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1. Lessons from PROMINENT and prospects for pemafibrate

Author

Jean-Charles Fruchart, Jamila Fruchart-Najib, Shizuya Yamashita, Peter Libby, Koutaro Yokote, Tatsuhiko Kodama, Yohei Tomita, Paul M. Ridker, Michel P. Hermans, and Alberto Zambon

Subjects
PROMINENT trial, Pemafibrate, Type 2 diabetes mellitus, Diabetic retinopathy, Peripheral artery disease, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract The neutral result of the PROMINENT trial has led to questions about the future for pemafibrate. This commentary discusses possible reasons for the lack of benefit observed in the trial. There were, however, indicators suggesting therapeutic potential in microvascular ischaemic complications associated with peripheral artery disease, with subsequent analysis showing reduction in the incidence of lower extremity ischaemic ulceration or gangrene. Reassurance about the safety of pemafibrate, together with emerging data from PROMINENT and experimental studies, also suggest benefit with pemafibrate in non-alcoholic fatty liver disease (alternatively referred to as metabolic dysfunction-associated steatotic liver disease) and microangiopathy associated with diabetes, which merit further study.

Published
2024
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2. Interleukin-6 and Cardiovascular Events in Healthy Adults

Author

Muhammad Shahzeb Khan, MD, MSc, Khawaja M. Talha, MBBS, Muhammad Haisum Maqsood, MD, Jennifer A. Rymer, MD, MBA, Barry A. Borlaug, MD, Kieran F. Docherty, MD, Ambarish Pandey, MD, Florian Kahles, MD, Maja Cikes, MD, Carolyn S.P. Lam, MD, Anique Ducharme, MD, Adrian A. Voors, MD, Adrian F. Hernandez, MD, A. Michael Lincoff, MD, Mark C. Petrie, MD, Paul M. Ridker, MD, MPH, and Marat Fudim, MD, MHS

Subjects
cardiovascular disease, ethnicity, inflammation, interleukin-6, population, race, Diseases of the circulatory (Cardiovascular) system, RC666-701, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Background: Elevated interleukin (IL)-6 levels have been linked to adverse outcomes in patients with and without baseline cardiovascular disease (CVD). Objectives: The purpose of this study was to examine the association between circulating IL-6 levels and CVD events without baseline CVD across racial and ethnic groups. Methods: We conducted an observational analysis utilizing the MESA (Multi-Ethnic Study of Atherosclerosis), a multicenter, prospective community-based study of CVD at baseline from four racial and ethnic groups. IL-6 levels were measured at the time of enrollment (visit 1) and were divided into 3 terciles. Patient baseline characteristics and outcomes, including all-cause mortality, CV mortality, heart failure, and non-CV mortality, were included. Cox proportional hazard regression models were used to assess associations between IL-6 levels and study outcomes with IL-6 tercile 1 as reference. Results: Of 6,622 individuals, over half were women (53%) with a median age of 62 (IQR: 53-70) years. Racial and ethnic composition was non-Hispanic White (39%) followed by African American (27%), Hispanic (22%), and Chinese American (12%). Compared to tercile 1, participants with IL-6 tercile 3 had a higher adjusted risk of and all-cause mortality (HR: 1.98 [95% CI: 1.67-2.36]), CV mortality (HR: 1.55 [95% CI: 1.05-2.30]), non-CV mortality (HR: 2.05 [95% CI: 1.65-2.56]), and heart failure (HR: 1.48 [95% CI: 0.99-2.19]). When tested as a continuous variable, higher levels of IL-6 were associated with an increased risk of all individual outcomes. Compared to non-Hispanic White participants, the unadjusted and adjusted risk of all outcomes across all races and ethnicities was similar across all IL-6 terciles. Conclusions: High levels of circulating IL-6 are associated with worse CV outcomes and increased all-cause mortality consistently across all racial and ethnic groups.

Published
2024
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3. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Rosalie B. T. M. Sterenborg, Inga Steinbrenner, Yong Li, Melissa N. Bujnis, Tatsuhiko Naito, Eirini Marouli, Tessel E. Galesloot, Oladapo Babajide, Laura Andreasen, Arne Astrup, Bjørn Olav Åsvold, Stefania Bandinelli, Marian Beekman, John P. Beilby, Jette Bork-Jensen, Thibaud Boutin, Jennifer A. Brody, Suzanne J. Brown, Ben Brumpton, Purdey J. Campbell, Anne R. Cappola, Graziano Ceresini, Layal Chaker, Daniel I. Chasman, Maria Pina Concas, Rodrigo Coutinho de Almeida, Simone M. Cross, Francesco Cucca, Ian J. Deary, Alisa Devedzic Kjaergaard, Justin B. Echouffo Tcheugui, Christina Ellervik, Johan G. Eriksson, Luigi Ferrucci, Jan Freudenberg, GHS DiscovEHR, Regeneron Genetics Center, Christian Fuchsberger, Christian Gieger, Franco Giulianini, Martin Gögele, Sarah E. Graham, Niels Grarup, Ivana Gunjača, Torben Hansen, Barbara N. Harding, Sarah E. Harris, Stig Haunsø, Caroline Hayward, Jennie Hui, Till Ittermann, J. Wouter Jukema, Eero Kajantie, Jørgen K. Kanters, Line L. Kårhus, Lambertus A. L. M. Kiemeney, Margreet Kloppenburg, Brigitte Kühnel, Jari Lahti, Claudia Langenberg, Bruno Lapauw, Graham Leese, Shuo Li, David C. M. Liewald, Allan Linneberg, Jesus V. T. Lominchar, Jian’an Luan, Nicholas G. Martin, Antonela Matana, Marcel E. Meima, Thomas Meitinger, Ingrid Meulenbelt, Braxton D. Mitchell, Line T. Møllehave, Samia Mora, Silvia Naitza, Matthias Nauck, Romana T. Netea-Maier, Raymond Noordam, Casia Nursyifa, Yukinori Okada, Stefano Onano, Areti Papadopoulou, Colin N. A. Palmer, Cristian Pattaro, Oluf Pedersen, Annette Peters, Maik Pietzner, Ozren Polašek, Peter P. Pramstaller, Bruce M. Psaty, Ante Punda, Debashree Ray, Paul Redmond, J. Brent Richards, Paul M. Ridker, Tom C. Russ, Kathleen A. Ryan, Morten Salling Olesen, Ulla T. Schultheiss, Elizabeth Selvin, Moneeza K. Siddiqui, Carlo Sidore, P. Eline Slagboom, Thorkild I. A. Sørensen, Enrique Soto-Pedre, Tim D. Spector, Beatrice Spedicati, Sundararajan Srinivasan, John M. Starr, David J. Stott, Toshiko Tanaka, Vesela Torlak, Stella Trompet, Johanna Tuhkanen, André G. Uitterlinden, Erik B. van den Akker, Tibbert van den Eynde, Melanie M. van der Klauw, Diana van Heemst, Charlotte Verroken, W. Edward Visser, Dina Vojinovic, Henry Völzke, Melanie Waldenberger, John P. Walsh, Nicholas J. Wareham, Stefan Weiss, Cristen J. Willer, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Hanneke J. C. M. Wouters, Margaret J. Wright, Qiong Yang, Tatijana Zemunik, Wei Zhou, Gu Zhu, Sebastian Zöllner, Johannes W. A. Smit, Robin P. Peeters, Anna Köttgen, Alexander Teumer, and Marco Medici

Subjects
Science
Abstract

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Published
2024
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4. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Author

Markus Scholz, Katrin Horn, Janne Pott, Matthias Wuttke, Andreas Kühnapfel, M. Kamal Nasr, Holger Kirsten, Yong Li, Anselm Hoppmann, Mathias Gorski, Sahar Ghasemi, Man Li, Adrienne Tin, Jin-Fang Chai, Massimiliano Cocca, Judy Wang, Teresa Nutile, Masato Akiyama, Bjørn Olav Åsvold, Nisha Bansal, Mary L. Biggs, Thibaud Boutin, Hermann Brenner, Ben Brumpton, Ralph Burkhardt, Jianwen Cai, Archie Campbell, Harry Campbell, John Chalmers, Daniel I. Chasman, Miao Ling Chee, Miao Li Chee, Xu Chen, Ching-Yu Cheng, Renata Cifkova, Martha Daviglus, Graciela Delgado, Katalin Dittrich, Todd L. Edwards, Karlhans Endlich, J. Michael Gaziano, Ayush Giri, Franco Giulianini, Scott D. Gordon, Daniel F. Gudbjartsson, Stein Hallan, Pavel Hamet, Catharina A. Hartman, Caroline Hayward, Iris M. Heid, Jacklyn N. Hellwege, Bernd Holleczek, Hilma Holm, Nina Hutri-Kähönen, Kristian Hveem, Berend Isermann, Jost B. Jonas, Peter K. Joshi, Yoichiro Kamatani, Masahiro Kanai, Mika Kastarinen, Chiea Chuen Khor, Wieland Kiess, Marcus E. Kleber, Antje Körner, Peter Kovacs, Alena Krajcoviechova, Holly Kramer, Bernhard K. Krämer, Mikko Kuokkanen, Mika Kähönen, Leslie A. Lange, James P. Lash, Terho Lehtimäki, Hengtong Li, Bridget M. Lin, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Patrik K. E. Magnusson, Nicholas G. Martin, Koichi Matsuda, Yuri Milaneschi, Pashupati P. Mishra, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Winfried März, Matthias Nauck, Kjell Nikus, Ilja M. Nolte, Raymond Noordam, Yukinori Okada, Isleifur Olafsson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Markus Perola, Nicola Pirastu, Ozren Polasek, David J. Porteous, Tanja Poulain, Bruce M. Psaty, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Humaira Rasheed, Dermot F. Reilly, Kenneth M. Rice, Anne Richmond, Paul M. Ridker, Jerome I. Rotter, Igor Rudan, Charumathi Sabanayagam, Veikko Salomaa, Neil Schneiderman, Ben Schöttker, Mario Sims, Harold Snieder, Klaus J. Stark, Kari Stefansson, Hannah Stocker, Michael Stumvoll, Patrick Sulem, Gardar Sveinbjornsson, Per O. Svensson, E-Shyong Tai, Kent D. Taylor, Bamidele O. Tayo, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Laurent F. Thomas, Johanne Tremblay, Anke Tönjes, Peter J. van der Most, Veronique Vitart, Uwe Völker, Ya Xing Wang, Chaolong Wang, Wen Bin Wei, John B. Whitfield, Sarah H. Wild, James F. Wilson, Thomas W. Winkler, Tien-Yin Wong, Mark Woodward, Xueling Sim, Audrey Y. Chu, Mary F. Feitosa, Unnur Thorsteinsdottir, Adriana M. Hung, Alexander Teumer, Nora Franceschini, Afshin Parsa, Anna Köttgen, Pascal Schlosser, and Cristian Pattaro

Subjects
Science
Abstract

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Published
2024
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5. Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial

Author

Joseph Bledsoe, Scott C. Woller, Maria Brooks, Frank C. Sciurba, Jerry A. Krishnan, Deborah Martin, Peter Hou, Janet Y. Lin, Andrei Kindzelski, Eileen Handberg, Bridget-Anne Kirwan, Elaine Zaharris, Lauren Castro, Nancy L. Shapiro, Carl J. Pepine, Sarah Majercik, Zhuxuan Fu, Yongqi Zhong, Vidya Venugopal, Yu-Hsuan Lai, Paul M. Ridker, and Jean M. Connors

Subjects
SARS-CoV-2, COVID-19, Pulmonary embolism, PE, Venous thromboembolic disease, VTE, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. Methods A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. Results Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p

Published
2023
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6. Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Author

Lisa de las Fuentes, Karen L. Schwander, Michael R. Brown, Amy R. Bentley, Thomas W. Winkler, Yun Ju Sung, Patricia B. Munroe, Clint L. Miller, Hugo Aschard, Stella Aslibekyan, Traci M. Bartz, Lawrence F. Bielak, Jin Fang Chai, Ching-Yu Cheng, Rajkumar Dorajoo, Mary F. Feitosa, Xiuqing Guo, Fernando P. Hartwig, Andrea Horimoto, Ivana Kolčić, Elise Lim, Yongmei Liu, Alisa K. Manning, Jonathan Marten, Solomon K. Musani, Raymond Noordam, Sandosh Padmanabhan, Tuomo Rankinen, Melissa A. Richard, Paul M. Ridker, Albert V. Smith, Dina Vojinovic, Alan B. Zonderman, Maris Alver, Mathilde Boissel, Kaare Christensen, Barry I. Freedman, Chuan Gao, Franco Giulianini, Sarah E. Harris, Meian He, Fang-Chi Hsu, Brigitte Kühnel, Federica Laguzzi, Xiaoyin Li, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Alaitz Poveda, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Tamar Sofer, Fumihiko Takeuchi, Bamidele O. Tayo, Peter J. van der Most, Niek Verweij, Erin B. Ware, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Yiqiang Zhan, Najaf Amin, Dan E. Arking, Christie Ballantyne, Eric Boerwinkle, Jennifer A. Brody, Ulrich Broeckel, Archie Campbell, Mickaël Canouil, Xiaoran Chai, Yii-Der Ida Chen, Xu Chen, Kumaraswamy Naidu Chitrala, Maria Pina Concas, Ulf de Faire, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ahn Do, Jessica D. Faul, Virginia Fisher, James S. Floyd, Terrence Forrester, Yechiel Friedlander, Giorgia Girotto, C. Charles Gu, Göran Hallmans, Sami Heikkinen, Chew-Kiat Heng, Georg Homuth, Steven Hunt, M. Arfan Ikram, David R. Jacobs, Maryam Kavousi, Chiea Chuen Khor, Tuomas O. Kilpeläinen, Woon-Puay Koh, Pirjo Komulainen, Carl D. Langefeld, Jingjing Liang, Kiang Liu, Jianjun Liu, Kurt Lohman, Reedik Mägi, Ani W. Manichaikul, Colin A. McKenzie, Thomas Meitinger, Yuri Milaneschi, Matthias Nauck, Christopher P. Nelson, Jeffrey R. O’Connell, Nicholette D. Palmer, Alexandre C. Pereira, Thomas Perls, Annette Peters, Ozren Polašek, Olli T. Raitakari, Kenneth Rice, Treva K. Rice, Stephen S. Rich, Charumathi Sabanayagam, Pamela J. Schreiner, Xiao-Ou Shu, Stephen Sidney, Mario Sims, Jennifer A. Smith, John M. Starr, Konstantin Strauch, E. Shyong Tai, Kent D. Taylor, Michael Y. Tsai, André G. Uitterlinden, Diana van Heemst, Melanie Waldenberger, Ya-Xing Wang, Wen-Bin Wei, Gregory Wilson, Deng Xuan, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Diane M. Becker, Amélie Bonnefond, Donald W. Bowden, Richard S. Cooper, Ian J. Deary, Jasmin Divers, Tõnu Esko, Paul W. Franks, Philippe Froguel, Christian Gieger, Jost B. Jonas, Norihiro Kato, Timo A. Lakka, Karin Leander, Terho Lehtimäki, Patrik K. E. Magnusson, Kari E. North, Ioanna Ntalla, Brenda Penninx, Nilesh J. Samani, Harold Snieder, Beatrice Spedicati, Pim van der Harst, Henry Völzke, Lynne E. Wagenknecht, David R. Weir, Mary K. Wojczynski, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Claude Bouchard, Daniel I. Chasman, Michele K. Evans, Ervin R. Fox, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Sharon L. R. Kardia, Jose Eduardo Krieger, Dennis O. Mook-Kanamori, Patricia A. Peyser, Michael M. Province, Bruce M. Psaty, Igor Rudan, Xueling Sim, Blair H. Smith, Rob M. van Dam, Cornelia M. van Duijn, Tien Yin Wong, Donna K. Arnett, Dabeeru C. Rao, James Gauderman, Ching-Ti Liu, Alanna C. Morrison, Jerome I. Rotter, and Myriam Fornage

Subjects
educational attainment, lipids, cholesterol, triglycerides, genome-wide association study, meta-analysis, Genetics, QH426-470
Abstract

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Published
2023
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7. Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization [version 1; peer review: 2 approved]

Author

Natasha H. J. Ng, Sara M. Willems, Jian'an Luan, Rebecca S. Fine, Juan Fernandez, Jennifer Wessel, Eleanor Wheeler, Gaelle Marenne, Hidetoshi Kitajima, Hanieh Yaghootkar, Xueling Sim, Ian J. Deary, Sai Chen, Shuai Wang, Yii-Der Ida Chen, Caroline Hayward, Yuning Chen, Jennifer L. Asimit, Claudia Langenberg, Tibor V. Varga, Archie Campbell, Rona J. Strawbridge, Shuang Feng, Tarunveer S. Ahluwalia, Erica L. Kleinbrink, Emil V. Appel, Ping An, Lawrence F. Bielak, Dan E. Arking, Jennifer A. Brody, Nathan A. Bihlmeyer, David Porteous, Ayse Demirkan, Audrey Y. Chu, Franco Giulianini, James S. Floyd, Stefan Gustafsson, Xiuqing Guo, Johanna Jakobsdottir, Anne U. Jackson, Stavroula Kanoni, Richard A. Jensen, Igor Rudan, Man Li, Sirkka Keinanen-Kiukaanniemi, Alisa K. Manning, Yingchang Lu, Karina Meidtner, Jonathan Marten, Giorgio Pistis, Taulant Muka, Kenneth M. Rice, Bram Prins, Albert Vernon Smith, Serena Sanna, Lorraine Southam, Jennifer A. Smith, Vinicius Tragante, Heather M. Stringham, Helen R. Warren, Sander W. van der Laan, Andrianos M. Yiorkas, Jie Yao, Wei Zhao, Weihua Zhang, Heather M. Highland, Mariaelisa Graff, Eirini Marouli, Anne E. Justice, Wesam A. Alhejily, Saima Afaq, Folkert W. Asselbergs, Najaf Amin, Michiel L. Bots, Lori L. Bonnycastle, Ji Chen, Ivan Brandslund, Abbas Dehghan, John Danesh, Tapani Ebeling, Jessica D. Faul, Aliki-Eleni Farmaki, Steve Franks, Paul W. Franks, Anette P. Gjesing, Andreas Fritsche, Göran Hallmans, Mark O. Goodarzi, Karl-Heinz Herzig, Tamara B. Harris, Min A Jhun, Marie-France Hivert, Marit E. Jørgensen, Torben Jørgensen, Eero Kajantie, Pekka Jousilahti, Sharon L.R. Kardia, Maria Karaleftheri, Heikki A. Koistinen, Leena Kinnunen, Peter Kovacs, Pirjo Komulainen, Markku Laakso, Johanna Kuusisto, Aaron Leong, Lenore J. Launer, Jocelyn E. Manning Fox, Jaana Lindström, Nisa M. Maruthur, Satu Männistö, Antonella Mulas, Leena Moilanen, Matthew Neville, Mike A. Nalls, Alison Pattie, James S. Pankow, Hannu Puolijoki, Eva R.B. Petersen, Paul Redmond, Asif Rasheed, Michael Roden, Frida Renström, Juha Saltevo, Danish Saleheen, Sylvain Sebert, Kai Savonen, Alena Stančáková, Kerrin S. Small, Konstantin Strauch, Jakob Stokholm, Betina H. Thuesen, Juha Auvinen, E-Shyong Tai, Emmanouil Tsafantakis, Anke Tönjes, Jaakko Tuomilehto, Tiinamaija Tuomi, Marja Vääräsmäki, Matti Uusitupa, Magdalena Zoledziewska, Ilonca Vaartjes, Beverley Balkau, Goncalo Abecasis, Alexandra I. Blakemore, Hans Bisgaard, Heiner Boeing, Ruth J.F. Loos, Matthias Blüher, Klaus Bønnelykke, Eric Boerwinkle, Mark J. Caulfield, Erwin P. Bottinger, Daniel I. Chasman, John C. Chambers, Francis S. Collins, Ching-Yu Cheng, Francesco Cucca, Josef Coresh, George Dedoussis, Gert J. de Borst, Hester M. den Ruijter, Panos Deloukas, Ele Ferrannini, Michele K. Evans, Harald Grallert, Oscar H. Franco, Arfan Ikram, Joel N. Hirschhorn, Fredrik Karpe, Erik Ingelsson, Wieland Kiess, Carolina Medina-Gomez, Kay-Tee Kaw, Antje Körner, Jaspal S. Kooner, Cecilia M. Lindgren, Timo Lakka, Ching-Ti Liu, Leonard Lipovich, Patrick E. MacDonald, Jun Liu, Andrew D. Morris, Karen L. Mohlke, Alison Murray, Patricia B. Munroe, Gerard Pasterkamp, Colin N. A . Palmer, Patricia A. Peyser, Oluf Pedersen, Paul M. Ridker, Rainer Rauramaa, Patrik Rorsman, Olov Rolandsson, Veikko Salomaa, Frits R. Rosendaal, Robert Sladek, Matthias B. Schulze, Michael Stumvoll, Timothy D. Spector, Mark Walker, Cornelia M. van Duijn, David R. Weir, Nick J. Wareham, Tien Yin Wong, James G. Wilson, Alan B. Zonderman, Eleftheria Zeggini, Andrew P. Morris, Jerome I. Rotter, Jose C. Florez, Michael Boehnke, James B. Meigs, Mark I. McCarthy, Robert A. Scott, Anubha Mahajan, Inês Barroso, Anna L. Gloyn, Michael A. Province, Niels Grarup, Ruifang Li-Gao, Jette Bork-Jensen, Yongmei Liu, Allan Linneberg, Leslie A. Lange, Sandosh Padmanabhan, Gail Davies, Lars Lind, Bruce M. Psaty, Tea Skaaby, Torben Hansen, Ozren Polasek, John M. Starr, Dennis O. Mook-Kanamori, Vilmundur Gudnason, Kent D. Taylor, Marjo-Riitta Järvelin, Renée de Mutsert, Paul Elliott, Josée Dupuis, Blair H. Smith, and Andrew T. Hattersley

Subjects
exome chip, glycaemic traits, genetic discovery, effector genes, summary statistics resources, eng, Medicine, Science
Abstract

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

Published
2023
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8. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

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

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

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.

Published
2022
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9. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author

Thomas W. Winkler, Humaira Rasheed, Alexander Teumer, Mathias Gorski, Bryce X. Rowan, Kira J. Stanzick, Laurent F. Thomas, Adrienne Tin, Anselm Hoppmann, Audrey Y. Chu, Bamidele Tayo, Chris H. L. Thio, Daniele Cusi, Jin-Fang Chai, Karsten B. Sieber, Katrin Horn, Man Li, Markus Scholz, Massimiliano Cocca, Matthias Wuttke, Peter J. van der Most, Qiong Yang, Sahar Ghasemi, Teresa Nutile, Yong Li, Giulia Pontali, Felix Günther, Abbas Dehghan, Adolfo Correa, Afshin Parsa, Agnese Feresin, Aiko P. J. de Vries, Alan B. Zonderman, Albert V. Smith, Albertine J. Oldehinkel, Alessandro De Grandi, Alexander R. Rosenkranz, Andre Franke, Andrej Teren, Andres Metspalu, Andrew A. Hicks, Andrew P. Morris, Anke Tönjes, Anna Morgan, Anna I. Podgornaia, Annette Peters, Antje Körner, Anubha Mahajan, Archie Campbell, Barry I. Freedman, Beatrice Spedicati, Belen Ponte, Ben Schöttker, Ben Brumpton, Bernhard Banas, Bernhard K. Krämer, Bettina Jung, Bjørn Olav Åsvold, Blair H. Smith, Boting Ning, Brenda W. J. H. Penninx, Brett R. Vanderwerff, Bruce M. Psaty, Candace M. Kammerer, Carl D. Langefeld, Caroline Hayward, Cassandra N. Spracklen, Cassianne Robinson-Cohen, Catharina A. Hartman, Cecilia M. Lindgren, Chaolong Wang, Charumathi Sabanayagam, Chew-Kiat Heng, Chiara Lanzani, Chiea-Chuen Khor, Ching-Yu Cheng, Christian Fuchsberger, Christian Gieger, Christian M. Shaffer, Christina-Alexandra Schulz, Cristen J. Willer, Daniel I. Chasman, Daniel F. Gudbjartsson, Daniela Ruggiero, Daniela Toniolo, Darina Czamara, David J. Porteous, Dawn M. Waterworth, Deborah Mascalzoni, Dennis O. Mook-Kanamori, Dermot F. Reilly, E. Warwick Daw, Edith Hofer, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, E-Shyong Tai, Eulalia Catamo, Federica Rizzi, Feng Guo, Fernando Rivadeneira, Franco Guilianini, Gardar Sveinbjornsson, Georg Ehret, Gerard Waeber, Ginevra Biino, Giorgia Girotto, Giorgio Pistis, Girish N. Nadkarni, Graciela E. Delgado, Grant W. Montgomery, Harold Snieder, Harry Campbell, Harvey D. White, He Gao, Heather M. Stringham, Helena Schmidt, Hengtong Li, Hermann Brenner, Hilma Holm, Holgen Kirsten, Holly Kramer, Igor Rudan, Ilja M. Nolte, Ioanna Tzoulaki, Isleifur Olafsson, Jade Martins, James P. Cook, James F. Wilson, Jan Halbritter, Janine F. Felix, Jasmin Divers, Jaspal S. Kooner, Jeannette Jen-Mai Lee, Jeffrey O’Connell, Jerome I. Rotter, Jianjun Liu, Jie Xu, Joachim Thiery, Johan Ärnlöv, Johanna Kuusisto, Johanna Jakobsdottir, Johanne Tremblay, John C. Chambers, John B. Whitfield, John M. Gaziano, Jonathan Marten, Josef Coresh, Jost B. Jonas, Josyf C. Mychaleckyj, Kaare Christensen, Kai-Uwe Eckardt, Karen L. Mohlke, Karlhans Endlich, Katalin Dittrich, Kathleen A. Ryan, Kenneth M. Rice, Kent D. Taylor, Kevin Ho, Kjell Nikus, Koichi Matsuda, Konstantin Strauch, Kozeta Miliku, Kristian Hveem, Lars Lind, Lars Wallentin, Laura M. Yerges-Armstrong, Laura M. Raffield, Lawrence S. Phillips, Lenore J. Launer, Leo-Pekka Lyytikäinen, Leslie A. Lange, Lorena Citterio, Lucija Klaric, M. Arfan Ikram, Marcus Ising, Marcus E. Kleber, Margherita Francescatto, Maria Pina Concas, Marina Ciullo, Mario Piratsu, Marju Orho-Melander, Markku Laakso, Markus Loeffler, Markus Perola, Martin H. de Borst, Martin Gögele, Martina La Bianca, Mary Ann Lukas, Mary F. Feitosa, Mary L. Biggs, Mary K. Wojczynski, Maryam Kavousi, Masahiro Kanai, Masato Akiyama, Masayuki Yasuda, Matthias Nauck, Melanie Waldenberger, Miao-Li Chee, Miao-Ling Chee, Michael Boehnke, Michael H. Preuss, Michael Stumvoll, Michael A. Province, Michele K. Evans, Michelle L. O’Donoghue, Michiaki Kubo, Mika Kähönen, Mika Kastarinen, Mike A. Nalls, Mikko Kuokkanen, Mohsen Ghanbari, Murielle Bochud, Navya Shilpa Josyula, Nicholas G. Martin, Nicholas Y. Q. Tan, Nicholette D. Palmer, Nicola Pirastu, Nicole Schupf, Niek Verweij, Nina Hutri-Kähönen, Nina Mononen, Nisha Bansal, Olivier Devuyst, Olle Melander, Olli T. Raitakari, Ozren Polasek, Paolo Manunta, Paolo Gasparini, Pashupati P. Mishra, Patrick Sulem, Patrik K. E. Magnusson, Paul Elliott, Paul M. Ridker, Pavel Hamet, Per O. Svensson, Peter K. Joshi, Peter Kovacs, Peter P. Pramstaller, Peter Rossing, Peter Vollenweider, Pim van der Harst, Rajkumar Dorajoo, Ralene Z. H. Sim, Ralph Burkhardt, Ran Tao, Raymond Noordam, Reedik Mägi, Reinhold Schmidt, Renée de Mutsert, Rico Rueedi, Rob M. van Dam, Robert J. Carroll, Ron T. Gansevoort, Ruth J. F. Loos, Sala Cinzia Felicita, Sanaz Sedaghat, Sandosh Padmanabhan, Sandra Freitag-Wolf, Sarah A. Pendergrass, Sarah E. Graham, Scott D. Gordon, Shih-Jen Hwang, Shona M. Kerr, Simona Vaccargiu, Snehal B. Patil, Stein Hallan, Stephan J. L. Bakker, Su-Chi Lim, Susanne Lucae, Suzanne Vogelezang, Sven Bergmann, Tanguy Corre, Tarunveer S. Ahluwalia, Terho Lehtimäki, Thibaud S. Boutin, Thomas Meitinger, Tien-Yin Wong, Tobias Bergler, Ton J. Rabelink, Tõnu Esko, Toomas Haller, Unnur Thorsteinsdottir, Uwe Völker, Valencia Hui Xian Foo, Veikko Salomaa, Veronique Vitart, Vilmantas Giedraitis, Vilmundur Gudnason, Vincent W. V. Jaddoe, Wei Huang, Weihua Zhang, Wen Bin Wei, Wieland Kiess, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Xin Gao, Xueling Sim, Ya Xing Wang, Yechiel Friedlander, Yih-Chung Tham, Yoichiro Kamatani, Yukinori Okada, Yuri Milaneschi, Zhi Yu, Lifelines cohort study, DiscovEHR/MyCode study, VA Million Veteran Program, Klaus J. Stark, Kari Stefansson, Carsten A. Böger, Adriana M. Hung, Florian Kronenberg, Anna Köttgen, Cristian Pattaro, and Iris M. Heid

Subjects
Biology (General), QH301-705.5
Abstract

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Published
2022
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10. Candidate loci shared among periodontal disease, diabetes and bone density

Author

Yau-Hua Yu, Bjorn Steffensen, Paul M. Ridker, Julie E. Buring, and Daniel I. Chasman

Subjects
genetics, oral health, diabet mellitus, periodontal disease, bone densities, GWAS, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionWhile periodontal disease (PD) has been associated with type 2 diabetes (T2D) and osteoporosis, the underlying genetic mechanisms for these associations remain largely unknown. The aim of this study is to apply cross-trait genetic analyses to investigate the potentially shared biology among PD, T2D, and bone mineral density (BMD) by assessing pairwise genetic correlations and searching for shared polymorphisms.MethodsWe applied cross-trait genetic analyses leveraging genome-wide association study (GWAS) summary statistics for: Periodontitis/loose teeth from the UKBB/GLIDE consortium (PerioLT, N=506594), T2D from the DIAGRAM consortium (Neff=228825), and BMD from the GEFOS consortium (N=426824). Among all three, pair-wise genetic correlations were estimated with linkage disequilibrium (LD) score regression. Multi-trait meta-analysis of GWAS (MTAG) and colocalization analyses were performed to discover shared genome-wide significant variants (pMTAG

Published
2023
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11. The genomics of heart failure: design and rationale of the HERMES consortium

Author

R. Thomas Lumbers, Sonia Shah, Honghuang Lin, Tomasz Czuba, Albert Henry, Daniel I. Swerdlow, Anders Mälarstig, Charlotte Andersson, Niek Verweij, Michael V. Holmes, Johan Ärnlöv, Per Svensson, Harry Hemingway, Neneh Sallah, Peter Almgren, Krishna G. Aragam, Geraldine Asselin, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R. Brown, Hans‐Peter Brunner‐La Rocca, David J. Carey, Mark D. Chaffin, Daniel I. Chasman, Olympe Chazara, Xing Chen, Xu Chen, Jonathan H. Chung, William Chutkow, John G.F. Cleland, James P. Cook, Simon deDenus, Abbas Dehghan, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Gunnar Engström, Tõnu Esko, Ghazaleh Fatemifar, Stephan B. Felix, Chris Finan, Ian Ford, Francoise Fougerousse, René Fouodjio, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Christopher M. Haggerty, Pim van derHarst, Åsa K. Hedman, Anna Helgadottir, Hans Hillege, Craig L. Hyde, Jaison Jacob, J. Wouter Jukema, Frederick Kamanu, Isabella Kardys, Maryam Kavousi, Kay‐Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Bill Kraus, Karoline Kuchenbaecker, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian'an Luan, Patrik Magnusson, Anubha Mahajan, Douglas Mann, Kenneth B. Margulies, Nicholas A. Marston, Winfried März, John J.V. McMurray, Olle Melander, Giorgio Melloni, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Christopher Newton‐Cheh, Alexander Niessner, Teemu Niiranen, Christoph Nowak, Michelle L. O'Donoghue, Anjali T. Owens, Colin N.A. Palmer, Guillaume Paré, Markus Perola, Louis‐Philippe Lemieux Perreault, Eliana Portilla‐Fernandez, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P.R. Romaine, Carolina Roselli, Jerome I. Rotter, Christian T. Ruff, Marc S. Sabatine, Perttu Salo, Veikko Salomaa, Jessica vanSetten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Kari Stefansson, Steen Stender, David J. Stott, Garðar Sveinbjörnsson, Mari‐Liis Tammesoo, Jean‐Claude Tardif, Kent D. Taylor, Maris Teder‐Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp‐Pedersen, Stella Trompet, Danny Tuckwell, Benoit Tyl, Andre G. Uitterlinden, Felix Vaura, Abirami Veluchamy, Peter M. Visscher, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Peter E. Weeke, Raul Weiss, Harvey D. White, Kerri L. Wiggins, Heming Xing, Jian Yang, Yifan Yang, Laura M. Yerges‐Armstrong, Bing Yu, Faiez Zannad, Faye Zhao, Regeneron Genetics Center, Jemma B. Wilk, Hilma Holm, Naveed Sattar, Steven A. Lubitz, David E. Lanfear, Svati Shah, Michael E. Dunn, Quinn S. Wells, Folkert W. Asselbergs, Aroon D. Hingorani, Marie‐Pierre Dubé, Nilesh J. Samani, Chim C. Lang, Thomas P. Cappola, Patrick T. Ellinor, Ramachandran S. Vasan, and J. Gustav Smith

Subjects
Heart failure, Cardiomyopathy, Genetics, Biomarkers, Association studies, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Published
2021
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12. Testing the Effects of Disease‐Modifying Antirheumatic Drugs on Vascular Inflammation in Rheumatoid Arthritis: Rationale and Design of the TARGET Trial

Author

Jon T. Giles, Pamela M. Rist, Katherine P. Liao, Ahmed Tawakol, Zahi A. Fayad, Venkatesh Mani, Nina P. Paynter, Paul M. Ridker, Robert J. Glynn, Fengxin Lu, Rachel Broderick, Meredith Murray, Kathleen M. M. Vanni, Daniel H. Solomon, and Joan M. Bathon

Subjects
Diseases of the musculoskeletal system, RC925-935
Abstract

Individuals with rheumatoid arthritis (RA) are at increased risk for atherosclerotic cardiovascular disease (ASCVD) events relative to the general population, potentially mediated by atherosclerotic plaques that are more inflamed and rupture prone. We sought to address whether RA immunomodulators reduce vascular inflammation, thereby reducing ASCVD risk, and whether such reduction depends on the type of immunomodulator. The TARGET (Treatments Against RA and Effect on 18‐Fluorodeoxyglucose [18F‐FDG] Positron Emission Tomography [PET]/Computed Tomography [CT]) trial (NCT02374021) will enroll 150 patients with RA with active disease and an inadequate response to methotrexate. Participants will be randomized to add either a tumor necrosis factor (TNF) inhibitor (etanercept or adalimumab) or sulfasalazine and hydroxychloroquine to their background methotrexate. Participants will undergo full‐body 18F‐FDG–labelled PET scanning at baseline and after 6 months. Efficacy and safety evaluations will occur every 6 weeks, with therapy modified in a treat‐to‐target approach. The primary outcome is the comparison of change in arterial inflammation in the wall of the aorta and carotid arteries between the randomized treatment groups, specifically, the change in the mean of the maximum target‐to‐background ratio of arterial 18F‐FDG uptake in the most diseased segment of either the aorta and carotid arteries. A secondary analysis will compare the effects of achieving low disease activity or remission with those of moderate to high disease activity on vascular inflammation. The TARGET trial will test, for the first time, whether RA treatments reduce arterial inflammation and whether such reduction differs according to treatment strategy with either TNF inhibitors or a combination of nonbiologic disease‐modifying antirheumatic drugs.

Published
2021
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13. Adverse Effects of Low‐Dose Methotrexate in a Randomized Double‐Blind Placebo‐Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial

Author

Kathleen M.M. Vanni, Nancy Berliner, Nina P. Paynter, Robert J. Glynn, Jean MacFadyen, Joshua Colls, Fengxin Lu, Chang Xu, Paul M. Ridker, and Daniel H. Solomon

Subjects
Diseases of the musculoskeletal system, RC925-935
Abstract

Objective Low‐dose methotrexate (LD‐MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD‐MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD‐MTX versus placebo in a large randomized controlled trial (RCT). Methods We prespecified secondary analyses of a double‐blind, placebo‐controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada. Subjects were randomly allocated to LD‐MTX (20 mg/week maximum) or placebo. All subjects received folic acid (1 mg daily for 6days/week). We assessed the frequency of blindly adjudicated hematologic and malignant adverse events (AEs). Results A total of 2391 subjects were randomized to LD‐MTX (mean dosage 14.9 mg/week), and 2395 were randomized to placebo. During follow‐up, in the LD‐MTX arm, simultaneous two‐line cytopenias (n = 92 [3.9%]) or pancytopenia (n = 13 [0.54%]) were infrequent. Pancytopenia developed as soon as 4 months and as late as 3.5 years after beginning LD‐MTX, though the latter subject had been recently diagnosed with multiple myeloma. Overall skin cancer risk was increased in users of LD‐MTX compared with users of placebo, which driven largely by a statistically significant increased risk of squamous cell skin cancer (hazard ratio [HR] 3.31; 95% confidence interval [CI] 1.63‐6.71). Melanoma was increased in LD‐MTX, but this was not statistically significant (HR 2.33; 95% CI 0.60‐9.01). Conclusions Among subjects using LD‐MTX, simultaneous two‐line cytopenias and pancytopenia were uncommon. We found more cases of skin cancer, particularly squamous cell carcinomas, in the LD‐MTX arm than the placebo arm.

Published
2020
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14. Prediction of Lifetime and 10-Year Risk of Cancer in Individual Patients With Established Cardiovascular Disease

Author

Cilie C. van ’t Klooster, MD, Paul M. Ridker, MD, PhD, Nancy R. Cook, PhD, Joachim G.J.V. Aerts, MD, PhD, Jan Westerink, MD, PhD, Folkert W. Asselbergs, MD, PhD, Yolanda van der Graaf, MD, PhD, Frank L.J. Visseren, MD, PhD, F.W. Asselbergs, H.M. Nathoe, G.J. de Borst, M.L. Bots, M.I. Geerlings, M.H. Emmelot, P.A. de Jong, T. Leiner, A.T. Lely, N.P. van der Kaaij, L.J. Kappelle, Y. Ruigrok, M.C. Verhaar, and J. Westerink

Subjects
colorectal cancer, lung cancer, risk prediction, Diseases of the circulatory (Cardiovascular) system, RC666-701, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Cardiovascular disease (CVD) and cancer share many common risk factors; patients with CVD also may be at risk of developing cancer. Objectives: The aim of this study was to derive and externally validate prediction models for the estimation of lifetime and 10-year risk for total, colorectal, and lung cancer in patients with established CVD. Methods: Data from patients with established CVD from the UCC-SMART cohort (N = 7,280) were used for model development, and from the CANTOS trial (N = 9,322) for model validation. Predictors were selected based on previously published cancer risk scores, clinical availability, and presence in the derivation dataset. Fine and Gray competing risk-adjusted lifetime models were developed for the outcomes total, colorectal, and lung cancer. Results: Selected predictors were age, sex, smoking, weight, height, alcohol use, antiplatelet use, diabetes, and C-reactive protein. External calibration for the 4-year risk of lung, colorectal, and total cancer was reasonable in our models, as was discrimination with C-statistics of 0.74, 0.64, and 0.63, respectively. Median predicted lifetime and 10-year risks in CANTOS were 26% (range 1% to 52%) and 13% (range 1% to 31%) for total cancer; 4% (range 0% to 13%) and 2% (range 0% to 6%) for colorectal cancer; and 5% (range 0% to 37%) and 2% (range 0% to 24%) for lung cancer. Conclusions: Lifetime and 10-year risk of total, colorectal, and lung cancer can be estimated reasonably well in patients with established CVD with readily available clinical predictors. With additional study, these tools could be used in clinical practice to further aid in the emphasis of healthy lifestyle changes and to guide thresholds for targeted diagnostics and screening.

Published
2020
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15. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Rebecca Gutmann, Christopher M. Haggerty, Pim van der Harst, Craig L. Hyde, Erik Ingelsson, J. Wouter Jukema, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian’an Luan, Patrik Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify R. Mordi, Thomas Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali T. Owens, Colin N. A. Palmer, Helen M. Parry, Markus Perola, Eliana Portilla-Fernandez, Bruce M. Psaty, Regeneron Genetics Center, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari-Liis Tammesoo, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Stella Trompet, Benoit Tyl, Andre G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faiez Zannad, Jing Hua Zhao, Harry Hemingway, Nilesh J. Samani, John J. V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton-Cheh, Anders Malarstig, Hilma Holm, Steven A. Lubitz, Naveed Sattar, Michael V. Holmes, Thomas P. Cappola, Folkert W. Asselbergs, Aroon D. Hingorani, Karoline Kuchenbaecker, Patrick T. Ellinor, Chim C. Lang, Kari Stefansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, and R. Thomas Lumbers

Subjects
Science
Abstract

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

Published
2020
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16. Interleukin-6 Levels and Cardiovascular Events in the Cardiovascular Inflammation Reduction Trial: Consistent Associations for Incident Coronary, Cerebrovascular, and Peripheral Artery Disease

Author

Lucas Marinho, Aaron W. Aday, Nancy R. Cook, Alan R. Morrison, Navneet Narula, Jagat Narula, Francesca Bartoli-Leonard, Elena Aikawa, Jocelyn M. Beach, Paul M. Ridker, and Aruna D. Pradhan

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Published
2022
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17. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Amand F. Schmidt, Michael V. Holmes, David Preiss, Daniel I. Swerdlow, Spiros Denaxas, Ghazaleh Fatemifar, Rupert Faraway, Chris Finan, Dennis Valentine, Zammy Fairhurst-Hunter, Fernando Pires Hartwig, Bernardo Lessa Horta, Elina Hypponen, Christine Power, Max Moldovan, Erik van Iperen, Kees Hovingh, Ilja Demuth, Kristina Norman, Elisabeth Steinhagen-Thiessen, Juri Demuth, Lars Bertram, Christina M. Lill, Stefan Coassin, Johann Willeit, Stefan Kiechl, Karin Willeit, Dan Mason, John Wright, Richard Morris, Goya Wanamethee, Peter Whincup, Yoav Ben-Shlomo, Stela McLachlan, Jackie F. Price, Mika Kivimaki, Catherine Welch, Adelaida Sanchez-Galvez, Pedro Marques-Vidal, Andrew Nicolaides, Andrie G. Panayiotou, N. Charlotte Onland-Moret, Yvonne T. van der Schouw, Giuseppe Matullo, Giovanni Fiorito, Simonetta Guarrera, Carlotta Sacerdote, Nicholas J. Wareham, Claudia Langenberg, Robert A. Scott, Jian’an Luan, Martin Bobak, Sofia Malyutina, Andrzej Pająk, Ruzena Kubinova, Abdonas Tamosiunas, Hynek Pikhart, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Tine Jess, Jackie Cooper, Steve E. Humphries, Murray Brilliant, Terrie Kitchner, Hakon Hakonarson, David S. Carrell, Catherine A. McCarty, Kirchner H. Lester, Eric B. Larson, David R. Crosslin, Mariza de Andrade, Dan M. Roden, Joshua C. Denny, Cara Carty, Stephen Hancock, John Attia, Elizabeth Holliday, Rodney Scott, Peter Schofield, Martin O’Donnell, Salim Yusuf, Michael Chong, Guillaume Pare, Pim van der Harst, M. Abdullah Said, Ruben N. Eppinga, Niek Verweij, Harold Snieder, Lifelines Cohort authors, Tim Christen, D. O. Mook-Kanamori, the ICBP Consortium, Stefan Gustafsson, Lars Lind, Erik Ingelsson, Raha Pazoki, Oscar Franco, Albert Hofman, Andre Uitterlinden, Abbas Dehghan, Alexander Teumer, Sebastian Baumeister, Marcus Dörr, Markus M. Lerch, Uwe Völker, Henry Völzke, Joey Ward, Jill P. Pell, Tom Meade, Ingrid E. Christophersen, Anke H. Maitland-van der Zee, Ekaterina V. Baranova, Robin Young, Ian Ford, Archie Campbell, Sandosh Padmanabhan, Michiel L. Bots, Diederick E. Grobbee, Philippe Froguel, Dorothée Thuillier, Ronan Roussel, Amélie Bonnefond, Bertrand Cariou, Melissa Smart, Yanchun Bao, Meena Kumari, Anubha Mahajan, Jemma C. Hopewell, Sudha Seshadri, the METASTROKE Consortium of the ISGC, Caroline Dale, Rui Providencia E. Costa, Paul M. Ridker, Daniel I. Chasman, Alex P. Reiner, Marylyn D. Ritchie, Leslie A. Lange, Alex J. Cornish, Sara E. Dobbins, Kari Hemminki, Ben Kinnersley, Marc Sanson, Karim Labreche, Matthias Simon, Melissa Bondy, Philip Law, Helen Speedy, James Allan, Ni Li, Molly Went, Niels Weinhold, Gareth Morgan, Pieter Sonneveld, Björn Nilsson, Hartmut Goldschmidt, Amit Sud, Andreas Engert, Markus Hansson, Harry Hemingway, Folkert W. Asselbergs, Riyaz S. Patel, Brendan J. Keating, Naveed Sattar, Richard Houlston, Juan P. Casas, and Aroon D. Hingorani

Subjects
Genetic association studies, Mendelian randomisation, LDL-cholesterol, Phenome-wide association scan, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Published
2019
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18. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

Author

Dmitry Shungin, Simon Haworth, Kimon Divaris, Cary S. Agler, Yoichiro Kamatani, Myoung Keun Lee, Kelsey Grinde, George Hindy, Viivi Alaraudanjoki, Paula Pesonen, Alexander Teumer, Birte Holtfreter, Saori Sakaue, Jun Hirata, Yau-Hua Yu, Paul M. Ridker, Franco Giulianini, Daniel I. Chasman, Patrik K. E. Magnusson, Takeaki Sudo, Yukinori Okada, Uwe Völker, Thomas Kocher, Vuokko Anttonen, Marja-Liisa Laitala, Marju Orho-Melander, Tamar Sofer, John R. Shaffer, Alexandre Vieira, Mary L. Marazita, Michiaki Kubo, Yasushi Furuichi, Kari E. North, Steve Offenbacher, Erik Ingelsson, Paul W. Franks, Nicholas J. Timpson, and Ingegerd Johansson

Subjects
Science
Abstract

Dental caries and periodontitis are among the most common medical conditions. Here, the authors report a GWAS for measures of oral health that reveals 47 risk loci for caries, find genetic correlation with 31 other complex traits and use Mendelian randomization analyses to explore potential causal relationships.

Published
2019
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19. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential

Author

Jean-Charles Fruchart, Raul D. Santos, Carlos Aguilar-Salinas, Masanori Aikawa, Khalid Al Rasadi, Pierre Amarenco, Philip J. Barter, Richard Ceska, Alberto Corsini, Jean-Pierre Després, Patrick Duriez, Robert H. Eckel, Marat V. Ezhov, Michel Farnier, Henry N. Ginsberg, Michel P. Hermans, Shun Ishibashi, Fredrik Karpe, Tatsuhiko Kodama, Wolfgang Koenig, Michel Krempf, Soo Lim, Alberto J. Lorenzatti, Ruth McPherson, Jesus Millan Nuñez-Cortes, Børge G. Nordestgaard, Hisao Ogawa, Chris J. Packard, Jorge Plutzky, Carlos I. Ponte-Negretti, Aruna Pradhan, Kausik K. Ray, Željko Reiner, Paul M. Ridker, Massimiliano Ruscica, Shaukat Sadikot, Hitoshi Shimano, Piyamitr Sritara, Jane K. Stock, Ta-Chen Su, Andrey V. Susekov, André Tartar, Marja-Riitta Taskinen, Alexander Tenenbaum, Lale S. Tokgözoğlu, Brian Tomlinson, Anne Tybjærg-Hansen, Paul Valensi, Michal Vrablík, Walter Wahli, Gerald F. Watts, Shizuya Yamashita, Koutaro Yokote, Alberto Zambon, and Peter Libby

Subjects
Residual cardiovascular risk, Visceral obesity, Diabetes, Atherogenic dyslipidemia, Triglycerides, Remnant cholesterol, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

Published
2019
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20. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author

Tuomas O. Kilpeläinen, Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa de las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. Musani, Melissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii-Der Ida Chen, Maria Pina Concas, John Connell, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Lifelines Cohort Study, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau van der Ende, Diana van Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf de Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim van der Harst, Jana V. Van Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. van Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. van Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao, and Ruth J. F. Loos

Subjects
Science
Abstract

GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

Published
2019
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21. Children’s physical activity levels in a sports-oriented summer day camp

Author

Elizabeth Y. Barnett, Paul M. Ridker, Cassandra A. Okechukwu, Jessica L. Barrett, and Steven L. Gortmaker

Subjects
Exercise, Child, Summer camp, Tennis, Accelerometer, Sports medicine, RC1200-1245
Abstract

Physical activity engagement during childhood helps create lifelong patterns of health and fitness. Summer camps are an important domain of influence for health promotion, with over 14 million American children attending annually. No known studies have evaluated the impact of sports-focused camps on activity levels. We test the hypothesis that children attending a sports camp (STEC) spend more time in moderate-to-vigorous physical activity (MVPA) compared to children attending general day camps. A repeated measures design used waist-worn accelerometers to measure MVPA and vigorous physical activity (VPA) among children at a sports camp in Dorchester, Massachusetts (n = 40). We compared these data with data from a similar study at five Boston-area non-sports-focused summer day camps (BSC) (n = 142), resulting in 764 total person-days analyzed. Multivariable linear regression models estimated differences in percent of accelerometer-monitored time spent in physical activity, adjusting for potential confounders and clustering of observations. STEC children spent a higher percentage of time in MVPA and VPA compared to BSC children (MVPA: 11.4%, p = .005; VPA: 2.4%, p = .023). These findings support the hypothesis that sports-focused camps can provide children with significantly more activity than general day camps. STEC children also spend a higher percent of time in MVPA than do children in a school-day national sample (NHANES). This is the first study to document that a sports-oriented camp generates more physical activity compared to a general summer camp. Our findings are relevant for public health efforts to promote physical activity and prevent chronic disease.

Published
2018
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22. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Author

Peter K. Joshi, Nicola Pirastu, Katherine A. Kentistou, Krista Fischer, Edith Hofer, Katharina E. Schraut, David W. Clark, Teresa Nutile, Catriona L. K. Barnes, Paul R. H. J. Timmers, Xia Shen, Ilaria Gandin, Aaron F. McDaid, Thomas Folkmann Hansen, Scott D. Gordon, Franco Giulianini, Thibaud S. Boutin, Abdel Abdellaoui, Wei Zhao, Carolina Medina-Gomez, Traci M. Bartz, Stella Trompet, Leslie A. Lange, Laura Raffield, Ashley van der Spek, Tessel E. Galesloot, Petroula Proitsi, Lisa R. Yanek, Lawrence F. Bielak, Antony Payton, Federico Murgia, Maria Pina Concas, Ginevra Biino, Salman M. Tajuddin, Ilkka Seppälä, Najaf Amin, Eric Boerwinkle, Anders D. Børglum, Archie Campbell, Ellen W. Demerath, Ilja Demuth, Jessica D. Faul, Ian Ford, Alessandro Gialluisi, Martin Gögele, MariaElisa Graff, Aroon Hingorani, Jouke-Jan Hottenga, David M. Hougaard, Mikko A. Hurme, M. Arfan Ikram, Marja Jylhä, Diana Kuh, Lannie Ligthart, Christina M. Lill, Ulman Lindenberger, Thomas Lumley, Reedik Mägi, Pedro Marques-Vidal, Sarah E. Medland, Lili Milani, Reka Nagy, William E. R. Ollier, Patricia A. Peyser, Peter P. Pramstaller, Paul M. Ridker, Fernando Rivadeneira, Daniela Ruggiero, Yasaman Saba, Reinhold Schmidt, Helena Schmidt, P. Eline Slagboom, Blair H. Smith, Jennifer A. Smith, Nona Sotoodehnia, Elisabeth Steinhagen-Thiessen, Frank J. A. van Rooij, André L. Verbeek, Sita H. Vermeulen, Peter Vollenweider, Yunpeng Wang, Thomas Werge, John B. Whitfield, Alan B. Zonderman, Terho Lehtimäki, Michele K. Evans, Mario Pirastu, Christian Fuchsberger, Lars Bertram, Neil Pendleton, Sharon L. R. Kardia, Marina Ciullo, Diane M. Becker, Andrew Wong, Bruce M. Psaty, Cornelia M. van Duijn, James G. Wilson, J. Wouter Jukema, Lambertus Kiemeney, André G. Uitterlinden, Nora Franceschini, Kari E. North, David R. Weir, Andres Metspalu, Dorret I. Boomsma, Caroline Hayward, Daniel Chasman, Nicholas G. Martin, Naveed Sattar, Harry Campbell, Tōnu Esko, Zoltán Kutalik, and James F. Wilson

Subjects
Science
Abstract

Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

Published
2017
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23. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

Author

Yadav Sapkota, Valgerdur Steinthorsdottir, Andrew P. Morris, Amelie Fassbender, Nilufer Rahmioglu, Immaculata De Vivo, Julie E. Buring, Futao Zhang, Todd L. Edwards, Sarah Jones, Dorien O, Daniëlle Peterse, Kathryn M. Rexrode, Paul M. Ridker, Andrew J. Schork, Stuart MacGregor, Nicholas G. Martin, Christian M. Becker, Sosuke Adachi, Kosuke Yoshihara, Takayuki Enomoto, Atsushi Takahashi, Yoichiro Kamatani, Koichi Matsuda, Michiaki Kubo, Gudmar Thorleifsson, Reynir T. Geirsson, Unnur Thorsteinsdottir, Leanne M. Wallace, iPSYCH-SSI-Broad Group, Jian Yang, Digna R. Velez Edwards, Mette Nyegaard, Siew-Kee Low, Krina T. Zondervan, Stacey A. Missmer, Thomas D'Hooghe, Grant W. Montgomery, Daniel I. Chasman, Kari Stefansson, Joyce Y. Tung, and Dale R. Nyholt

Subjects
Science
Abstract

Endometriosis is a major cause of infertility. Molecular mechanisms underlying the disease involve genetic and environmental risk factors. In a meta-analysis of eleven GWA studies, Sapkota and colleagues identify five novel risk loci, implicating steroid sex hormone pathways in the pathogenesis.

Published
2017
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24. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author

Anne E. Justice, Thomas W. Winkler, Mary F. Feitosa, Misa Graff, Virginia A. Fisher, Kristin Young, Llilda Barata, Xuan Deng, Jacek Czajkowski, David Hadley, Julius S. Ngwa, Tarunveer S. Ahluwalia, Audrey Y. Chu, Nancy L. Heard-Costa, Elise Lim, Jeremiah Perez, John D. Eicher, Zoltán Kutalik, Luting Xue, Anubha Mahajan, Frida Renström, Joseph Wu, Qibin Qi, Shafqat Ahmad, Tamuno Alfred, Najaf Amin, Lawrence F. Bielak, Amelie Bonnefond, Jennifer Bragg, Gemma Cadby, Martina Chittani, Scott Coggeshall, Tanguy Corre, Nese Direk, Joel Eriksson, Krista Fischer, Mathias Gorski, Marie Neergaard Harder, Momoko Horikoshi, Tao Huang, Jennifer E. Huffman, Anne U. Jackson, Johanne Marie Justesen, Stavroula Kanoni, Leena Kinnunen, Marcus E. Kleber, Pirjo Komulainen, Meena Kumari, Unhee Lim, Jian'an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Ani Manichaikul, Jonathan Marten, Rita P. S. Middelberg, Martina Müller-Nurasyid, Pau Navarro, Louis Pérusse, Natalia Pervjakova, Cinzia Sarti, Albert Vernon Smith, Jennifer A. Smith, Alena Stančáková, Rona J. Strawbridge, Heather M. Stringham, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W. van der Laan, Peter J. van der Most, Jana V. Van Vliet-Ostaptchouk, Sailaja L. Vedantam, Niek Verweij, Jacqueline M. Vink, Veronique Vitart, Ying Wu, Loic Yengo, Weihua Zhang, Jing Hua Zhao, Martina E. Zimmermann, Niha Zubair, Gonçalo R. Abecasis, Linda S. Adair, Saima Afaq, Uzma Afzal, Stephan J. L. Bakker, Traci M. Bartz, John Beilby, Richard N. Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Daniele Braga, Brendan M. Buckley, Steve Buyske, Harry Campbell, John C. Chambers, Francis S. Collins, Joanne E. Curran, Gert J. de Borst, Anton J. M. de Craen, Eco J. C. de Geus, George Dedoussis, Graciela E. Delgado, Hester M. den Ruijter, Gudny Eiriksdottir, Anna L. Eriksson, Tõnu Esko, Jessica D. Faul, Ian Ford, Terrence Forrester, Karl Gertow, Bruna Gigante, Nicola Glorioso, Jian Gong, Harald Grallert, Tanja B. Grammer, Niels Grarup, Saskia Haitjema, Göran Hallmans, Anders Hamsten, Torben Hansen, Tamara B. Harris, Catharina A. Hartman, Maija Hassinen, Nicholas D. Hastie, Andrew C. Heath, Dena Hernandez, Lucia Hindorff, Lynne J. Hocking, Mette Hollensted, Oddgeir L. Holmen, Georg Homuth, Jouke Jan Hottenga, Jie Huang, Joseph Hung, Nina Hutri-Kähönen, Erik Ingelsson, Alan L. James, John-Olov Jansson, Marjo-Riitta Jarvelin, Min A. Jhun, Marit E. Jørgensen, Markus Juonala, Mika Kähönen, Magnus Karlsson, Heikki A. Koistinen, Ivana Kolcic, Genovefa Kolovou, Charles Kooperberg, Bernhard K. Krämer, Johanna Kuusisto, Kirsti Kvaløy, Timo A. Lakka, Claudia Langenberg, Lenore J. Launer, Karin Leander, Nanette R. Lee, Lars Lind, Cecilia M. Lindgren, Allan Linneberg, Stephane Lobbens, Marie Loh, Mattias Lorentzon, Robert Luben, Gitta Lubke, Anja Ludolph-Donislawski, Sara Lupoli, Pamela A. F. Madden, Reija Männikkö, Pedro Marques-Vidal, Nicholas G. Martin, Colin A. McKenzie, Barbara McKnight, Dan Mellström, Cristina Menni, Grant W. Montgomery, AW (Bill) Musk, Narisu Narisu, Matthias Nauck, Ilja M. Nolte, Albertine J. Oldehinkel, Matthias Olden, Ken K. Ong, Sandosh Padmanabhan, Patricia A. Peyser, Charlotta Pisinger, David J. Porteous, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Laura J. Rasmussen-Torvik, Rajesh Rawal, Treva Rice, Paul M. Ridker, Lynda M. Rose, Stephanie A. Bien, Igor Rudan, Serena Sanna, Mark A. Sarzynski, Naveed Sattar, Kai Savonen, David Schlessinger, Salome Scholtens, Claudia Schurmann, Robert A. Scott, Bengt Sennblad, Marten A. Siemelink, Günther Silbernagel, P Eline Slagboom, Harold Snieder, Jan A. Staessen, David J. Stott, Morris A. Swertz, Amy J. Swift, Kent D. Taylor, Bamidele O. Tayo, Barbara Thorand, Dorothee Thuillier, Jaakko Tuomilehto, Andre G. Uitterlinden, Liesbeth Vandenput, Marie-Claude Vohl, Henry Völzke, Judith M. Vonk, Gérard Waeber, Melanie Waldenberger, R. G. J. Westendorp, Sarah Wild, Gonneke Willemsen, Bruce H. R. Wolffenbuttel, Andrew Wong, Alan F. Wright, Wei Zhao, M Carola Zillikens, Damiano Baldassarre, Beverley Balkau, Stefania Bandinelli, Carsten A. Böger, Dorret I. Boomsma, Claude Bouchard, Marcel Bruinenberg, Daniel I. Chasman, Yii-DerIda Chen, Peter S. Chines, Richard S. Cooper, Francesco Cucca, Daniele Cusi, Ulf de Faire, Luigi Ferrucci, Paul W. Franks, Philippe Froguel, Penny Gordon-Larsen, Hans- Jörgen Grabe, Vilmundur Gudnason, Christopher A. Haiman, Caroline Hayward, Kristian Hveem, Andrew D. Johnson, J Wouter Jukema, Sharon L. R. Kardia, Mika Kivimaki, Jaspal S. Kooner, Diana Kuh, Markku Laakso, Terho Lehtimäki, Loic Le Marchand, Winfried März, Mark I. McCarthy, Andres Metspalu, Andrew P. Morris, Claes Ohlsson, Lyle J. Palmer, Gerard Pasterkamp, Oluf Pedersen, Annette Peters, Ulrike Peters, Ozren Polasek, Bruce M. Psaty, Lu Qi, Rainer Rauramaa, Blair H. Smith, Thorkild I. A. Sørensen, Konstantin Strauch, Henning Tiemeier, Elena Tremoli, Pim van der Harst, Henrik Vestergaard, Peter Vollenweider, Nicholas J. Wareham, David R. Weir, John B. Whitfield, James F. Wilson, Jessica Tyrrell, Timothy M. Frayling, Inês Barroso, Michael Boehnke, Panagiotis Deloukas, Caroline S. Fox, Joel N. Hirschhorn, David J. Hunter, Tim D. Spector, David P. Strachan, Cornelia M. van Duijn, Iris M. Heid, Karen L. Mohlke, Jonathan Marchini, Ruth J. F. Loos, Tuomas O. Kilpeläinen, Ching-Ti Liu, Ingrid B. Borecki, Kari E. North, and L Adrienne Cupples

Subjects
Science
Abstract

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Published
2017
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25. Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease

Author

Aaron W. Aday and Paul M. Ridker

Subjects
vascular inflammation, atherosclerosis, residual risk, prevention, randomized trials, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiovascular risk. Additionally, these trials have demonstrated that many individuals remain at increased risk due to persistent elevations in hsCRP despite significant reductions in low-density lipoprotein cholesterol (LDL-C) levels. This “residual inflammatory risk” has increasingly become a viable pharmacologic target. In this review, we summarize the data linking inflammation to atherosclerosis with a particular focus on residual inflammatory risk. Additionally, we detail the results of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), which showed that directly reducing inflammation with an IL-1β antagonist reduces cardiovascular event rates independent of LDL-C. These positive data are contrasted with neutral evidence from CIRT in which low-dose methotrexate neither reduced the critical IL-1β to IL-6 to CRP pathway of innate immunity, nor reduced cardiovascular event rates.

Published
2019
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26. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Janina S. Ried, Janina Jeff M., Audrey Y. Chu, Jennifer L. Bragg-Gresham, Jenny van Dongen, Jennifer E. Huffman, Tarunveer S. Ahluwalia, Gemma Cadby, Niina Eklund, Joel Eriksson, Tõnu Esko, Mary F. Feitosa, Anuj Goel, Mathias Gorski, Caroline Hayward, Nancy L. Heard-Costa, Anne U. Jackson, Eero Jokinen, Stavroula Kanoni, Kati Kristiansson, Zoltán Kutalik, Jari Lahti, Jian'an Luan, Reedik Mägi, Anubha Mahajan, Massimo Mangino, Carolina Medina-Gomez, Keri L. Monda, Ilja M. Nolte, Louis Pérusse, Inga Prokopenko, Lu Qi, Lynda M. Rose, Erika Salvi, Megan T. Smith, Harold Snieder, Alena Stančáková, Yun Ju Sung, Ioanna Tachmazidou, Alexander Teumer, Gudmar Thorleifsson, Pim van der Harst, Ryan W. Walker, Sophie R. Wang, Sarah H. Wild, Sara M. Willems, Andrew Wong, Weihua Zhang, Eva Albrecht, Alexessander Couto Alves, Stephan J. L. Bakker, Cristina Barlassina, Traci M. Bartz, John Beilby, Claire Bellis, Richard N. Bergman, Sven Bergmann, John Blangero, Matthias Blüher, Eric Boerwinkle, Lori L. Bonnycastle, Stefan R. Bornstein, Marcel Bruinenberg, Harry Campbell, Yii-Der Ida Chen, Charleston W. K. Chiang, Peter S. Chines, Francis S Collins, Fracensco Cucca, L Adrienne Cupples, Francesca D’Avila, Eco J .C. de Geus, George Dedoussis, Maria Dimitriou, Angela Döring, Johan G. Eriksson, Aliki-Eleni Farmaki, Martin Farrall, Teresa Ferreira, Krista Fischer, Nita G. Forouhi, Nele Friedrich, Anette Prior Gjesing, Nicola Glorioso, Mariaelisa Graff, Harald Grallert, Niels Grarup, Jürgen Gräßler, Jagvir Grewal, Anders Hamsten, Marie Neergaard Harder, Catharina A. Hartman, Maija Hassinen, Nicholas Hastie, Andrew Tym Hattersley, Aki S. Havulinna, Markku Heliövaara, Hans Hillege, Albert Hofman, Oddgeir Holmen, Georg Homuth, Jouke-Jan Hottenga, Jennie Hui, Lise Lotte Husemoen, Pirro G. Hysi, Aaron Isaacs, Till Ittermann, Shapour Jalilzadeh, Alan L. James, Torben Jørgensen, Pekka Jousilahti, Antti Jula, Johanne Marie Justesen, Anne E. Justice, Mika Kähönen, Maria Karaleftheri, Kay Tee Khaw, Sirkka M. Keinanen-Kiukaanniemi, Leena Kinnunen, Paul B. Knekt, Heikki A. Koistinen, Ivana Kolcic, Ishminder K. Kooner, Seppo Koskinen, Peter Kovacs, Theodosios Kyriakou, Tomi Laitinen, Claudia Langenberg, Alexandra M. Lewin, Peter Lichtner, Cecilia M. Lindgren, Jaana Lindström, Allan Linneberg, Roberto Lorbeer, Mattias Lorentzon, Robert Luben, Valeriya Lyssenko, Satu Männistö, Paolo Manunta, Irene Mateo Leach, Wendy L. McArdle, Barbara Mcknight, Karen L. Mohlke, Evelin Mihailov, Lili Milani, Rebecca Mills, May E. Montasser, Andrew P. Morris, Gabriele Müller, Arthur W. Musk, Narisu Narisu, Ken K. Ong, Ben A. Oostra, Clive Osmond, Aarno Palotie, James S. Pankow, Lavinia Paternoster, Brenda W. Penninx, Irene Pichler, Maria G. Pilia, Ozren Polašek, Peter P. Pramstaller, Olli T Raitakari, Tuomo Rankinen, D. C. Rao, Nigel W. Rayner, Rasmus Ribel-Madsen, Treva K. Rice, Marcus Richards, Paul M. Ridker, Fernando Rivadeneira, Kathy A. Ryan, Serena Sanna, Mark A. Sarzynski, Salome Scholtens, Robert A. Scott, Sylvain Sebert, Lorraine Southam, Thomas Hempel Sparsø, Valgerdur Steinthorsdottir, Kathleen Stirrups, Ronald P. Stolk, Konstantin Strauch, Heather M. Stringham, Morris A. Swertz, Amy J. Swift, Anke Tönjes, Emmanouil Tsafantakis, Peter J. van der Most, Jana V. Van Vliet-Ostaptchouk, Liesbeth Vandenput, Erkki Vartiainen, Cristina Venturini, Niek Verweij, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Judith M. Vonk, Gérard Waeber, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Thomas W. Winkler, Alan F. Wright, Laura M. Yerges-Armstrong, Jing Hua Zhao, M. Carola Zillikens, Dorret I. Boomsma, Claude Bouchard, John C. Chambers, Daniel I. Chasman, Daniele Cusi, Ron T. Gansevoort, Christian Gieger, Torben Hansen, Andrew A. Hicks, Frank Hu, Kristian Hveem, Marjo-Riitta Jarvelin, Eero Kajantie, Jaspal S. Kooner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Andres Metspalu, Inger Njølstad, Claes Ohlsson, Albertine J. Oldehinkel, Lyle J. Palmer, Oluf Pedersen, Markus Perola, Annette Peters, Bruce M. Psaty, Hannu Puolijoki, Rainer Rauramaa, Igor Rudan, Veikko Salomaa, Peter E. H. Schwarz, Alan R. Shudiner, Jan H. Smit, Thorkild I. A. Sørensen, Timothy D. Spector, Kari Stefansson, Michael Stumvoll, Angelo Tremblay, Jaakko Tuomilehto, André G. Uitterlinden, Matti Uusitupa, Uwe Völker, Peter Vollenweider, Nicholas J. Wareham, Hugh Watkins, James F. Wilson, Eleftheria Zeggini, Goncalo R. Abecasis, Michael Boehnke, Ingrid B. Borecki, Panos Deloukas, Cornelia M. van Duijn, Caroline Fox, Leif C. Groop, Iris M. Heid, David J. Hunter, Robert C. Kaplan, Mark I. McCarthy, Kari E. North, Jeffrey R. O'Connell, David Schlessinger, Unnur Thorsteinsdottir, David P. Strachan, Timothy Frayling, Joel N. Hirschhorn, Martina Müller-Nurasyid, and Ruth J. F. Loos

Subjects
Science
Abstract

Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.

Published
2016
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27. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

Tuomas O. Kilpeläinen, Jayne F. Martin Carli, Alicja A. Skowronski, Qi Sun, Jennifer Kriebel, Mary F Feitosa, Åsa K. Hedman, Alexander W. Drong, James E. Hayes, Jinghua Zhao, Tune H. Pers, Ursula Schick, Niels Grarup, Zoltán Kutalik, Stella Trompet, Massimo Mangino, Kati Kristiansson, Marian Beekman, Leo-Pekka Lyytikäinen, Joel Eriksson, Peter Henneman, Jari Lahti, Toshiko Tanaka, Jian’an Luan, Fabiola Del Greco M, Dorota Pasko, Frida Renström, Sara M. Willems, Anubha Mahajan, Lynda M. Rose, Xiuqing Guo, Yongmei Liu, Marcus E. Kleber, Louis Pérusse, Tom Gaunt, Tarunveer S. Ahluwalia, Yun Ju Sung, Yolande F. Ramos, Najaf Amin, Antoinette Amuzu, Inês Barroso, Claire Bellis, John Blangero, Brendan M. Buckley, Stefan Böhringer, Yii-Der I Chen, Anton J. N. de Craen, David R. Crosslin, Caroline E. Dale, Zari Dastani, Felix R. Day, Joris Deelen, Graciela E. Delgado, Ayse Demirkan, Francis M. Finucane, Ian Ford, Melissa E. Garcia, Christian Gieger, Stefan Gustafsson, Göran Hallmans, Susan E. Hankinson, Aki S Havulinna, Christian Herder, Dena Hernandez, Andrew A. Hicks, David J. Hunter, Thomas Illig, Erik Ingelsson, Andreea Ioan-Facsinay, John-Olov Jansson, Nancy S. Jenny, Marit E. Jørgensen, Torben Jørgensen, Magnus Karlsson, Wolfgang Koenig, Peter Kraft, Joanneke Kwekkeboom, Tiina Laatikainen, Karl-Heinz Ladwig, Charles A. LeDuc, Gordon Lowe, Yingchang Lu, Pedro Marques-Vidal, Christa Meisinger, Cristina Menni, Andrew P. Morris, Richard H. Myers, Satu Männistö, Mike A. Nalls, Lavinia Paternoster, Annette Peters, Aruna D. Pradhan, Tuomo Rankinen, Laura J. Rasmussen-Torvik, Wolfgang Rathmann, Treva K. Rice, J Brent Richards, Paul M. Ridker, Naveed Sattar, David B. Savage, Stefan Söderberg, Nicholas J. Timpson, Liesbeth Vandenput, Diana van Heemst, Hae-Won Uh, Marie-Claude Vohl, Mark Walker, Heinz-Erich Wichmann, Elisabeth Widén, Andrew R. Wood, Jie Yao, Tanja Zeller, Yiying Zhang, Ingrid Meulenbelt, Margreet Kloppenburg, Arne Astrup, Thorkild I. A. Sørensen, Mark A. Sarzynski, D. C. Rao, Pekka Jousilahti, Erkki Vartiainen, Albert Hofman, Fernando Rivadeneira, André G. Uitterlinden, Eero Kajantie, Clive Osmond, Aarno Palotie, Johan G. Eriksson, Markku Heliövaara, Paul B. Knekt, Seppo Koskinen, Antti Jula, Markus Perola, Risto K. Huupponen, Jorma S. Viikari, Mika Kähönen, Terho Lehtimäki, Olli T. Raitakari, Dan Mellström, Mattias Lorentzon, Juan P. Casas, Stefanie Bandinelli, Winfried März, Aaron Isaacs, Ko W. van Dijk, Cornelia M. van Duijn, Tamara B. Harris, Claude Bouchard, Matthew A. Allison, Daniel I. Chasman, Claes Ohlsson, Lars Lind, Robert A. Scott, Claudia Langenberg, Nicholas J. Wareham, Luigi Ferrucci, Timothy M. Frayling, Peter P. Pramstaller, Ingrid B. Borecki, Dawn M. Waterworth, Sven Bergmann, Gérard Waeber, Peter Vollenweider, Henrik Vestergaard, Torben Hansen, Oluf Pedersen, Frank B. Hu, P Eline Slagboom, Harald Grallert, Tim D. Spector, J.W. Jukema, Robert J. Klein, Erik E Schadt, Paul W. Franks, Cecilia M. Lindgren, Rudolph L. Leibel, and Ruth J. F. Loos

Subjects
Science
Abstract

This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.

Published
2016
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28. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith Foster, Qiong Yang, Ming-Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi-An Ko, Christian Fuchsberger, Bamidele Tayo, Michael Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Pio d’Adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. van der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, George B. Ehret, Georg Homuth, Stefan Coassin, Gian-Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H-Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, Ivana Persico, J. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean-Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo-Pekka Lyytikäinen, Loic Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia-Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst-Hensch, Nicole Soranzo, Olivier Devuyst, Olli Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L. R. Kardia, Sheila Ulivi, Shih-Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tonu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei-Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J. F. Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. de Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H. Linda Kao, and Caroline S. Fox

Subjects
Science
Abstract

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Published
2016
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29. Antiinflammatory Therapy in Clinical Care: The CANTOS Trial and Beyond

Author

Aaron W. Aday and Paul M. Ridker

Subjects
vascular inflammation, atherosclerosis, canakinumab, prevention, randomized trials, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Inflammation is a critical pathway in the pathogenesis of atherosclerosis. Previous studies have shown that plasma levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, are associated with cardiovascular disease independent of traditional risk factors. Randomized trial data have also shown that statins reduce not only hsCRP but also cardiovascular event rates independent of their effect on low-density lipoprotein cholesterol (LDL-C) level. More recently, the CANTOS trial showed that directly reducing inflammation with canakinumab, an interleukin (IL)-1β neutralizing monoclonal antibody, could also reduce cardiovascular event rates. These mark the first phase 3 trial results validating inflammation as a viable target for preventing cardiovascular disease. In this review, we recap the role of inflammation in cardiovascular disease and highlight previous trial data showing its modulation with statins and other agents. We also detail the CANTOS trial results and discuss its implications for clinicians as well as future directions for anti-inflammatory therapy in the prevention of cardiovascular disease.

Published
2018
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30. Physical Activity and Incident Cardiovascular Disease in Women: Is the Relation Modified by Level of Global Cardiovascular Risk?

Author

Andrea K. Chomistek, Nancy R. Cook, Eric B. Rimm, Paul M. Ridker, Julie E. Buring, and I.‐Min Lee

Subjects
coronary heart disease, exercise, primary prevention, risk assessment, stroke, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background The inverse association between physical activity and cardiovascular disease (CVD) is well‐ established and has previously been shown in people with and without single CVD risk factors. We examined whether level of global cardiovascular risk, on the basis of the pooled cohort equation or Reynolds risk score, which include multiple risk factors, modified the physical activity–CVD association. Methods and Results Participants in the prospective WHS (Women's Health Study; n=27 536) reported their leisure‐time physical activity at study entry (1992–1995) and during follow‐up through 2013. Participants were divided into 10‐year cardiovascular risk groups on the basis of the pooled cohort equation and Reynolds risk score. The primary outcome was incident total CVD. The CVD hazard ratio for active (≥500 kcal/wk of physical activity) compared with inactive (

Published
2018
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31. Gene Variation of Endoplasmic Reticulum Aminopeptidases 1 and 2, and Risk of Blood Pressure Progression and Incident Hypertension among 17,255 Initially Healthy Women

Author

Robert Y. L. Zee, Alicia Rivera, Yaritza Inostroza, Paul M. Ridker, Daniel I. Chasman, and Jose R. Romero

Subjects
Genetics, QH426-470
Abstract

Recent studies have demonstrated the importance of endoplasmic reticulum aminopeptidase (ERAP) in blood pressure (BP) homeostasis. To date, no large prospective, genetic–epidemiological data are available on genetic variation within ERAP and hypertension risk. The association of 45 genetic variants of ERAP1 and ERAP2 was investigated in 17,255 Caucasian female participants from the Women’s Genome Health Study. All subjects were free of hypertension at baseline. During an 18-year follow-up period, 10,216 incident hypertensive cases were identified. Multivariable linear, logistic, and Cox regression analyses were performed to assess the relationship of genotypes with baseline BP levels, BP progression at 48 months, and incident hypertension assuming an additive genetic model. Linear regression analyses showed associations of four tSNPs (ERAP1: rs27524; ERAP2: rs3733904, rs4869315, and rs2549782; all p

Published
2018
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32. Genetic loci associated with circulating levels of very long-chain saturated fatty acids[S]

Author

Rozenn N. Lemaitre, Irena B. King, Edmond K. Kabagambe, Jason H.Y. Wu, Barbara McKnight, Ani Manichaikul, Weihua Guan, Qi Sun, Daniel I. Chasman, Millennia Foy, Lu Wang, Jingwen Zhu, David S. Siscovick, Michael Y. Tsai, Donna K. Arnett, Bruce M. Psaty, Luc Djousse, Yii-Der I. Chen, Weihong Tang, Lu-Chen Weng, Hongyu Wu, Majken K. Jensen, Audrey Y. Chu, David R. Jacobs, Jr., Stephen S. Rich, Dariush Mozaffarian, Lyn Steffen, Eric B. Rimm, Frank B. Hu, Paul M. Ridker, Myriam Fornage, and Yechiel Friedlander

Subjects
arachidic acid, behenic acid, lignoceric acid, sphingolipids, Biochemistry, QD415-436
Abstract

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10−13). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10−40) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10−26) and lignoceric acid (P = 3.20 × 10−21). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

Published
2015
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33. Association between Vitamin D Genetic Risk Score and Cancer Risk in a Large Cohort of U.S. Women

Author

Paulette D. Chandler, Deirdre K. Tobias, Lu Wang, Stephanie A. Smith-Warner, Daniel I. Chasman, Lynda Rose, Edward L. Giovannucci, Julie E. Buring, Paul M. Ridker, Nancy R. Cook, JoAnn E. Manson, and Howard D. Sesso

Subjects
vitamin D, cancer, genetic risk score, Mendelian randomization, mortality, Nutrition. Foods and food supply, TX341-641
Abstract

Some observational studies suggest an inverse association between circulating 25-hydroxyvitamin D (25OHD) and cancer incidence and mortality. We conducted a Mendelian randomization analysis of the relationship between a vitamin D genetic risk score (GRS, range 0–10), comprised of five single nucleotide polymorphisms (SNPs) of vitamin D status in the DHCR7, CYP2R1 and GC genes and cancer risk among women. Analysis was performed in the Women’s Genome Health Study (WGHS), including 23,294 women of European ancestry who were cancer-free at baseline and followed for 20 years for incident cancer. In a subgroup of 1782 WGHS participants with 25OHD measures at baseline, the GRS was associated with circulating 25OHD mean (SD) = 67.8 (26.1) nmol/L, 56.9 (18.7) nmol/L in the lowest versus 73.2 (27.9) nmol/L in the highest quintile of the GRS (p trend < 0.0001 across quintiles). However, in age-adjusted Cox proportional hazards models, higher GRS (reflecting higher 25OHD levels) was not associated (cases; Hazard Ratio (HR) (95% Confidence Interval (CI)), p-value) with incident total cancer: (n = 3985; 1.01 (1.00–1.03), p = 0.17), breast (n = 1560; 1.02 (0.99–1.05), p = 0.21), colorectal (n = 329; 1.06 (1.00–1.13), p = 0.07), lung (n = 330; 1.00 (0.94–1.06), p = 0.89) or total cancer death (n = 770; 1.00 (0.96–1.04), p = 0.90). Results were similar in fully-adjusted models. A GRS for higher circulating 25OHD was not associated with cancer incidence or mortality.

Published
2018
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34. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author

Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar

Subjects
Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Published
2023

36. Coronary Flow Reserve, Inflammation, and Myocardial Strain

Author

Viviany R. Taqueti, Amil M. Shah, Brendan M. Everett, Aruna D. Pradhan, Gregory Piazza, Courtney Bibbo, Jon Hainer, Victoria Morgan, Ana Carolina do A. H. de Souza, Hicham Skali, Ron Blankstein, Sharmila Dorbala, Samuel Z. Goldhaber, Michel R. Le May, Benjamin J.W. Chow, Robert A. deKemp, Fadi G. Hage, Rob S. Beanlands, Peter Libby, Robert J. Glynn, Scott D. Solomon, Paul M. Ridker, and Marcelo F. Di Carli

Subjects
Cardiology and Cardiovascular Medicine
Published
2023

37. Comparative Effects of Low-Dose Rosuvastatin, Placebo, and Dietary Supplements on Lipids and Inflammatory Biomarkers

Author

Luke J. Laffin, Dennis Bruemmer, Michelle Garcia, Danielle M. Brennan, Ellen McErlean, Douglas S. Jacoby, Erin D. Michos, Paul M Ridker, Tracy Y. Wang, Karol E. Watson, Howard G. Hutchinson, and Steven E. Nissen

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Supplements are commonly used by individuals with indications for lipid-lowering therapy, but evidence of their effectiveness to lower low-density lipoprotein cholesterol (LDL-C) is lacking, particularly when compared with statins.The trial objective was to compare the efficacy of a low-dose statin with placebo and 6 common supplements in impacting lipid and inflammatory biomarkers.This was a single-center, prospective, randomized, single-blind clinical trial among adults with no history of atherosclerotic cardiovascular disease (ASCVD), an LDL-C of 70 to 189 mg/dL, and an increased 10-year risk of ASCVD. Participants were randomized to rosuvastatin 5 mg daily, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice. The primary endpoint was the percent change in LDL-C from baseline for rosuvastatin 5 mg daily compared with placebo and each supplement after 28 days. The primary endpoint was evaluated in a hierarchical fashion with rosuvastatin first compared with placebo, then each supplement in a prespecified order using analysis of covariance.A total of 190 participants completed the study. The percent LDL-C reduction with rosuvastatin was greater than all supplements and placebo (P 0.001). The difference in LDL-C reduction with rosuvastatin compared with placebo was -35.2% (95% CI: -41.3% to -29.1%; P 0.001). None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. Adverse event rates were similar across study groups.Among individuals with increased 10-year risk for ASCVD, rosuvastatin 5 mg daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. (Supplements, Placebo, or Rosuvastatin Study [SPORT]; NCT04846231).

Published
2023

38. Canakinumab's Effect Against Subsequent Gout Flares and High‐Sensitivity C‐Reactive Protein Levels: A Causal Mediation Analysis

Author

Kazuki Yoshida, Robert J. Glynn, Hyon K. Choi, Brendan M. Everett, Yi Li, Jean G. MacFadyen, Paul M. Ridker, and Daniel H. Solomon

Subjects
Rheumatology
Abstract

The objective of this study was to quantify the value of early suppression of high-sensitivity C-reactive protein (hsCRP) levels as a biomarker of the protective role of canakinumab against future gout flares.We conducted a post hoc causal mediation analysis of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study for gout flares. The 3-month change in the log hsCRP level was the mediator of interest. We used linear regression for the hsCRP level mediator and Cox or Weibull regression for gout-flare outcomes, combining them in causal mediation analysis. We examined the cohort overall, as well as stratified by prevalent gout at baseline.We analyzed 9,221 patients without prevalent gout and 747 with prevalent gout. The Cox regression hazard ratio (HR) for a gout flare was 0.50 (95% confidence interval [95% CI] 0.37-0.68) comparing canakinumab with placebo, of which 6% was explained by the mediated effect through hsCRP level reduction in the first 3 months. In the prevalent-gout subgroup, the HR was 0.58 (95% CI 0.36-0.95), of which 31% was explained by the mediated effect through hsCRP level reduction. The Weibull analysis gave a proportion-mediated estimate of 47%. The indirect effect via hsCRP level reductions was unclear in the subgroup without prevalent gout.The first 3-month reduction in hsCRP level was not a good biomarker for canakinumab's protective effect on future gout flares in the overall cohort. Among patients with prevalent gout, there may be a potential role for early hsCRP level reduction as a biomarker for interleukin-1β inhibitors' future gout-flare benefit.

Published
2022

39. Interplay of Atherogenic Particle Number and Particle Size and the Risk of Coronary Heart Disease

Author

Karol M Pencina, Michael J Pencina, Patrick R Lawler, James C Engert, Line Dufresne, Paul M Ridker, George Thanassoulis, Samia Mora, and Allan D Sniderman

Subjects
Biochemistry (medical), Clinical Biochemistry
Abstract

Background We examined the interplay of apolipoprotein B (apoB) and LDL particle size, approximated by the LDL-cholesterol (LDL-C)/apoB ratio, on the risk of new-onset coronary heart disease (CHD). Methods Participants without cardiovascular disease from the UK Biobank (UKB; n = 308 182), the Women’s Health Study (WHS; n = 26 204), and the Framingham Heart Study (FHS; n = 2839) were included. Multivariable Cox models were used to assess the relationship between apoB and LDL-C/apoB ratio and incidence of CHD (14 994 events). Our analyses were adjusted for age, sex (except WHS), HDL-cholesterol (HDL-C), systolic blood pressure, antihypertensive treatment, diabetes, and smoking. Results In all 3 studies, there was a strong positive correlation between apoB and LDL-C (correlation coefficients r = 0.80 or higher) and a weak inverse correlation of apoB with LDL-C/apoB ratio (−0.28 ≤ r ≤ −0.14). For all 3 cohorts, CHD risk was higher for higher levels of apoB. Upon multivariable adjustment, the association between apoB and new-onset CHD remained robust and statistically significant in all 3 cohorts with hazard ratios per 1 SD (95% CI): 1.24 (1.22–1.27), 1.33 (1.20–1.47), and 1.24 (1.09–1.42) for UKB, WHS, and FHS, respectively. However, the association between LDL-C/apoB and CHD was statistically significant only in the FHS cohort: 0.78 (0.64–0.94). Conclusions Our analysis confirms that apoB is a strong risk factor for CHD. However, given the null association in 2 of the 3 studies, we cannot confirm that cholesterol-depleted LDL particles are substantially more atherogenic than cholesterol-replete particles. These results lend further support to routine measurement of apoB in clinical care.

Published
2022

40. Sugar-Sweetened Beverage Consumption and Plasma Lipoprotein Cholesterol, Apolipoprotein, and Lipoprotein Particle Size Concentrations in US Adults

Author

Danielle E Haslam, Daniel I Chasman, Gina M Peloso, Mark A Herman, Josée Dupuis, Alice H Lichtenstein, Caren E Smith, Paul M Ridker, Paul F Jacques, Samia Mora, and Nicola M McKeown

Subjects
Nutrition and Dietetics, Medicine (miscellaneous)
Abstract

Prospective cohort studies have found a relation between sugar-sweetened beverage consumption (SSB; sodas and fruit drinks) and dyslipidemia. There is limited evidence linking SSB consumption to emerging features of dyslipidemia, which can be characterized by variation in lipoprotein particle size, remnant-like particle (RLP), and apolipoprotein concentrations.To examine the association between SSB consumption and plasma lipoprotein cholesterol, apolipoprotein, and lipoprotein particle size concentrations among US adults.We examined participants from the Framingham Offspring Study (FOS) (1987-1995; n = 3047) and the Women's Health Study (1992; n = 26,218). Plasma LDL-C, apolipoprotein (apo) B, HDL-C, apoA1, triglyceride (TG), non-HDL-C, total: HDL-cholesterol ratio, and apoB: apoA1 concentrations were quantified in both cohorts, and apoE, apoC3, RLP-TG, and RLP-cholesterol concentrations in FOS only. Lipoprotein particle sizes were calculated from NMR signals for lipoprotein particle subclass concentrations (triglyceride-rich lipoprotein particles [TRL-P; very large, large, medium, small, and very small], LDL-particles [LDL-P; large, medium, and small], HDL-particles [HDL-P; large, medium, and small]). SSB consumption was estimated from food frequency questionnaire data. We examined the associations between SSB consumption and all lipoprotein and apoprotein measures in linear regression models, adjusting for confounding factors, such as lifestyle, diet, and traditional lipoprotein risk factors.SSB consumption was positively associated with LDL-C, apoB, TG, RLP-TG, RLP-C, non-HDL-C concentrations and total: HDL cholesterol and apoB: apoA1 ratio, and negatively associated with HDL-C and apoA1 concentrations (P-trend ranges from 0.0001 to 0.003). After adjustment for traditional lipoprotein risk factors, SSB consumers had smaller LDL-P and HDL-P sizes, lower concentrations of large LDL-P and medium HDL-P, and higher concentrations of small LDL-P, small HDL-P, and large TRL-P (P-trend ranges from 0.0001 to 0.0009).Higher SSB consumption was associated with multiple emerging features of dyslipidemia that have been linked to higher cardiometabolic risk in US adults.

Published
2022

41. Interleukin-1β suppression dampens inflammatory leucocyte production and uptake in atherosclerosis

Author

Nicholas H Adamstein, Wolfgang Koenig, Peter Libby, Christian Weber, Paul M. Ridker, Marcus-André Deutsch, Oliver Soehnlein, Carina Mauersberger, Hendrik B. Sager, Quinte Braster, Avril A. B. Robertson, Jan Hettwer, Benedikt Miritsch, Mark E. Cooper, Heribert Schunkert, Markus Krane, Xinghai Li, Aldo Moggio, Julia Hinterdobler, Hermann Gram, Olaf Groß, Thorsten Kessler, Biochemie, and RS: Carim - B01 Blood proteins & engineering

Subjects
Myeloid, Inflammasomes, Mice, Knockout, ApoE, Physiology, medicine.medical_treatment, Interleukin-1beta, Inflammasome, NLRP3 INFLAMMASOME, Mice, Physiology (medical), NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, Progenitor cell, MOLECULE, Inflammation, Innate immunity, Chemotactic Factors, business.industry, IL-1, Monocyte, Antibodies, Monoclonal, Endothelial Cells, Interleukin-1 beta, INHIBITOR, Atherosclerosis, MYELOPOIESIS, C-REACTIVE PROTEIN, FAMILY, Haematopoiesis, Canakinumab, Myocardial infarction, Cholesterol, Cytokine, medicine.anatomical_structure, TARGET, Immunology, CELLS, Bone marrow, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

AIMS: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies.METHODS AND RESULTS: In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for six weeks), we found that three weeks of NLRP3-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3 inflammasome inhibitor which blocks production and release of active IL-1β; or a murine analog of canakinumab) dampened accumulation of leukocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leukocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leukocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leukocyte supply by decreasing proliferation of bone marrow hematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leukocytes. Using bone marrow reconstitution experiments, we observed that hematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leukocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leukocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers.CONCLUSIONS: Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leukocyte 1) supply and 2) uptake into atherosclerotic aortas providing additional mechanistic insights into links between hematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies.TRANSLATIONAL PERSPECTIVE: Therapeutic targeting of vascular inflammation represents a promising avenue to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) reduces the incidence of cardiovascular events in patients with prior myocardial infarction. However, the mechanisms underlying these beneficial effects remain incompletely understood. This study explored how IL-1β and NLRP3-inflammasome suppression mitigated plaque progression. Our murine and human data reveal that pharmacological anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened inflammatory leukocyte accumulation in atherosclerotic aortas through 1) decreased blood inflammatory leukocyte supply and 2) reduced blood inflammatory leukocyte uptake into in atherosclerotic aortas. These data provide additional mechanistic insights into links between hematopoiesis and atherogenesis, and inform future anti-inflammatory interventions in patients with atherosclerosis.

Published
2022

42. Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Author

Florian, Thibord, Derek, Klarin, Jennifer A, Brody, Ming-Huei, Chen, Michael G, Levin, Daniel I, Chasman, Ellen L, Goode, Kristian, Hveem, Maris, Teder-Laving, Angel, Martinez-Perez, Dylan, Aïssi, Delphine, Daian-Bacq, Kaoru, Ito, Pradeep, Natarajan, Pamela L, Lutsey, Girish N, Nadkarni, Paul S, de Vries, Gabriel, Cuellar-Partida, Brooke N, Wolford, Jack W, Pattee, Charles, Kooperberg, Sigrid K, Braekkan, Ruifang, Li-Gao, Noemie, Saut, Corriene, Sept, Marine, Germain, Renae L, Judy, Kerri L, Wiggins, Darae, Ko, Christopher J, O'Donnell, Kent D, Taylor, Franco, Giulianini, Mariza, De Andrade, Therese H, Nøst, Anne, Boland, Jean-Philippe, Empana, Satoshi, Koyama, Thomas, Gilliland, Ron, Do, Jennifer E, Huffman, Xin, Wang, Wei, Zhou, Jose, Manuel Soria, Juan, Carlos Souto, Nathan, Pankratz, Jeffery, Haessler, Kristian, Hindberg, Frits R, Rosendaal, Constance, Turman, Robert, Olaso, Rachel L, Kember, Traci M, Bartz, Julie A, Lynch, Susan R, Heckbert, Sebastian M, Armasu, Ben, Brumpton, David M, Smadja, Xavier, Jouven, Issei, Komuro, Katharine R, Clapham, Ruth J F, Loos, Cristen J, Willer, Maria, Sabater-Lleal, James S, Pankow, Alexander P, Reiner, Vania M, Morelli, Paul M, Ridker, Astrid van Hylckama, Vlieg, Jean-François, Deleuze, Peter, Kraft, Daniel J, Rader, Kyung, Min Lee, Bruce M, Psaty, Anne, Heidi Skogholt, Joseph, Emmerich, Pierre, Suchon, Stephen S, Rich, Ha My T, Vy, Weihong, Tang, Rebecca D, Jackson, John-Bjarne, Hansen, Pierre-Emmanuel, Morange, Christopher, Kabrhel, David-Alexandre, Trégouët, Scott M, Damrauer, Andrew D, Johnson, Nicholas L, Smith, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
genome-wide association study, venous thromboembolism, Quantitative Trait Loci, Thrombosis, Genomics, Venous Thromboembolism, Polymorphism, Single Nucleotide, meta-analysis, Meta-analysis, Physiology (medical), Venous thrombosis, Genetics, Humans, genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetic Predisposition to Disease, venous thrombosis, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Published
2022

43. Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy

Author

Paul M Ridker, Nader Rifai, Jean MacFadyen, Robert J. Glynn, Lixia Jiao, Ph. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Jean-Claude Tardif, Christie M. Ballantyne, R. Preston Mason, and Deepak L. Bhatt

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Background: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl—Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk. Methods: Serum levels of interleukin-1β, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels ≥ 135 mg/dL and Results: At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1β (all P values P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was −1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator. Conclusions: Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Published
2022

44. Data from C-reactive Protein and Risk of Colorectal Adenoma According to Celecoxib Treatment

Author

Monica M. Bertagnolli, Ernest T. Hawk, Paul M. Ridker, Ann G. Zauber, Camelia S. Sima, and Andrew T. Chan

Abstract

Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP 3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (≤3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53–1.83) and 1.11 (95% CI = 0.61–2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention. Cancer Prev Res; 4(8); 1172–80. ©2011 AACR.

Published
2023

46. Data from Inhibition of IL1β by Canakinumab May Be Effective against Diverse Molecular Subtypes of Lung Cancer: An Exploratory Analysis of the CANTOS Trial

Author

Eric C. Svensson, Anne-Marie Martin, Paul M. Ridker, Margaret Dugan, Lynne Krajkovich, Margaret F. Prescott, Xiaoshan Wang, Ying A. Wang, Siyan Xu, Bharani Bharani-Dharan, Michael T. Beste, Angela Silvestro, Jason Baum, and Connie C. Wong

Abstract

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer.Significance:These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.

Published
2023

48. Data from Plasma C-Reactive Protein and Risk of Breast Cancer in Two Prospective Studies and a Meta-analysis

Author

Susan E. Hankinson, Bernard Rosner, Paul M. Ridker, Julie E. Buring, Shelley S. Tworoger, I-Min Lee, and Jun Wang

Abstract

Background: C-reactive protein (CRP) has been evaluated as a risk factor for breast cancer in epidemiologic studies. However, results from prospective studies are inconsistent.Methods: We evaluated the association using prediagnostic blood samples in a case–control study nested within the Nurses' Health Study (NHS) and the full cohort of the Women's Health Study (WHS). A total of 943 cases in the NHS and 1,919 cases in the WHS contributed to the analysis. Conditional logistic regression and Cox proportional hazards model were used in the NHS and WHS, respectively. We pooled our results with prior prospective studies using random effect meta-analysis.Results: In the NHS, higher CRP levels were associated with a suggestively increased risk of breast cancer [quintile 5 vs. 1: relative risk (RR), 1.27; 95% confidence interval (CI), 0.93–1.73; Ptrend = 0.02]; results did not vary significantly by tumor invasiveness or hormone receptor status. However, no association was observed in the WHS for overall risk (quintile 5 vs. 1: RR, 0.89; 95% CI, 0.76–1.06; Ptrend = 0.38) or by tumor invasiveness or hormone receptor status. The meta-analysis (including 5,371 cases from 11 studies) showed a modestly increased risk among women in the highest versus lowest categories of CRP (RR, 1.26; 95% CI, 1.07–1.49).Conclusions: Existing data from prospective studies suggest that CRP, a nonspecific marker of inflammation, is modestly positively associated with breast cancer risk.Impact: Our findings provide support to the concept that inflammation can influence breast cancer development. Cancer Epidemiol Biomarkers Prev; 24(8); 1199–206. ©2015 AACR.

Published
2023

49. Supplementary Tables 1-3 from Plasma C-Reactive Protein and Risk of Breast Cancer in Two Prospective Studies and a Meta-analysis

Author

Susan E. Hankinson, Bernard Rosner, Paul M. Ridker, Julie E. Buring, Shelley S. Tworoger, I-Min Lee, and Jun Wang

Abstract

Supplementary Tables 1-3. Supplementary Table 1. Summary of Previously Published Prospective Cohort Studies of Circulating CRP and Breast Cancer Risk. Supplementary Table 2. Plasma CRP Levels and Risk of Breast Cancer Overall by Menopausal Status, BMI, Aspirin Use in the NHS and WHS Respectively and the Combined Analysis. Supplementary Table 3. Plasma CRP Levels and Risk of Breast Cancer Overall by Years of Follow-up in the NHS and WHS Respectively.

Published
2023

50. Interactions Between Genetic Risk and Diet Influencing Risk of Incident Female Gout: Discovery and Replication Analysis of Four Prospective Cohorts

Author

Kehuan Lin, Natalie McCormick, Chio Yokose, Amit D. Joshi, Na Lu, Gary C. Curhan, Tony R. Merriman, Kenneth G. Saag, Paul M. Ridker, Julie E. Buring, Daniel I. Chasman, Frank B. Hu, and Hyon K. Choi

Subjects
Rheumatology, Immunology, Immunology and Allergy
Abstract

To examine whether the cross-sectional gene-diet interaction for prevalent hyperuricemia among women translates prospectively to risk of incident female gout.We analyzed the interaction between genetic predisposition and adherence to a healthy dietary pattern (i.e., Dietary Approaches to Stop Hypertension [DASH] score) on risk of incident female gout in 18,244 women from Nurses' Health Study (NHS; discovery) and 136,786 women from 3 additional prospective female cohorts from US and UK (replication). Genetic risk score (GRS) was calculated from 114 urate-associated loci.In the NHS and replication cohorts, association between diet and gout risk was larger and stronger among women with higher genetic risk. In all cohorts combined, compared with women with unhealthy DASH score (mean), multivariable relative risk (mRR) for incident female gout among women with healthy DASH score (≥mean) was 0.67 (95% CI 0.60-0.76) among higher GRS (≥mean) and 0.91 (0.78-1.05) among lower GRS (P multiplicative interaction=0.001); mRR for higher vs. lower GRS was 2.03 (1.80-2.29) and 1.50 (1.31-1.71) among unhealthy and healthy DASH score groups, respectively. Additive interaction was also significant, in both the discovery and replication cohorts (P0.001), with 51% of the excess risk attributable to the additive gene-diet interaction in all cohorts combined.The deleterious effect of genetic predisposition on risk of incident female gout was more pronounced among women with unhealthy diet, with nearly half the excess risk attributable to this gene-diet interaction. These data elucidate the important synergy of genetics and diet for female gout development. This article is protected by copyright. All rights reserved.

Published
2023

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