y, Coronel J, Cotes C, Cuentas I, Cuervo A, Dussan MA, Echeverria L, Hernandez E, Ibarra J, Isaza D, Jimenez D, Lopez P, Manzur F, Mejia I, Mendoza Y, Molina DI, Patino JM, Rodriguez D, Rodriguez LM, Rodriguez SM, Sanchez Vallejo G, Luz Serrano H, Sotomayor A, Urina M, Vesga B, Yupanqui H, Akrap B, Busic N, Ciglenecki N, Cmrecnjak J, Fucak E, Gabor M, Jeric M, Jutrisa N, Kordic K, Planinc I, Popovic Z, Radeljic V, Sesto I, Sutalo K, Tusek S, Belohlavek J, Budkova J, Busak L, Capova L, Cech V, Cermak O, Coufalova Z, Cyprian R, Dedek V, Dedkova S, Ferkl R, Hanak P, Hanustiakova A, Homza M, Horackova K, Houra M, Iveta H, Kaiserova L, Kala P, Karel I, Kellnerova I, Koleckar P, Kreckova M, Krupicka J, Lorenc Z, Machova V, Malik J, Masarikova L, Matyasek I, Mikus M, Mikusova T, Ondrasik J, Otava M, Palubova L, Pavlickova L, Peterka M, Petrova I, Pokorna B, Povolny P, Radvan M, Reznakova S, Rickova Z, Roszkowska P, Rotreklova M, Samkova D, Skalicka H, Slechticka A, Sternthal P, Telekes P, Tesak M, Vesely P, Vesely J, Vins P, Vitovec M, Vodnansky P, Zidova M, Keba E, Laane E, Pool T, Randvee L, Ratnik E, Reimand M, Reinmets S, Rivis L, Siemann M, Stern M, Toom M, Vahula V, Apel T, Axthelm C, Ayasse D, Ayasse M, Baar M, Baeumer A, Bagi ES, Becker B, Binder A, Blankenberg S, Braun P, Johansen BB, Contzen C, Delfonso F, Denecke C, Dengler T, Donaubauer T, Eichinger G, Englmann E, Erhard M, Faghih M, Foerster A, Frankenstein L, Fuchs R, Furch G, Gaeb-Strasas B, Germann H, Giese C, Goette A, Gravenhorst-Muenter U, Haege R, Haenel T, Hagemann D, Hagenow A, Hanefeld M, Heider J, Heisters J, Hennig D, Hielscher S, Himpel-Boenninghoff A, Holscher A, Hornig M, Jeserich M, Kaczmarek N, Kanitz S, Kara YD, Khariouzov A, Kiefer R, Kiroglu K, Klamm M, Klein C, Korth-Wiemann B, Krapivsky A, Kuenzler J, Kuntzsch A, Landers B, Lappo M, Laube S, Leggewie S, Lehmann D, Lepp H, Lierse T, Lindner C, Luecke-Uzar M, Luedemann J, Marschke T, Maruzzo S, Mauersberger K, Maus O, Meinrich M, Meissner A, Moehring B, Muehlhaus J, Mueller S, Muenter KC, Muenzel T, Naumann R, Nebel J, Neumann J, Nuding S, Overhoff U, Papke B, Pencz I, Peter Y, Peukert AM, Radde I, Rau T, Regner S, Reichenbach D, Reimer D, Rinke A, Roettges R, Romanski A, Rummel R, Samer H, Sanuri M, Sarnighausen HE, Schäfer B, Scheibner T, Schermaul KH, Schindler A, Schlundt C, Schmidt E, Schmidt K, Schnabel A, Schoen N, Schorn K, Schroeder T, Schulenburg D, Schulz M, Schulze U, Schulze J, Schumacher M, Schwerin G, Schwerin M, Stadelmeier S, Stahl HD, Stahl A, Stockhausen J, Stockhausen G, Stoessel J, Stolze K, Stratmann M, Szymanowski N, Teschner AB, Teske A, Uecker C, Veit S, Voeller H, Walter I, Walter J, Walther I, Weber HG, Weimer J, Wichterich K, Wiebusch A, Willmerdinger M, Willner C, Winkelmann B, Winkler J, Wistuba T, Woehrle J, Wohnlich T, Wolf S, Woyczak D, Wrage P, Zirlik A, Anadiotis A, Chachalis G, Dermitzakis A, Kafarakis P, Kaldara E, Kolokathis F, Kostakou P, Lekakis J, Manolis A, Mantas I, Megalou A, Milkas A, Nanas J, Olympios CD, Patsilinakos S, Perperis A, Poulimenos L, Saloustros I, Tsioufis K, Tsorbatzoglou K, Vardas P, Zarifis I, Aguilar M, Arango JL, Borrayo NA, Corona V, Guerrero A, Guzman I, Haase F, De Krumbach L, Montenegro P, Munoz R, Munoz N, Paniagua A, Solares A, Vogel M, Anita S, Blazsek Z, Decsi K, Fulop T, Hangyal T, Hegedus V, Kalina A, Karakai H, Katona A, Kiss RG, Kovacs A, Laszlo Z, Lupkovics G, Medvegy M, Merkely B, Mihaly N, Nagy AC, Dékány JN, Nikoletta P, Noori E, Penzes J, Poor F, Sarszegi Z, Simay A, Simon J, Szakal I, Szatmarine V, Szocs A, Zilahi Z, Karsai XZ, Andersen K, Sigurdadottir E, Skuladottir F, Abdullakutty J, Abhaichand R, Abhyankar A, Agarwal DK, Aggarwal RK, Ahire N, Awasthi AK, Babu R, Bai A, Bali HK, Banker D, Bhadade S, Bisne V, Bohra P, Raghu C, Chauhan D, Chauhan H, Chavada J, Chaware G, Chella S, Chintala P, Dash D, Desai D, Devasia T, Dhanak R, Dobariya H, Dudhatra N, Duhan S, Fulwani M, Ghondale N, Ghosh S, Gohel P, Govindaraj D, Goyal B, Goyal S, Gundala AK, Gupta M, Hardas S, Iby M, Jagtap P, Jain A, Joshi U, Karpuram M, Kaur H, Khan A, Khan R, Kodem DR, Koeitti P, Kulkarni L, Kullal P, Kumar KS, Kumbla M, Latheef K, Lohkare M, Santosh MJ, Makhe B, Mandati M, Mehta A, Minocha G, Mittal A, Modi R, Mohan K, Oomman A, Pai R, Pai V, Palaniswami N, Pansheriya A, Parekh N, Patel J, Patel R, Patole T, Praveen M, Radhakrishnan V, Rajan B A, Rajasekhar D, Rao M, Rao MB, Rao NM, Rathnavel S, Rathore A, Rathore SRS, Rawat S, Reddy NC, Sarma R, Sathe S, Shah J, Shaikh P, Sharma K, Sharma S, Sharma T, Shetty P, Sidhu G, Singh V, Sohi GS, Srinath VS, Raju SS, Taran A, Thakkar B, Velusamy K, Vijan V, Vora V, Vuriya AK, Agosta GF, Antonicelli R, Ardissino D, Argiolas G, Baldin MG, Benedetti G, Berti S, Bevilacqua MT, Bolognesi MG, Dessalvi CC, Calabrese A, Campanale EG, Candusso R, Caso P, Cosmi F, Crea F, Crocamo A, De Caterina R, De Rosa S, Destro M, Di Biase M, Dognini GP, Eleuteri E, Fedele F, Ferrario M, Gabrielli D, Gamba C, Ganau A, Gravellone M, Iannopollo G, Indolfi C, Infusino F, Invitti C, Landolfi A, Lembo G, Liberato NL, Mannucci E, Marino P, Mariottoni B, Marziali A, Mercuro G, Monti L, Mos L, Mureddu V, Musumeci MB, Panzarino C, Parente A, Perotti M, Filardi PP, Petrillo C, Piatti P, Priori S, Racca V, Ragghianti B, Renda G, Righini V, Sarcone M, Senni M, Soro E, Tamburrini P, Vallone L, Villani GQ, Volpe M, Ajioka M, Akai Y, Ashino K, Baden M, Doi M, Eki Y, Endo T, Fukuike C, Hagiwara Y, Hasegawa K, Higuchi Y, Higuchi T, Hioki M, Hirayama A, Hiroma J, Hosokawa S, Ichisawa M, Iijima T, Inada T, Inagaki M, Ito K, Kaigawa K, Kajihara S, Kamiya H, Kamiya J, Kaneno Y, Katahira K, Kataoka M, Kawai M, Kawasaki T, Kojima E, Komura Y, Kuramochi T, Kuruma T, Kyo E, Mani H, Miyamoto T, Morii I, Morinaga Y, Morisawa T, Nagai Y, Naka T, Nakamura Y, Nakamura S, Nakayoshi K, Nishibe A, Ogawa M, Okada Y, Okawa M, Sakamoto Y, Sakurada M, Sasaki S, Seki S, Shimomura H, Shinozaki T, Sugimoto N, Suzuki A, Taguchi S, Takahashi J, Takase S, Tanabe K, Tanaka A, Tani S, Tomioka J, Tsuboi H, Tsuji M, Tsujita K, Tsujiyama S, Umesu A, Yamada T, Yamaguchi E, Yamamoto H, Yamamoto T, Yamane M, Yanase T, Yasuoka S, Yasutake M, Yokoyama M, Yoshida M, Yoshimoto E, Yunoki C, Balode A, Dormidontova G, Flaksa I, Nagele-Luse I, Rancane G, Sime I, Bartuseviciene S, Cepinskiene L, Dobilas V, Grigaraviciene I, Marcinkeviciene J, Mazutavicius R, Miliuniene R, Motiejuniene R, Norkiene S, Norkute-Macijauske U, Rudys A, Slapikas R, Stonkute K, Strazdiene D, Tijuneliene E, Urbonas G, Vanagiene S, Viezelis M, Arenas Leon JL, Bayram E, Carrillo J, Davalos C, De Los Rios M, Delgadillo T, Hernández N, Leon S, Mendoza N, Muñoz W, Ramos G, Anneveldt A, Bakker H, Brouwer M, Bunschoten P, De Boer 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A, Pagett K, Pogson A, Price R, Price D, Procter K, Pye M, Redfearn H, Rewbury J, Ryding A, Sattar N, Sharp A, Shaw P, Simpson H, Smith W, Squire I, Storey R, Teenan M, Thomas H, Townend J, Trevelyan J, Wakeling J, Walukiewicz P, Wilkinson S, Zaman A, Acevedo L, Benton J, Abbate A, Aboufakher R, Acampora M, Acampora D, Aceto L, Acevedo B, Acheatel R, Adams M, Adams A, Ahmad I, Ahmed SH, Aish B, Akyea-Djamson A, Al Joundi T, Alcide P, Alfieri A, Alfonso T, Alfrey A, Allen J, Alllison DC, Almaliky T, Amos A, Angiolillo D, Antolick A, Ara M, Aragorn L, Arevalo S, Armas E, Arthur A, Asafu-Adjaye N, Ashcom T, Ashford M, Aslam A, Ather N, Atieh M, Aull L, Ayala M, Azizad M, Backer T, Baehl S, Bailey S, Bair S, Baker C, Ballmajo M, Pieretti HB, Baquero A, Barnett S, Baron S, Bartkowiak A, Bashir K, Beall K, Beauregard LA, Sarah S, Beckett L, Belejchak P, Bendelow T, Bender D, Benjamin S, Berdoff R, Berger V, Bergeron P, Berk M, Bernstein M, Binns Y, Bitzer V, Blahey M, Bloch S, Bluemel J, Boffetti P, Boley K, Bonner J, Boudreaux R, Boulanger K, Bradley A, Bramlet D, Bredlau C, Briggs S, Brousalis L, Brown S, Brown C, Buchannan C, Burke W, Burley T, Burton C, Burtt D, Byars W, Caballero-Valiente B, Carr K, Halliwell TC, Castillo J, Cei L, Cerda L, Chambers J, Chamblee T, Chattin W, Chee L, Chen YC, Cherlin R, Cheung D, Chiodi L, Christensen L, Christenson S, Cislowski D, Clavier-Firmin C, Colfer H, Colvin T, Cosgrove N, Covert C, Cox B, Cox R, Craig W, Crandall L, Crepps K, Cromer M, Cruz H, Cruz H, Cruz M, Cucher F, Damron M, Dave K, Dave B, Davis M, Davis B, Dawkins-Hughes S, Dean J, Debnam S, Defosse C, Dehning M, Dela Llana A, Dellorso M, Denham D, Desalle D, Dettmer M, Dhawan M, Diago M, Dicken T, Diederich C, Diederich M, Diehl R, Digangi D, Diller P, Dimattia M, Dodds G, Doggett J, Donahue K, Doughty L, Dragutksy B, Dreese M, Dunhurst F, Dunn D, Dutka C, Earl J, Eaton C, Eaves W, Ebeling K, Eder F, Edgerton L, Edillo C, Edwards J, Edwards T, Einhorn D, El Hafi S, 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Hodnett P, Hoffman M, Hogan C, Holmes Z, Rees DH, Hotchkiss D, Huang P, Humbert J, Hutchens E, Iachini K, Ibarra M, Igbokidi O, Ilahi T, Imbrognio M, Ipp E, Iteld B, Jacques G, Jafri A, Jafry B, Jardula M, Jefferson D, Jenkins R, Johnson E, Johnson J, Jones S, Kawahara M, Kelehan S, Kelly R, Kendall T, Kereiakes D, Khan M, Khan S, Kick J, Kimmel M, King T, King A, Kirkland S, Kissel S, Kitchens D, Klein P, Klugherz B, Korban E, Koren M, Korte M, Kostis J, Kotek L, Kozak M, Kreutter F, Kusnick B, Labovitz R, Lail J, Lamance J, Lamas G, Lambert J, Lambert C, Landzberg J, Langdon J, Lavoie W, Ledger G, Lee T, Lee K, Lehman R, Leimbach W, Lennard M, Lepor N, Lester F, Levin P, Levinson L, Lewis D, Lillo J, Link L, Long C, Longaker R, Lorch G, Lucksinger G, Lynd S, Rhudy JM, Madder R, Magness K, Maheshwari A, Alan A, Malek M, Maletz L, Malhotra V, Malhotra S, Mandviwala M, Mani CK, Manuel J, Marchelletta N, Marshall L, Marsters M, Martin L, Martinez E, Mavromatis K, Maynard R, Mays M, Mays B, Mbulaiteye A, Mcalister R, Mccoy C, Mccrary D Jr, Mccullough-O'Brien H, Mcdonald M, Mcgill J, Mcgrew F, Mckenzie C, Mclaurin B, Mclellan BA, Mcneil D, Mcneill R, Mehrle A, Melbie K, Melliza T, Messina T, Meyer R, Michel K, Mikdadi G, Miller C, Miller R, Miller A, Miller G, Miller W, Mitchell J, Moats DJR, Mody F, Moffat J, Molk B, Molter D, Monroe T, Montero H, Montgomery R, Mookherjee D, Moran J, Moriarty P, Morrison J, Morton D, Moshayedi P, Mosley J, Moustafa M, Munshi K, Murray A, Mustafa J, Nadar V, Naidu R, Nalley J, Navy S, Neil L, Neutel JM, Niblack P, Nicely V, Nicolai M, Nijmeh G, Nikas A, Nikyar A, Nixon S, Norman L, Noto G, Nour K, Nugent A, Ocman B, Odegard A, Olsen S, Ortiz-Carrasquillo R, Ossino N, Paez H, Palchick B, Paliwal Y, Pannell R, Parfait V, Partridge J, Patel B, Patel R, Patel M, Patel S, Paysor C, Pena A, Pereira S, Perez M, Perez A, Perkins H, Perry B, Peters P, Phillippi C, Phillips A, Phillips A, Piacente R, Pintado M, Pish R, Pitt W, Poling T, Pomposini 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M., Everett, B. M., Thuren, T., Macfadyen, J. G., Chang, W. H., Ballantyne, C., FONSECA E PIRES, CARLOS EDUARDO, Nicolau, J., Koenig, W., Anker, S. D., Kastelein, J. J. P., Cornel, J. H., Pais, P., Pella, D., Genest, J., Cifkova, R., Lorenzatti, A., Forster, T., Kobalava, Z., Vida-Simiti, L., Flather, M., Shimokawa, H., Ogawa, H., Dellborg, M., Rossi, P. R. F., Troquay, R. P. T., Libby, P., Glynn R., J, CANTOS Trial, Group, Perrone, Filardi, P, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes

Subjects
0301 basic medicine, 030204 cardiovascular system & hematology, law.invention, 0302 clinical medicine, c-reactive protein, Randomized controlled trial, law, Cardiovascular Disease, middle aged, double-blind method, antibodies, Myocardial infarction, humans, Stroke, interleukin-1beta, biology, Antibodies, Monoclonal, drug, General Medicine, Lipid, Aged, anti-inflammatory agents, monoclonal, humanized, atherosclerosis, cardiovascular diseases, dose-response relationship, female, incidence, infections, lipids, male, myocardial infarction, neutropenia, secondary prevention, stroke, Anti-Inflammatory Agent, aged, Editorial, Atherosclerosi, Monoclonal, Human, medicine.drug, medicine.medical_specialty, Neutropenia, Antibodies, Monoclonal, Humanized, Infections, Placebo, antibodies, monoclonal, dose-response relationship, drug, infection, medicine (all), 03 medical and health sciences, Internal medicine, medicine, Dose-Response Relationship, Drug, business.industry, Antiinflammatory Therapy, Canakinumab, for Atherosclerotic Disease, C-reactive protein, medicine.disease, Surgery, Canakinumab, 030104 developmental biology, biology.protein, business
Abstract

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.)

Published
2017
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