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Your search keyword '"Kirchner, H. Lester"' showing total 599 results
Start Over Author "Kirchner, H. Lester" Publication Type Academic Journals
599 results on '"Kirchner, H. Lester"'

3. Limitations of Noninvasive Tests-Based Population-Level Risk Stratification Strategy for Nonalcoholic Fatty Liver Disease

Author

Behari, Jaideep, Bradley, Allison, Townsend, Kevin, Becich, Michael J., Cappella, Nickie, Chuang, Cynthia H., Fernandez, Soledad A., Ford, Daniel E., Kirchner, H. Lester, Morgan, Richard, Paranjape, Anuradha, Silverstein, Jonathan C., Williams, David A., Donahoo, W. Troy, Asrani, Sumeet K., Ntanios, Fady, Ateya, Mohammad, Hegeman-Dingle, Rozelle, McLeod, Euan, and McTigue, Kathleen

Published
2024
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4. Abstract 4145340: Health System Variability in Lipid Management for Patients with Atherosclerotic Cardiovascular Disease: An Analysis from Cv-MOBIUS

Author

Shah, Nishant, Shrader, Peter, Shoji, Satoshi, Martin, Seth, Fernandez, Soledad, Chamberlain, Alanna, Arnold, Jonathan, Shapiro, Michael, Effron, Mark, Chrischilles, Elizabeth, Allred, Clint, Priest, Elisa, Syed, Mahanaz, Kirchner, H Lester, Leja, Monika, Ahmad, Zahid, Kalich, Bethany, Dhalwani, Nafeesa, Jones, Laney, Wojcik, Cezary, Peterson, Eric, and Navar, Ann Marie

Published
2024
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9. Exploring Social Cognition Tests to Differentiate Frontotemporal Dementia from Depression

Author

Lichtenstein, Maya L, Stewart, Peter V, Kirchner, H Lester, Finney, Glen, and Feldman, Howard H

Subjects
Biological Psychology, Psychology, Clinical Research, Mental Health, Brain Disorders, Aging, Behavioral and Social Science, Alzheimer's Disease, Frontotemporal Dementia (FTD), Rare Diseases, Depression, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurosciences, Mental health, Neurological, Humans, Frontotemporal Dementia, Pilot Projects, Social Cognition, Neuropsychological Tests, Cognition, Clinical Sciences, Cognitive Sciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

Behavioral-variant frontotemporal dementia (bvFTD) is challenging to recognize, and often misdiagnosed as depression (DEP). Evidence suggests changes in social cognition (SoCog) precede general cognitive decline in bvFTD. Currently, there are no screening measures of social cognition. 17 bvFTD, 16 DEP, and 18 control participants underwent 6 SoCog tests measuring: emotion recognition; theory of mind; empathy; insight. We used χ 2 , Wilcoxon rank sum, Kruskal-Wallis tests to compare groups, with decision tree analysis to identify items that best differentiated bvFTD from DEP. bvFTD performed significantly worse on all SoCog tasks compared with other groups. Decision tree analysis yielded a 5-item test with ROC area under the curve of 0.973 (95% CI: 0.928, 1.0) for differentiating bvFTD versus depression. These results suggest that it may be feasible to develop a screening measure of social cognition.

Published
2023

12. Performance of a stool-based quantitative PCR assay for the diagnosis of tuberculosis in adolescents and adults: a multinational, prospective diagnostic accuracy study

Author

Kay, Alexander, Vasiliu, Anca, Carratala-Castro, Lucia, Mtafya, Bariki, Mendez Reyes, Jose Euberto, Maphalala, Nontobeko, Munguambe, Shilzia, Mulengwa, Durbbin, Ness, Tara, Saavedra, Belen, Bacha, Jason, Maphalala, Gugu, Mejia, Rojelio, Mtetwa, Godwin, Acacio, Sozinho, Manjate, Patricia, Mambuque, Edson, Shiba, Nosisa, Kota, Nokwanda, Ziyane, Mangaliso, Ntinginya, Nyanda Elias, Lange, Christoph, Kirchner, H Lester, DiNardo, Andrew R, Garcia-Basteiro, Alberto L, and Mandalakas, Anna Maria

Published
2024
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14. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis

Author

Martinez, Leonardo, Cords, Olivia, Horsburgh, C Robert, Andrews, Jason R, Consortium, Pediatric TB Contact Studies, Acuna-Villaorduna, Carlos, Ahuja, Shama Desai, Altet, Neus, Augusto, Orvalho, Baliashvili, Davit, Basu, Sanjay, Becerra, Mercedes, Bonnet, Maryline, Boom, W Henry, Borgdorff, Martien, Boulahbal, Fadila, Carvalho, Anna Cristina C, Cayla, Joan A, Chakhaia, Tsira, Chan, Pei-Chun, Cohen, Ted, Croda, Julio, Datta, Sumona, del Corral, Helena, Denholm, Justin T, Dietze, Reynaldo, Dobler, Claudia C, Donkor, Simon, Egere, Uzochukwu, Ellner, Jerrold J, Espinal, Marcos, Evans, Carlton A, Fang, Chi-Tai, Fielding, Katherine, Fox, Greg J, García, Luis F, García-Basteiro, Alberto L, Geis, Steffen, Graham, Stephen M, Grandjean, Louis, Hannoun, Djohar, Hatherill, Mark, Hauri, Anja M, Hesseling, Anneke C, Hill, Philip C, Huang, Li-Min, Huerga, Helena, Hussain, Rabia, Jarlsberg, Leah, Jones-López, Edward C, Kato, Seiya, Kato-Maeda, Midori, Kampmann, Beate, Kirchner, H Lester, Kritski, Afrânio, Lange, Christoph, Lee, Chih-Hsin, Lee, Li-Na, Lee, Meng-Rui, Lemos, Antonio Carlos, Lienhardt, Christian, Ling, Du-Lin, Liu, Qiao, Lo, Nathan C, Long, Richard, Lopez-Varela, Elisa, Lu, Peng, Magee, Matthew, Malone, LaShaunda L, Mandalakas, Anna M, Martinson, Neil A, Mazahir, Rufaida, Murray, Megan B, Netto, Eduardo Martins, Otero, Larissa, Parsonnet, Julie, Reingold, Arthur, Schaaf, H Simon, Seddon, James A, Sharma, Surendra, Singh, Jitendra, Singh, Sarman, Sloot, Rosa, Sotgiu, Giovanni, Stein, Catherine M, Iqbal, Najeeha Talat, Triasih, Rina, Trieu, Lisa, van der Loeff, Maarten F Schim, Van der Stuyft, Patrick, van Schalkwyk, Cari, Vashishtha, Richa, Verhagen, Lilly M, Villalba, Julian A, Wang, Jann-Yuan, Whalen, Christopher C, Yoshiyama, Takashi, Zar, Heather J, Zellweger, Jean-Pierre, and Zhu, Limei

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Health Sciences, Infectious Diseases, Rare Diseases, Prevention, Pediatric, Tuberculosis, Emerging Infectious Diseases, Infection, Good Health and Well Being, Adolescent, Age Factors, Child, Child, Preschool, Contact Tracing, Disease Transmission, Infectious, Family Characteristics, Female, Global Health, Humans, Incidence, Male, Mycobacterium tuberculosis, Risk Assessment, Sex Factors, Tuberculosis, Pulmonary, Pediatric TB Contact Studies Consortium, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundTens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.MethodsIn this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).FindingsIn total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4-37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30-0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05-0·15]) among those with a positive result for tuberculosis infection. Among all children

Published
2020

18. Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium

Author

Inker, Lesley A, Grams, Morgan E, Levey, Andrew S, Coresh, Josef, Cirillo, Massimo, Collins, John F, Gansevoort, Ron T, Gutierrez, Orlando M, Hamano, Takayuki, Heine, Gunnar H, Ishikawa, Shizukiyo, Jee, Sun Ha, Kronenberg, Florian, Landray, Martin J, Miura, Katsuyuki, Nadkarni, Girish N, Peralta, Carmen A, Rothenbacher, Dietrich, Schaeffner, Elke, Sedaghat, Sanaz, Shlipak, Michael G, Zhang, Luxia, van Zuilen, Arjan D, Hallan, Stein I, Kovesdy, Csaba P, Woodward, Mark, Levin, Adeera, Astor, Brad, Appel, Larry, Greene, Tom, Chen, Teresa, Chalmers, John, Arima, Hisatomi, Perkovic, Vlado, Yatsuya, Hiroshi, Tamakoshi, Koji, Li, Yuanying, Hirakawa, Yoshihisa, Matsushita, Kunihiro, Grams, Morgan, Sang, Yingying, Polkinghorne, Kevan, Chadban, Steven, Atkins, Robert, Djurdjev, Ognjenka, Liu, Lisheng, Zhao, Minghui, Wang, Fang, Wang, Jinwei, Ebert, Natalie, Martus, Peter, Tang, Mila, Heine, Gunnar, Emrich, Insa, Seiler, Sarah, Zawada, Adam, Nally, Joseph, Navaneethan, Sankar, Schold, Jesse, Shlipak, Michael, Sarnak, Mark, Katz, Ronit, Hiramoto, Jade, Iso, Hiroyasu, Yamagishi, Kazumasa, Umesawa, Mitsumasa, Muraki, Isao, Fukagawa, Masafumi, Maruyama, Shoichi, Hasegawa, Takeshi, Fujii, Naohiko, Wheeler, David, Emberson, John, Townend, John, Landray, Martin, Brenner, Hermann, Schöttker, Ben, Saum, Kai-Uwe, Fox, Caroline, Hwang, Shih-Jen, Köttgen, Anna, Schneider, Markus P, Eckardt, Kai-Uwe, Green, Jamie, Kirchner, H Lester, and Chang, Alex R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Kidney Disease, Women's Health, Clinical Research, Renal and urogenital, Good Health and Well Being, Aged, Albuminuria, Blood Chemical Analysis, Creatinine, Cross-Sectional Studies, Disease Progression, Female, Global Health, Glomerular Filtration Rate, Humans, Hypertension, Renal, Internationality, Kidney Function Tests, Male, Middle Aged, Predictive Value of Tests, Renal Insufficiency, Chronic, Retrospective Studies, Sensitivity and Specificity, Severity of Illness Index, Urinalysis, CKD Prognosis Consortium, CKD stage, Chronic kidney disease, albuminuria, anemia, diabetes, glomerular filtration rate, hematocrit, hemoglobin, hyperparathyroidism, hypertension, individual-level meta-analysis, kidney function, laboratory abnormality, laboratory tests, meta-analysis, serum bicarbonate, serum calcium, serum intact parathyroid hormone, serum phosphorus, serum potassium, staging system, Public Health and Health Services, Urology & Nephrology, Clinical sciences
Abstract

Rationale & objectiveChronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.Study designCross-sectional individual participant-level analyses in a global consortium.Setting & study populations17 CKD and 38 general population and high-risk cohorts.Selection criteria for studiesCohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.Data extractionData were obtained and analyzed between July 2015 and January 2018.Analytical approachWe modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.ResultsThe CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).LimitationsVariations in study era, health care delivery system, typical diet, and laboratory assays.ConclusionsLower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

Published
2019

21. Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium

Author

Chang, Alex R, Grams, Morgan E, Ballew, Shoshana H, Bilo, Henk, Correa, Adolfo, Evans, Marie, Gutierrez, Orlando M, Hosseinpanah, Farhad, Iseki, Kunitoshi, Kenealy, Timothy, Klein, Barbara, Kronenberg, Florian, Lee, Brian J, Li, Yuanying, Miura, Katsuyuki, Navaneethan, Sankar D, Roderick, Paul J, Valdivielso, Jose M, Visseren, Frank LJ, Zhang, Luxia, Gansevoort, Ron T, Hallan, Stein I, Levey, Andrew S, Matsushita, Kunihiro, Shalev, Varda, Woodward, Mark, Astor, Brad, Appel, Larry, Greene, Tom, Chen, Teresa, Chalmers, John, Arima, Hisatomi, Perkovic, Vlado, Yatsuya, Hiroshi, Tamakoshi, Koji, Hirakawa, Yoshihisa, Coresh, Josef, Sang, Yingying, Polkinghorne, Kevan, Chadban, Steven, Atkins, Robert, Levin, Adeera, Djurdjev, Ognjenka, Klein, Ron, Lee, Kristine, Liu, Lisheng, Zhao, Minghui, Wang, Fang, Wang, Jinwei, Tang, Mila, Heine, Gunnar, Emrich, Insa, Zawada, Adam, Bauer, Lucie, Nally, Joseph, Schold, Jesse, Shlipak, Michael, Sarnak, Mark, Katz, Ronit, Hiramoto, Jade, Iso, Hiroyasu, Yamagishi, Kazumasa, Umesawa, Mitsumasa, Muraki, Isao, Fukagawa, Masafumi, Maruyama, Shoichi, Hamano, Takayuki, Hasegawa, Takeshi, Fujii, Naohiko, Jafar, Tazeen, Hatcher, Juanita, Poulter, Neil, Chaturvedi, Nish, Wheeler, David, Emberson, John, Townend, John, Landray, Martin, Brenner, Hermann, Schöttker, Ben, Saum, Kai-Uwe, Rothenbacher, Dietrich, Fox, Caroline, Hwang, Shih-Jen, Köttgen, Anna, Schneider, Markus P, Eckardt, Kai-Uwe, Green, Jamie, Kirchner, H Lester, Ito, Sadayoshi, Miyazaki, Mariko, Nakayama, Masaaki, Yamada, Cirillo, Massimo, Romundstad, Solfrid, Øvrehus, Marius, Langlo, Knut Asbjørn, Irie, Fujiko, Sairenchi, Toshimi, Rebholz, Casey M, and Young, Bessie

Subjects
Epidemiology, Health Sciences, Obesity, Kidney Disease, Cardiovascular, Aging, Prevention, Nutrition, Clinical Research, Good Health and Well Being, Adiposity, Adult, Aged, Aged, 80 and over, Body Height, Body Mass Index, Cohort Studies, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Mortality, Risk Factors, Waist Circumference, CKD Prognosis Consortium, Clinical Sciences, Public Health and Health Services, General & Internal Medicine, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

ObjectiveTo evaluate the associations between adiposity measures (body mass index, waist circumference, and waist-to-height ratio) with decline in glomerular filtration rate (GFR) and with all cause mortality.DesignIndividual participant data meta-analysis.SettingCohorts from 40 countries with data collected between 1970 and 2017.ParticipantsAdults in 39 general population cohorts (n=5 459 014), of which 21 (n=594 496) had data on waist circumference; six cohorts with high cardiovascular risk (n=84 417); and 18 cohorts with chronic kidney disease (n=91 607).Main outcome measuresGFR decline (estimated GFR decline ≥40%, initiation of kidney replacement therapy or estimated GFR

Published
2019

22. Grams ME, Sang Y, Ballew SH, et al, for the Chronic Kidney Disease Prognosis Consortium. Predicting timing of clinical outcomes in patients with chronic kidney disease and severely decreased glomerular filtration rate. Kidney Int. 2018;93:1442–1451

Author

Astor, Brad, Appel, Lawrence J, Levin, Adeera, Tang, Mila, Djurdjev, Ognjenka, Navaneethan, Sankar D, Jolly, Stacey E, Schold, Jesse D, Nally, Joseph V, Wheeler, David C, Emberson, Jonathan, Townend, John, Landray, Martin, Feldman, Harold I, Hsu, Chi-yuan, Lash, James P, Kalra, Philip A, Ritchie, James P, Maharajan, Raman, Middleton, Rachel J, O’Donoghue, Donal J, Eckardt, Kai-Uwe, Schneider, Markus P, Köttgen, Anna, Kronenberg, Florian, Bärthlein, Barbara, Chang, Alex R, Green, Jamie A, Kirchner, H Lester, Ho, Kevin, Marks, Angharad, Black, Corri, Prescott, Gordon J, Fluck, Nick, Nakayama, Masaaki, Miyazaki, Mariko, Yamamoto, Tae, Yamada, Wang, Angela Yee-Moon, Cheung, Sharon, Wong, Sharon, Chu, Jessie, Wu, Henry, Garg, Amit X, McArthur, Eric, Nash, Danielle M, Shalev, Varda, Chodick, Gabriel, Blankestijn, Peter J, Wetzels, Jack FM, van Zuilen, Arjan D, van den Brand, Jan A, Levey, Andrew S, Inker, Lesley A, Sarnak, Mark J, Tighiouart, Hocine, Zhang, Haitao, Stengel, Benedicte, Metzger, Marie, Flamant, Martin, Houillier, Pascal, Haymann, Jean-Philippe, Rios, Pablo G, Mazzuchi, Nelson, Gadola, Liliana, Lamadrid, Verónica, Sola, Laura, Collins, John F, Elley, C Raina, Kenealy, Timothy, Moranne, Olivier, Couchoud, Cecile, Vigneau, Cecile, Brunskill, Nigel J, Major, Rupert W, Shepherd, David, Medcalf, James F, Kovesdy, Csaba P, Kalantar-Zadeh, Kamyar, Molnar, Miklos Z, Sumida, Keiichi, Potukuchi, Praveen K, Heerspink, Hiddo JL, de Zeeuw, Dick, Brenner, Barry, Carrero, Juan Jesus, Gasparini, Alessandro, Qureshi, Abdul Rashid, Elinder, Carl-Gustaf, Visseren, Frank LJ, van der Graaf, Yolanda, Evans, Marie, Stendahl, Maria, Schön, Staffan, Segelmark, Mårten, Prütz, Karl-Göran, Naimark, David M, Tangri, Navdeep, and Mark, Patrick B

Subjects
Renal and urogenital, Chronic Kidney Disease Prognosis Consortium, Clinical Sciences, Urology & Nephrology
Abstract

The Chronic Kidney Disease (CKD) Prognosis Consortium is a collaborative author of the above-mentioned article. The CKD Prognosis Consortium investigators/collaborators are as follows: • African American Study of Kidney Disease and Hypertension (AASK): Brad Astor, Lawrence J. Appel; Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events (CanPREDDICT): Adeera Levin, Mila Tang, Ognjenka Djurdjev; Cleveland Clinic CKD Registry Study (CCF): Sankar D. Navaneethan, Stacey E. Jolly, Jesse D. Schold, Joseph V. Nally Jr.; Chronic Renal Impairment in Birmingham (CRIB): David C. Wheeler, Jonathan Emberson, John Townend, Martin Landray; Chronic Renal Insufficiency Cohort Study (CRIC): Harold I. Feldman, Chi-yuan Hsu, James P. Lash, Lawrence J. Appel; Chronic Renal Insufficiency Standards Implementation Study (CRISIS): Philip A. Kalra, James P. Ritchie, Raman Maharajan, Rachel J. Middleton, Donal J. O'Donoghue; German Chronic Kidney Disease Study (GCKD): Kai-Uwe Eckardt, Markus P. Schneider, Anna Köttgen, Florian Kronenberg, Barbara Bärthlein; Geisinger Health System: Alex R. Chang, Jamie A. Green, H. Lester Kirchner, Kevin Ho; Grampian Laboratory Outcomes, Morbidity and Mortality Studies – 2 (GLOMMS2): Angharad Marks, Corri Black, Gordon J. Prescott, Nick Fluck; Gonryo Study: Masaaki Nakayama, Mariko Miyazaki, Tae Yamamoto, Gen Yamada; Hong Kong CKD Studies: Angela Yee-Moon Wang, Sharon Cheung, Sharon Wong, Jessie Chu, Henry Wu; Ontario Institute for Clinical Evaluative Sciences, Provincial Kidney, Dialysis and Transplantation program (ICES KDT): Amit X. Garg, Eric McArthur, Danielle M. Nash; Maccabi Health System: Varda Shalev, Gabriel Chodick; Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of a Nurse Practitioner (MASTERPLAN): Peter J. Blankestijn, Jack F.M. Wetzels, Arjan D. van Zuilen, Jan A. van den Brand; Modification of Diet in Renal Disease Study (MDRD): Andrew S. Levey, Lesley A. Inker, Mark J. Sarnak, Hocine Tighiouart; Nanjing CKD Network Cohort Study (Nanjing CKD): Haitao Zhang; NephroTest Study (NephroTest): Benedicte Stengel, Marie Metzger, Martin Flamant, Pascal Houillier, Jean-Philippe Haymann; National Renal Healthcare Program – Uruguay (NRHP-URU): Pablo G. Rios, Nelson Mazzuchi, Liliana Gadola, Verónica Lamadrid, Laura Sola; New Zealand Diabetes Cohort Study (NZDCS): John F. Collins, C. Raina Elley, Timothy Kenealy; Parcours de Soins des Personnes Agées (PSPA): Olivier Moranne, Cecile Couchoud, Cecile Vigneau; Primary-Secondary Care Partnership to Prevent Adverse Outcomes in Chronic Kidney Disease (PSP CKD): Nigel J. Brunskill, Rupert W. Major, David Shepherd, James F. Medcalf; Racial and Cardiovascular Risk Anomalies in CKD Cohort (RCAV): Csaba P. Kovesdy, Kamyar Kalantar-Zadeh, Miklos Z. Molnar, Keiichi Sumida, Praveen K. Potukuchi; Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL): Hiddo J.L. Heerspink, Dick de Zeeuw, Barry Brenner; Stockholm CREAtinine Measurements Cohort (SCREAM): Juan Jesus Carrero, Alessandro Gasparini, Abdul Rashid Qureshi, Carl-Gustaf Elinder; Second Manifestations of ARTerial Disease Study (SMART): Frank L.J. Visseren, Yolanda van der Graaf; Swedish Renal Registry CKD Cohort (SRR CKD): Marie Evans, Maria Stendahl, Staffan Schön, Mårten Segelmark, Karl-Göran Prütz; Sunnybrook Cohort: David M. Naimark, Navdeep Tangri; West of Scotland CKD Study: Patrick B. Mark, Jamie P. Traynor, Colin C. Geddes, Peter C. Thomson.• CKD Prognosis Consortium Steering Committee: Alex R. Chang, Josef Coresh (Chair), Ron T. Gansevoort, Morgan E. Grams, Anna Köttgen, Andrew S. Levey, Kunihiro Matsushita, Mark Woodward, Luxia Zhang.• CKD Prognosis Consortium Data Coordinating Center: Shoshana H. Ballew (Assistant Project Director), Jingsha Chen (Programmer), Josef Coresh (Principal Investigator), Morgan E. Grams (Director of Nephrology Initiatives), Lucia Kwak (Programmer), Kunihiro Matsushita (Director), Yingying Sang (Lead Programmer), Aditya Surapaneni (Programmer), Mark Woodward (Senior Statistician).• Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on Prognosis and Optimal Management of Patients with Advanced CKD: Kai-Uwe Eckardt (Conference Co-Chair), Brenda R. Hemmelgarn (Conference Co-Chair), David C. Wheeler (KDIGO Co-Chair), Wolfgang C. Winkelmayer (KDIGO Co-Chair), John Davis (CEO), Danielle Green (Managing Director), Michael Cheung (Chief Scientific Officer), Tanya Green (Communications Director), Melissa McMahan (Programs Director).

Published
2018

23. Evans M, Grams ME, Sang Y, et al., for the Chronic Kidney Disease Prognosis Consortium. Risk factors for prognosis in patients with severely decreased GFR. Kidney Int Rep. 2018;3:625–637

Author

Astor, Brad, Appel, Lawrence J, Levin, Adeera, Djurdjev, Ognjenka, Tang, Mila, Navaneethan, Sankar D, Jolly, Stacey E, Schold, Jesse D, Nally, Joseph V, Wheeler, David C, Emberson, Jonathan, Townend, John, Landray, Martin, Feldman, Harold I, Hsu, Chi-yuan, Lash, James P, Kalra, Philip A, Ritchie, James P, Maharajan, Raman, Alderson, Helen, Lane, Beverly, Eckardt, Kai-Uwe, Schneider, Markus P, Köttgen, Anna, Kronenberg, Florian, Bärthlein, Barbara, Chang, Alex R, Green, Jamie A, Kirchner, H Lester, Ho, Kevin, Marks, Angharad, Black, Corri, Prescott, Gordon J, Fluck, Nick, Nakayama, Masaaki, Miyazaki, Mariko, Yamamoto, Tae, Yamada, Wang, Angela Yee-Moon, Cheung, Sharon, Wong, Sharon, Chu, Jessie, Wu, Henry, Shalev, Varda, Chodick, Gabriel, Blankestijn, Peter J, Wetzels, Jack FM, van Zuilen, Arjan D, van den Brand, Jan A, Levey, Andrew S, Inker, Lesley A, Sarnak, Mark J, Tighiouart, Hocine, Zhang, Haitao, Stengel, Benedicte, Rios, Pablo G, Mazzuchi, Nelson, Gadola, Liliana, Lamadrid, Verónica, Sola, Laura, Collins, John F, Elley, C Raina, Kenealy, Timothy, Moranne, Olivier, Couchoud, Cecile, Vigneau, Cecile, Brunskill, Nigel J, Major, Rupert W, Shepherd, David, Medcalf, James F, Kovesdy, Csaba P, Kalantar-Zadeh, Kamyar, Molnar, Miklos Z, Sumida, Keiichi, Potukuchi, Praveen K, Heerspink, Hiddo JL, de Zeeuw, Dick, Brenner, Barry, Carrero, Juan Jesus, Barany, Peter, Qureshi, Abdul Rashid, Elinder, Carl-Gustaf, Visseren, Frank LJ, van der Graaf, Yolanda, Evans, Marie, Stendahl, Maria, Schön, Staffan, Segelmark, Mårten, Prütz, Karl-Göran, Naimark, David M, Tangri, Navdeep, Mark, Patrick B, Traynor, Jamie P, Geddes, Colin C, Thomson, Peter C, and Coresh, Josef

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Renal and urogenital, Good Health and Well Being, Chronic Kidney Disease Prognosis Consortium, Biomedical and clinical sciences, Health sciences
Abstract

[This corrects the article DOI: 10.1016/j.ekir.2018.01.002.].

Published
2018

24. Serum potassium and adverse outcomes across the range of kidney function: a CKD Prognosis Consortium meta-analysis.

Author

Kovesdy, Csaba P, Matsushita, Kunihiro, Sang, Yingying, Brunskill, Nigel J, Carrero, Juan J, Chodick, Gabriel, Hasegawa, Takeshi, Heerspink, Hiddo L, Hirayama, Atsushi, Landman, Gijs WD, Levin, Adeera, Nitsch, Dorothea, Wheeler, David C, Coresh, Josef, Hallan, Stein I, Shalev, Varda, Grams, Morgan E, Astor, Brad, Appel, Larry, Greene, Tom, Chen, Teresa, Chalmers, John, Woodward, Mark, Arima, Hisatomi, Perkovic, Vlado, Djurdjev, Ognjenka, Zhang, Luxia, Liu, Lisheng, Zhao, Minghui, Wang, Fang, Wang, Jinwei, Tang, Mila, Iso, Hiroyasu, Yamagishi, Kazumasa, Umesawa, Mitsumasa, Muraki, Isao, Fukagawa, Masafumi, Maruyama, Shoichi, Hamano, Takayuki, Fujii, Naohiko, Wheeler, David, Emberson, John, Townend, John, Landray, Martin, Green, Jamie, Kirchner, H Lester, Chang, Alex R, Cirillo, Massimo, Jee, Sun Ha, Kimm, Heejin, Mok, Yejin, Wetzels, Jack FM, Blankestijn, Peter J, van Zuilen, Arjan D, Bots, M, Sarnak, Mark, Inker, Lesley, Roderick, Paul, Fletcher, Astrid, Bottinger, Erwin, Nadkarni, Girish N, Ellis, Stephen B, Nadukuru, Rajiv, Brunskill, Nigel, Major, Rupert, Shepherd, David, Medcalf, James, Gansevoort, Ron T, Bakker, Stephan JL, Heerspink, Hiddo J Lambers, Jassal, Simerjot K, Bergstrom, Jaclyn, Ix, Joachim H, Barrett-Connor, Elizabeth, Kovesdy, Csaba, Kalantar-Zadeh, Kamyar, de Zeeuw, Dick, Brenner, Barry, Gasparini, Alessandro, Elinder, Carl-Gustaf, Barany, Peter, Evans, Marie, Segelmark, Mårten, Stendahl, Maria, Schön, Staffan, Tangri, Navdeep, Sud, Maneesh, Naimark, David, Wen, Chi-Pang, and Tsao, Chwen-Keng

Subjects
Kidney Disease, Prevention, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Renal and urogenital, Cardiovascular, Good Health and Well Being, Adult, Aged, Albuminuria, Cardiovascular Diseases, Cause of Death, Comorbidity, Glomerular Filtration Rate, Humans, Hyperkalemia, Hypokalemia, Kidney Failure, Chronic, Middle Aged, Prognosis, Renal Insufficiency, Chronic, Risk Factors, Potassium, Estimated glomerular filtration rate, End-stage renal disease, Mortality, CKD Prognosis Consortium, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

AimsBoth hypo- and hyperkalaemia can have immediate deleterious physiological effects, and less is known about long-term risks. The objective was to determine the risks of all-cause mortality, cardiovascular mortality, and end-stage renal disease associated with potassium levels across the range of kidney function and evaluate for consistency across cohorts in a global consortium.Methods and resultsWe performed an individual-level data meta-analysis of 27 international cohorts [10 general population, 7 high cardiovascular risk, and 10 chronic kidney disease (CKD)] in the CKD Prognosis Consortium. We used Cox regression followed by random-effects meta-analysis to assess the relationship between baseline potassium and adverse outcomes, adjusted for demographic and clinical characteristics, overall and across strata of estimated glomerular filtration rate (eGFR) and albuminuria. We included 1 217 986 participants followed up for a mean of 6.9 years. The average age was 55 ± 16 years, average eGFR was 83 ± 23 mL/min/1.73 m2, and 17% had moderate- to-severe increased albuminuria levels. The mean baseline potassium was 4.2 ± 0.4 mmol/L. The risk of serum potassium of >5.5 mmol/L was related to lower eGFR and higher albuminuria. The risk relationship between potassium levels and adverse outcomes was U-shaped, with the lowest risk at serum potassium of 4-4.5 mmol/L. Compared with a reference of 4.2 mmol/L, the adjusted hazard ratio for all-cause mortality was 1.22 [95% confidence interval (CI) 1.15-1.29] at 5.5 mmol/L and 1.49 (95% CI 1.26-1.76) at 3.0 mmol/L. Risks were similar by eGFR, albuminuria, renin-angiotensin-aldosterone system inhibitor use, and across cohorts.ConclusionsOutpatient potassium levels both above and below the normal range are consistently associated with adverse outcomes, with similar risk relationships across eGFR and albuminuria.

Published
2018

28. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author

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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Diabetes, Atherosclerosis, Cardiovascular, Metabolic and endocrine, Amino Acid Substitution, Angiopoietin-Like Protein 4, Animals, Blood Glucose, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Gene Silencing, Genetic Association Studies, Genetic Variation, Heterozygote, Homeostasis, Humans, Insulin Resistance, Lipoprotein Lipase, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Risk Factors, Exome Sequencing
Abstract

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

Published
2018

29. Measures of chronic kidney disease and risk of incident peripheral artery disease: a collaborative meta-analysis of individual participant data

Author

Matsushita, Kunihiro, Ballew, Shoshana H, Coresh, Josef, Arima, Hisatomi, Ärnlöv, Johan, Cirillo, Massimo, Ebert, Natalie, Hiramoto, Jade S, Kimm, Heejin, Shlipak, Michael G, Visseren, Frank LJ, Gansevoort, Ron T, Kovesdy, Csaba P, Shalev, Varda, Woodward, Mark, Kronenberg, Florian, Chalmers, John, Perkovic, Vlado, Grams, Morgan E, Sang, Yingying, Schaeffner, Elke, Martus, Peter, Levin, Adeera, Djurdjev, Ognjenka, Tang, Mila, Heine, Gunnar, Seiler, Sarah, Zawada, Adam, Emrich, Insa, Sarnak, Mark, Katz, Ronit, Brenner, Hermann, Schöttker, Ben, Rothenbacher, Dietrich, Saum, Kai-Uwe, Köttgen, Anna, Schneider, Markus, Eckardt, Kai-Uwe, Green, Jamie, Kirchner, H Lester, Chang, Alex R, Black, Corri, Marks, Angharad, Prescott, Gordon, Clark, Laura, Fluck, Nick, Jee, Sun Ha, Mok, Yejin, Chodick, Gabriel, Wetzels, Jack FM, Blankestijn, Peter J, van Zuilen, Arjan D, Bots, M, Peralta, Carmen, Hiromoto, Jade, Bottinger, Erwin, Nadkarni, Girish N, Ellis, Stephen B, Nadukuru, Rajiv, Kenealy, Timothy, Elley, C Raina, Collins, John F, Drury, Paul L, Bakker, Stephan JL, Heerspink, Hiddo J Lambers, Jassal, Simerjot K, Bergstrom, Jaclyn, Ix, Joachim H, Barrett-Connor, Elizabeth, Kalantar-Zadeh, Kamyar, Carrero, Juan J, Gasparini, Alessandro, Qureshi, Abdul Rashid, Barany, Peter, Algra, Ale, van der Graaf, Yolanda, Evans, Marie, Segelmark, Mårten, Stendahl, Maria, Schön, Staffan, Tangri, Navdeep, Sud, Maneesh, Naimark, David, Lannfelt, Lars, Larsson, Anders, Hallan, Stein, Levey, Andrew S, Chen, Jingsha, and Kwak, Lucia

Subjects
Clinical Research, Kidney Disease, Prevention, Renal and urogenital, Good Health and Well Being, Adult, Aged, Albuminuria, Creatinine, Databases, Factual, Female, Glomerular Filtration Rate, Humans, Incidence, Male, Middle Aged, Peripheral Arterial Disease, Renal Insufficiency, Chronic, Risk Factors, Chronic Kidney Disease Prognosis Consortium, Medical Biochemistry and Metabolomics, Clinical Sciences, Public Health and Health Services
Abstract

BackgroundSome evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease.MethodsIn this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics.FindingsWe analysed 817 084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. 18 261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 7·4 years [IQR 5·7-8·9], range 2·0-15·8 years across cohorts). Both chronic kidney disease measures were independently associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 1·73 m2, adjusted hazard ratios (HRs) for incident study-specific peripheral artery disease was 1·22 (95% CI 1·14-1·30) at an eGFR of 45 mL/min per 1·73 m2 and 2·06 (1·70-2·48) at an eGFR of 15 mL/min per 1·73 m2. Compared with an ACR of 5 mg/g, the adjusted HR for incident study-specific peripheral artery disease was 1·50 (1·41-1·59) at an ACR of 30 mg/g and 2·28 (2·12-2·44) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 3·68 (95% CI 3·00-4·52) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 5·76 [4·90-6·77] for incident peripheral artery disease and 10·61 [5·70-19·77] for amputation in eGFR

Published
2017

30. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Author

Dewey, Frederick E, Gusarova, Viktoria, Dunbar, Richard L, O'Dushlaine, Colm, Schurmann, Claudia, Gottesman, Omri, McCarthy, Shane, Van Hout, Cristopher V, Bruse, Shannon, Dansky, Hayes M, Leader, Joseph B, Murray, Michael F, Ritchie, Marylyn D, Kirchner, H Lester, Habegger, Lukas, Lopez, Alex, Penn, John, Zhao, An, Shao, Weiping, Stahl, Neil, Murphy, Andrew J, Hamon, Sara, Bouzelmat, Aurelie, Zhang, Rick, Shumel, Brad, Pordy, Robert, Gipe, Daniel, Herman, Gary A, Sheu, Wayne HH, Lee, I-Te, Liang, Kae-Woei, Guo, Xiuqing, Rotter, Jerome I, Chen, Yii-Der I, Kraus, William E, Shah, Svati H, Damrauer, Scott, Small, Aeron, Rader, Daniel J, Wulff, Anders Berg, Nordestgaard, Børge G, Tybjærg-Hansen, Anne, van den Hoek, Anita M, Princen, Hans MG, Ledbetter, David H, Carey, David J, Overton, John D, Reid, Jeffrey G, Sasiela, William J, Banerjee, Poulabi, Shuldiner, Alan R, Borecki, Ingrid B, Teslovich, Tanya M, Yancopoulos, George D, Mellis, Scott J, Gromada, Jesper, and Baras, Aris

Subjects
Biomedical and Clinical Sciences, Atherosclerosis, Clinical Research, Genetics, Heart Disease, Human Genome, Heart Disease - Coronary Heart Disease, Cardiovascular, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Angiopoietin-Like Protein 3, Angiopoietin-like Proteins, Angiopoietins, Animals, Antibodies, Monoclonal, Cardiovascular Diseases, Coronary Artery Disease, Disease Models, Animal, Dose-Response Relationship, Drug, Double-Blind Method, Dyslipidemias, Female, Humans, Lipid Metabolism, Lipids, Male, Mice, Mice, Inbred Strains, Middle Aged, Mutation, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundLoss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease.MethodsWe sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol.ResultsIn the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%.ConclusionsGenetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

Published
2017

31. Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease

Author

Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V, Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A, Klarin, Derek, Natarajan, Pradeep, Zekavat, Seyedeh M, Gupta, Namrata, Peloso, Gina M, Borecki, Ingrid B, Teslovich, Tanya M, Asselta, Rosanna, Duga, Stefano, Merlini, Piera A, Correa, Adolfo, Kessler, Thorsten, Wilson, James G, Bown, Matthew J, Hall, Alistair S, Braund, Peter S, Carey, David J, Murray, Michael F, Kirchner, H Lester, Leader, Joseph B, Lavage, Daniel R, Manus, J Neil, Hartze, Dustin N, Samani, Nilesh J, Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Juang, Jyh-Ming J, Hsiung, Chao A, Lin, Shih-Yi, Wang, Jun-Sing, Tada, Hayato, Kawashiri, Masa-Aki, Inazu, Akihiro, Yamagishi, Masakazu, Katsuya, Tomohiro, Nakashima, Eitaro, Nakatochi, Masahiro, Yamamoto, Ken, Yokota, Mitsuhiro, Momozawa, Yukihide, Rotter, Jerome I, Lander, Eric S, Rader, Daniel J, Danesh, John, Ardissino, Diego, Gabriel, Stacey, Willer, Cristen J, Abecasis, Goncalo R, Saleheen, Danish, Kubo, Michiaki, Kato, Norihiro, Ida Chen, Yii-Der, Dewey, Frederick E, and Kathiresan, Sekar

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Heart Disease - Coronary Heart Disease, Atherosclerosis, Heart Disease, Cardiovascular, Adult, Aged, Case-Control Studies, Cholesterol Ester Transfer Proteins, Coronary Disease, Female, Genetic Variation, Humans, Male, Middle Aged, Risk Factors, case-control studies, cholesteryl ester transfer protein, coronary disease, lipids, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

RationaleTherapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition.ObjectiveTo test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD.Methods and resultsWe sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P

Published
2017

32. Abstract 13914: Additional ASCVD Risk Factors for Patients With Diabetes: FIB-4 Score and NLR Are Higher in Adults With Diabetes and Current Risk Enhancers vs No Risk Enhancers in Real-World Evidence

Author

Chapagain, Himal, Alish, Yousef, Becich, Michael, Bradley, Alison, Fernandez, Soledad, Ford, Dan, Hwang, Wenke, Jeong, Jong, Jurczak, Martha, Kirchner, H Lester, McTigue, Kathleen M, Morgan, Richard, Paranjape, Anuradha, Thomas, Neena, Williams, David, and Arnold, Jonathan

Published
2022
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34. Abstract 12482: Practical Adherence to AHA/ACC 2018 Guidelines Among Secondary Prevention Patients

Author

Kainat, Aleesha, Alish, Yousef, Ateya, Mohammad, Becich, Michael J, Bradley, Alison, Demicco, David A, Fernandez, Soledad, Ford, Dan, Hegeman-Dingle, Rozelle, Hwang, Wenke, Jeong, Jong, Jurczak, Martha O, Kirchner, H Lester, McLeod, Euan, McTigue, Kathleen M, Morgan, Richard S, Paranjape, Anuradha, Saccone, Phillip, Thomas, Neena, Townsend, Kevin A, Williams, David A, and Arnold, Jonathan

Published
2022
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37. Deep-learning-assisted analysis of echocardiographic videos improves predictions of all-cause mortality

Author

Ulloa Cerna, Alvaro E., Jing, Linyuan, Good, Christopher W., vanMaanen, David P., Raghunath, Sushravya, Suever, Jonathan D., Nevius, Christopher D., Wehner, Gregory J., Hartzel, Dustin N., Leader, Joseph B., Alsaid, Amro, Patel, Aalpen A., Kirchner, H. Lester, Pfeifer, John M., Carry, Brendan J., Pattichis, Marios S., Haggerty, Christopher M., and Fornwalt, Brandon K.

Published
2021
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38. Innovative Implementation Strategies for Familial Hypercholesterolemia Cascade Testing: The Impact of Genetic Counseling.

Author

Morgan, Kelly M., Campbell-Salome, Gemme, Walters, Nicole L., Betts, Megan N., Brangan, Andrew, Johns, Alicia, Kirchner, H. Lester, Lindsey-Mills, Zoe, McGowan, Mary P., Tricou, Eric P., Rahm, Alanna Kulchak, Sturm, Amy C., and Jones, Laney K.

Subjects
GENETIC counseling, FAMILIAL hypercholesterolemia, POISSON regression, CHATBOTS, GENETIC testing
Abstract

The IMPACT-FH study implemented strategies (packet, chatbot, direct contact) to promote family member cascade testing for familial hypercholesterolemia (FH). We evaluated the impact of genetic counseling (GC) on medical outcomes, strategy selection, and cascade testing. Probands (i.e., patients with FH) were recommended to complete GC and select sharing strategies. Comparisons were performed for both medical outcomes and strategy selection between probands with or without GC. GEE models for Poisson regression were used to examine the relationship between proband GC completion and first-degree relative (FDR) cascade testing. Overall, 46.3% (81/175) of probands completed GC. Probands with GC had a median LDL-C reduction of −13.0 mg/dL (−61.0, 4.0) versus −1.0 mg/dL (−16.0, 17.0) in probands without GC (p = 0.0054). Probands with and without GC selected sharing strategies for 65.3% and 40.3% of FDRs, respectively (p < 0.0001). Similarly, 27.1% of FDRs of probands with GC completed cascade testing, while 12.0% of FDRs of probands without GC completed testing (p = 0.0043). Direct contact was selected for 47 relatives in total and completed for 39, leading to the detection of 18 relatives with FH. Proband GC was associated with improved medical outcomes and increased FDR cascade testing. Direct contact effectively identified FH cases for the subset who participated. [ABSTRACT FROM AUTHOR]

Published
2024
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39. Positive impact of genetic counseling assistants on genetic counseling efficiency, patient volume, and cost in a cancer genetics clinic

Author

Hallquist, Miranda L.G., Tricou, Eric P., Hallquist, Michael N., Savatt, Juliann M., Rocha, Heather, Evans, Alyson E., Deckard, Nicole, Hu, Yirui, Kirchner, H. Lester, Pervola, Josie, Rahm, Alanna Kulchak, Rashkin, Misha, Schmidlen, Tara J., Schwartz, Marci L.B., Williams, Janet L., Williams, Marc S., and Buchanan, Adam H.

Published
2020
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41. A Machine Learning Approach to Management of Heart Failure Populations

Author

Jing, Linyuan, Ulloa Cerna, Alvaro E., Good, Christopher W., Sauers, Nathan M., Schneider, Gargi, Hartzel, Dustin N., Leader, Joseph B., Kirchner, H. Lester, Hu, Yirui, Riviello, David M., Stough, Joshua V., Gazes, Seth, Haggerty, Allyson, Raghunath, Sushravya, Carry, Brendan J., Haggerty, Christopher M., and Fornwalt, Brandon K.

Published
2020
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42. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis

Author

Acuna-Villaorduna, Carlos, Desai Ahuja, Shama, Altet, Neus, Augusto, Orvalho, Baliashvili, Davit, Basu, Sanjay, Becerra, Mercedes, Bonnet, Maryline, Henry Boom, W., Borgdorff, Martien, Boulahbal, Fadila, Carvalho, Anna Cristina C., Cayla, Joan A., Chakhaia, Tsira, Chan, Pei-Chun, Cohen, Ted, Croda, Julio, Datta, Sumona, del Corral, Helena, Denholm, Justin T., Dietze, Reynaldo, Dobler, Claudia C., Donkor, Simon, Egere, Uzochukwu, Ellner, Jerrold J., Espinal, Marcos, Evans, Carlton A., Fang, Chi-Tai, Fielding, Katherine, Fox, Greg J., García, Luis F., García-Basteiro, Alberto L., Geis, Steffen, Graham, Stephen M., Grandjean, Louis, Hannoun, Djohar, Hatherill, Mark, Hauri, Anja M., Hesseling, Anneke C., Hill, Philip C., Huang, Li-Min, Huerga, Helena, Hussain, Rabia, Jarlsberg, Leah, Jones-López, Edward C., Kato, Seiya, Kato-Maeda, Midori, Kampmann, Beate, Kirchner, H. Lester, Kritski, Afrânio, Lange, Christoph, Lee, Chih-Hsin, Lee, Li-Na, Lee, Meng-Rui, Lemos, Antonio Carlos, Lienhardt, Christian, Ling, Du-Lin, Liu, Qiao, Lo, Nathan C., Long, Richard, Lopez-Varela, Elisa, Lu, Peng, Magee, Matthew, Malone, LaShaunda L., Mandalakas, Anna M., Martinson, Neil A., Mazahir, Rufaida, Murray, Megan B., Netto, Eduardo Martins, Otero, Larissa, Parsonnet, Julie, Reingold, Arthur, Schaaf, H. Simon, Seddon, James A., Sharma, Surendra, Singh, Jitendra, Singh, Sarman, Sloot, Rosa, Sotgiu, Giovanni, Stein, Catherine M., Iqbal, Najeeha Talat, Triasih, Rina, Trieu, Lisa, van der Loeff, Maarten F Schim, Van der Stuyft, Patrick, van Schalkwyk, Cari, Vashishtha, Richa, Verhagen, Lilly M, Villalba, Julian A., Wang, Jann-Yuan, Whalen, Christopher C., Yoshiyama, Takashi, Zar, Heather J., Zellweger, Jean-Pierre, Zhu, Limei, Martinez, Leonardo, Cords, Olivia, Horsburgh, C Robert, and Andrews, Jason R

Published
2020
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43. The Relationship Between Integrated Pediatric Psychology and Primary Care Visit Length, Revenue, Content Over 24 Months

Author

Gormley, Matthew J., Meadows, Tawnya J., Hostermans, Shelley J., Kettlewell, Paul W., Kirchner, H. Lester, and O'Dell, Sean M.

Subjects
Childhood mental disorders -- Care and treatment, Child psychiatric services -- Economic aspects, Health care teams -- Methods -- Economic aspects, Primary health care -- Methods -- Economic aspects, Family and marriage, Health, Psychology and mental health
Abstract

Introduction: Integrating behavioral health providers into pediatric primary care to provide behavioral health (BH) services is both effective and efficient; however, the impact of pediatric integrated services on the operational and financial outcomes of primary care provider (PCP) visits has not been thoroughly investigated. The present study examined whether length of practice integration predicts the relationship between BH content addressed in a PCP visit, visit length, and revenue generation. Method: A total of 1,209 pediatric encounters with 25 PCPs across 7 primary care offices in a predominantly rural health system were abstracted for the presence or absence of BH content, visit length, duration of integration, and revenue. [x.sup.2] analyses and the generalized linear model framework were used to address the study objectives. Results: Integration was associated with more PCP visits with a BH topic discussed at 6-11 months of integration but not at 14-24 months. Visits with a BH topic were longer than medical-only visits and shorter when a practice was integrated for 6-11 months but not at 14-24 months of integration. Public insurance and integration were associated with lower revenue generation per minute. Visit content was not associated with PCP revenue. Discussion: Results suggest a relationship between integration and the operational and financial outcomes of PCP visits. This study shows that initial efficiencies or improvements (e.g., time, cost, content) associated with integrating BH may be lost over time. Future studies should evaluate sustainability in relation to program impact. Keywords: behavioral health, primary care, integrated care, pediatric, Greater than 20% of children and adolescents meet diagnostic criteria for at least one behavioral health (BH) disorder, and greater than 40% experience clinically significant impairment because of subclinical presentations [...]

Published
2020
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44. Prediction of mortality from 12-lead electrocardiogram voltage data using a deep neural network

Author

Raghunath, Sushravya, Ulloa Cerna, Alvaro E., Jing, Linyuan, vanMaanen, David P., Stough, Joshua, Hartzel, Dustin N., Leader, Joseph B., Kirchner, H. Lester, Stumpe, Martin C., Hafez, Ashraf, Nemani, Arun, Carbonati, Tanner, Johnson, Kipp W., Young, Katelyn, Good, Christopher W., Pfeifer, John M., Patel, Aalpen A., Delisle, Brian P., Alsaid, Amro, Beer, Dominik, Haggerty, Christopher M., and Fornwalt, Brandon K.

Published
2020
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46. Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies

Author

Appel, Lawrence J, Greene, Tom, Chen, Teresa K, Chalmers, John, Arima, Hisatomi, Perkovic, Vlado, Levin, Adeera, Djurdjev, Ognjenka, Tang, Mila, Nally, Joseph, Navaneethan, Sankar D, Schold, Jesse D, Weldegiorgis, Misghina, Herrington, William G, Smith, Margaret, Hsu, C Yenchih, Hwang, Shih-Jen, Chang, Alex R, Kirchner, H. Lester, Green, Jamie A, Ho, Kevin, Marks, Angharad, Prescott, Gordon, Clark, Laura E, Fluck, Nick, Shalev, Varda, Chodick, Gabriel, Blankestijn, Peter J, Van Zuilen, Arjan, Van den Brand, Jan A, Sarnak, Mark J, Bottinger, Erwin, Nadkarni, Girish N, Ellis, Stephen G, Nadukuru, Rajiv, Metzger, Marie, Flamant, Martin, Houillier, Pascal, Haymann, Jean-Philippe, Froissart, Marc, Kenealy, Timothy, Elley, Raina C, Collins, John F, Drury, Paul L, Cuddeback, John K, Ciemins, Elizabeth L, Stempniewicz, Rich, Nelson, Robert G, Knowler, William C, Bakker, Stephen J, Major, Rupert W, Medcalf, James F, Shepherd, David, Barrett-Connor, Elizabeth, Bergstrom, Jaclyn, Ix, Joachim H, Molnar, Miklos Z, Sumida, Keiichi, de Zeeuw, Dick, Brenner, Barry, Qureshi, Abdul R, Elinder, Carl-Gustaf, Runesson, Bjorn, Evans, Marie, Segelmark, Marten, Stendahl, Maria, Schön, Staffan, Naimark, David M, Tangri, Navdeep, Sud, Maneesh, Hirayama, Atsushi, Ichikawa, Kazunobu, Bilo, Henk JG, Landman, Gijs WD, Van Hateren, Kornelis JJ, Kleefstra, Nanne, Hallan, Stein I, Ballew, Shoshana H, Chen, Jingsha, Kwak, Lucia, Surapaneni, Aditya, Parving, Hans-Henrik, Rodby, Roger A., Rohde, Richard D, Lewis, Julia B, Lewis, Edmund, Perrone, Ronald D, Abebe, Kaleab Z, Hou, Fan F, Xie, Di, Hunsicker, Lawrence G, Imai, Enyu, Kobayashi, Fumiaki, Makino, Hirofumi, Ito, Sadayoshi, Remuzzi, Giuseppe, Ruggenenti, Piero, Eckardt, Kai-Uwe, Gudmundsdottir, Hrefna, Maciulaitis, Romaldas, Manley, Tom, Smith, Kimberly, Stockbridge, Norman, Thompson, Aliza, Vetter, Thorsten, Willis, Kerry, Zhang, Luxia, Coresh, Josef, Heerspink, Hiddo J L, Sang, Yingying, Matsushita, Kunihiro, Arnlov, Johan, Astor, Brad C, Black, Corri, Brunskill, Nigel J, Carrero, Juan-Jesus, Feldman, Harold I, Fox, Caroline S, Inker, Lesley A, Ishani, Areef, Jassal, Simerjot, Konta, Tsuneo, Polkinghorne, Kevan, Romundstad, Solfrid, Solbu, Marit D, Stempniewicz, Nikita, Stengel, Benedicte, Tonelli, Marcello, Umesawa, Mitsumasa, Waikar, Sushrut S, Wen, Chi-Pang, Wetzels, Jack F M, Woodward, Mark, Grams, Morgan E, Kovesdy, Csaba P, Levey, Andrew S, and Gansevoort, Ron T

Published
2019
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47. Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium

Author

Astor, Brad, Appel, Larry, Greene, Tom, Chen, Teresa, Chalmers, John, Woodward, Mark, Arima, Hisatomi, Perkovic, Vlado, Yatsuya, Hiroshi, Tamakoshi, Koji, Li, Yuanying, Hirakawa, Yoshihisa, Coresh, Josef, Matsushita, Kunihiro, Grams, Morgan, Sang, Yingying, Polkinghorne, Kevan, Chadban, Steven, Atkins, Robert, Levin, Adeera, Djurdjev, Ognjenka, Zhang, Luxia, Liu, Lisheng, Zhao, Minghui, Wang, Fang, Wang, Jinwei, Schaeffner, Elke, Ebert, Natalie, Martus, Peter, Tang, Mila, Heine, Gunnar, Emrich, Insa, Seiler, Sarah, Zawada, Adam, Nally, Joseph, Navaneethan, Sankar, Schold, Jesse, Shlipak, Michael, Sarnak, Mark, Katz, Ronit, Hiramoto, Jade, Iso, Hiroyasu, Yamagishi, Kazumasa, Umesawa, Mitsumasa, Muraki, Isao, Fukagawa, Masafumi, Maruyama, Shoichi, Hamano, Takayuki, Hasegawa, Takeshi, Fujii, Naohiko, Wheeler, David, Emberson, John, Townend, John, Landray, Martin, Brenner, Hermann, Schöttker, Ben, Saum, Kai-Uwe, Rothenbacher, Dietrich, Fox, Caroline, Hwang, Shih-Jen, Köttgen, Anna, Kronenberg, Florian, Schneider, Markus P., Eckardt, Kai-Uwe, Green, Jamie, Kirchner, H Lester, Chang, Alex R., Ho, Kevin, Ito, Sadayoshi, Miyazaki, Mariko, Nakayama, Masaaki, Yamada, Gen, Cirillo, Massimo, Irie, Fujiko, Sairenchi, Toshimi, Ishikawa, Shizukiyo, Yano, Yuichiro, Kotani, Kazuhiko, Nakamura, Takeshi, Jee, Sun Ha, Kimm, Heejin, Mok, Yejin, Chodick, Gabriel, Shalev, Varda, Wetzels, Jack F.M., Blankestijn, Peter J., van Zuilen, Arjan D., van den Brand, Jan, Inker, Lesley, Peralta, Carmen, Kollerits, Barbara, Ritz, Eberhard, Nitsch, Dorothea, Roderick, Paul, Fletcher, Astrid, Bottinger, Erwin, Nadkarni, Girish N., Ellis, Stephen B., Nadukuru, Rajiv, Ueshima, Hirotsugu, Okayama, Akira, Miura, Katsuyuki, Tanaka, Sachiko, Okamura, Tomonori, Kadota, Aya, Kenealy, Timothy, Elley, C Raina, Collins, John F., Drury, Paul L., Ohkubo, Takayoshi, Asayama, Kei, Metoki, Hirohito, Kikuya, Masahiro, Nelson, Robert G., Knowler, William C., Gansevoort, Ron T., Bakker, Stephan JL., Hak, Eelco, Heerspink, Hiddo J.L., Brunskill, Nigel, Major, Rupert, Shepherd, David, Medcalf, James, Jassal, Simerjot K., Bergstrom, Jaclyn, Ix, Joachim H., Barrett-Connor, Elizabeth, Kovesdy, Csaba, Kalantar-Zadeh, Kamyar, Sumida, Keiichi, Gutierrez, Orlando M., Muntner, Paul, Warnock, David, McClellan, William, de Zeeuw, Dick, Brenner, Barry, Sedaghat, Sanaz, Ikram, M Arfan, Hoorn, Ewout J., Dehghan, Abbas, Carrero, Juan J., Gasparini, Alessandro, Wettermark, Björn, Elinder, Carl-Gustaf, Wong, Tien Yin, Sabanayagam, Charumathi, Cheng, Ching-Yu, Visseren, Frank L.J., Evans, Marie, Segelmark, Mårten, Stendahl, Maria, Schön, Staffan, Tangri, Navdeep, Sud, Maneesh, Naimark, David, Wen, Chi-Pang, Tsao, Chwen-Keng, Tsai, Min-Kugng, Chen, Chien-Hua, Konta, Tsuneo, Hirayama, Atsushi, Ichikawa, Kazunobu, Lannfelt, Lars, Larsson, Anders, Ärnlöv, Johan, Bilo, Henk J.G., Landman, Gijs W.D., van Hateren, Kornelis J.J., Kleefstra, Nanne, Coresh (Chair, Josef, Grams, Morgan E., Hallan, Stein, Kovesdy, Csaba P., Levey, Andrew S., Ballew, Shoshana H., Chen, Jingsha, Kwak, Lucia, Surapaneni, Aditya, Inker, Lesley A., Heine, Gunnar H., Landray, Martin J., Peralta, Carmen A., Shlipak, Michael G., and Hallan, Stein I.

Published
2019
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48. 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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