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267 results on '"Dewey, Frederick E."'

1. 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

2. 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
Genetics, Heart Disease, Clinical Research, Atherosclerosis, Heart Disease - Coronary Heart Disease, Cardiovascular, Aetiology, 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
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

3. 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, Cardiovascular, Heart Disease, Atherosclerosis, Heart Disease - Coronary Heart Disease, 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

4. Clinical Interpretation and Implications of Whole-Genome Sequencing

Author

Dewey, Frederick E, Grove, Megan E, Pan, Cuiping, Goldstein, Benjamin A, Bernstein, Jonathan A, Chaib, Hassan, Merker, Jason D, Goldfeder, Rachel L, Enns, Gregory M, David, Sean P, Pakdaman, Neda, Ormond, Kelly E, Caleshu, Colleen, Kingham, Kerry, Klein, Teri E, Whirl-Carrillo, Michelle, Sakamoto, Kenneth, Wheeler, Matthew T, Butte, Atul J, Ford, James M, Boxer, Linda, Ioannidis, John PA, Yeung, Alan C, Altman, Russ B, Assimes, Themistocles L, Snyder, Michael, Ashley, Euan A, and Quertermous, Thomas

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Genetic Testing, Cancer, Biotechnology, Genetics, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Female, Genes, BRCA1, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genotype, Humans, Male, Middle Aged, Mutation, Pharmacogenetics, Reproducibility of Results, Sequence Analysis, DNA, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceWhole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.ObjectivesTo examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.Design, setting, and participantsAn exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Main outcomes and measuresGenome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.ResultsDepending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P

Published
2014

5. Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.

Author

Dewey, Frederick E, Chen, Rong, Cordero, Sergio P, Ormond, Kelly E, Caleshu, Colleen, Karczewski, Konrad J, Whirl-Carrillo, Michelle, Wheeler, Matthew T, Dudley, Joel T, Byrnes, Jake K, Cornejo, Omar E, Knowles, Joshua W, Woon, Mark, Sangkuhl, Katrin, Gong, Li, Thorn, Caroline F, Hebert, Joan M, Capriotti, Emidio, David, Sean P, Pavlovic, Aleksandra, West, Anne, Thakuria, Joseph V, Ball, Madeleine P, Zaranek, Alexander W, Rehm, Heidi L, Church, George M, West, John S, Bustamante, Carlos D, Snyder, Michael, Altman, Russ B, Klein, Teri E, Butte, Atul J, and Ashley, Euan A

Subjects
Humans, Thrombophilia, Genetic Predisposition to Disease, Risk Assessment, Pedigree, Sequence Alignment, Sequence Analysis, DNA, DNA Mutational Analysis, Base Sequence, Genotype, Haplotypes, Alleles, Genes, Synthetic, Genome, Human, Reference Standards, Female, Male, Genetic Variation, Genome-Wide Association Study, Biotechnology, Genetics, Human Genome, 2.1 Biological and endogenous factors, Generic health relevance, Developmental Biology
Abstract

Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

Published
2011

6. Correction to: Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants

Author

Buchanan, Adam H., Manickam, Kandamurugu, Meyer, Michelle N., Wagner, Jennifer K., Hallquist, Miranda L. G., Williams, Janet L., Rahm, Alanna Kulchak, Williams, Marc S., Chen, Zong-Ming E., Shah, Chaitali K., Garg, Tullika K., Lazzeri, Amanda L., Schwartz, Marci L. B., Lindbuchler, D’ Andra M., Fan, Audrey L., Leeming, Rosemary, Servano, III, Pedro O., Smith, Ashlee L., Vogel, Victor G., Abul-Husn, Noura S., Dewey, Frederick E., Lebo, Matthew S., Mason-Suares, Heather M., Ritchie, Marylyn D., Davis, F. Daniel, Carey, David J., Feinberg, David T., Faucett, W. Andrew, Ledbetter, David H., and Murray, Michael F.

Published
2021
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8. Genetic identification of familial hypercholesterolemia within a single U.S. health care system

Author

Abul-Husn, Noura S., Manickam, Kandamurugu, Jones, Laney K., Wright, Eric A., Hartzel, Dustin N., Gonzaga-Jauregui, Claudia, O'Dushlaine, Colm, Leader, Joseph B., Kirchner, H. Lester, Lindbuchler, D'Andra M., Barr, Marci L., Giovanni, Monica A., Ritchie, Marylyn D., Overton, John D., Reid, Jeffrey G., Metpally, Raghu P. R., Wardeh, Amr H., Borecki, Ingrid B., Yancopoulos, George D., Baras, Aris, Shuldiner, Alan R., Gottesman, Omri, Ledbetter, David H., Carey, David J., Dewey, Frederick E., and Murray, Michael F.

Published
2016

9. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology

Author

Nielsen, Jonas B., Thorolfsdottir, Rosa B., Fritsche, Lars G., Zhou, Wei, Skov, Morten W., Graham, Sarah E., Herron, Todd J., McCarthy, Shane, Schmidt, Ellen M., Sveinbjornsson, Gardar, Surakka, Ida, Mathis, Michael R., Yamazaki, Masatoshi, Crawford, Ryan D., Gabrielsen, Maiken E., Skogholt, Anne Heidi, Holmen, Oddgeir L., Lin, Maoxuan, Wolford, Brooke N., Dey, Rounak, Dalen, Håvard, Sulem, Patrick, Chung, Jonathan H., Backman, Joshua D., Arnar, David O., Thorsteinsdottir, Unnur, Baras, Aris, O’Dushlaine, Colm, Holst, Anders G., Wen, Xiaoquan, Hornsby, Whitney, Dewey, Frederick E., Boehnke, Michael, Kheterpal, Sachin, Mukherjee, Bhramar, Lee, Seunggeun, Kang, Hyun M., Holm, Hilma, Kitzman, Jacob, Shavit, Jordan A., Jalife, José, Brummett, Chad M., Teslovich, Tanya M., Carey, David J., Gudbjartsson, Daniel F., Stefansson, Kari, Abecasis, Gonçalo R., Hveem, Kristian, and Willer, Cristen J.

Published
2018
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10. Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants

Author

Buchanan, Adam H, Manickam, Kandamurugu, Meyer, Michelle N, Wagner, Jennifer K, Hallquist, Miranda L G, Williams, Janet L, Rahm, Alanna Kulchak, Williams, Marc S, Chen, Zong-Ming E, Shah, Chaitali K, Garg, Tullika K, Lazzeri, Amanda L, Schwartz, Marci L B, Lindbuchler, D'Andra M, Fan, Audrey L, Leeming, Rosemary, Servano, III, Pedro O, Smith, Ashlee L, Vogel, Victor G, Abul-Husn, Noura S, Dewey, Frederick E, Lebo, Matthew S, Mason-Suares, Heather M, Ritchie, Marylyn D, Davis, F Daniel, Carey, David J, Feinberg, David T, Faucett, W Andrew, Ledbetter, David H, and Murray, Michael F

Published
2018
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11. Early somatic mosaicism is a rare cause of long-QT syndrome

Author

Priest, James Rush, Gawad, Charles, Kahlig, Kristopher M., Yu, Joseph K., O’Hara, Thomas, Boyle, Patrick M., Rajamani, Sridharan, Clark, Michael J., Garcia, Sarah T. K., Ceresnak, Scott, Harris, Jason, Boyle, Sean, Dewey, Frederick E., Malloy-Walton, Lindsey, Dunn, Kyla, Grove, Megan, Perez, Marco V., Neff, Norma F., Chen, Richard, Maeda, Katsuhide, Dubin, Anne, Belardinelli, Luiz, West, John, Antolik, Christian, Macaya, Daniela, Quertermous, Thomas, Trayanova, Natalia A., Quake, Stephen R., and Ashley, Euan A.

Published
2016

13. Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants

Author

Haggerty, Christopher M., Damrauer, Scott M., Levin, Michael G., Birtwell, David, Carey, David J., Golden, Alicia M., Hartzel, Dustin N., Hu, Yirui, Judy, Renae, Kelly, Melissa A., Kember, Rachel L., Lester Kirchner, H., Leader, Joseph B., Liang, Lusha, McDermott-Roe, Chris, Babu, Apoorva, Morley, Michael, Nealy, Zachariah, Person, Thomas N., Pulenthiran, Arichanah, Small, Aeron, Smelser, Diane T., Stahl, Richard C., Sturm, Amy C., Williams, Heather, Baras, Aris, Margulies, Kenneth B., Cappola, Thomas P., Dewey, Frederick E., Verma, Anurag, Zhang, Xinyuan, Correa, Adolfo, Hall, Michael E., Wilson, James G., Ritchie, Marylyn D., Rader, Daniel J., Murray, Michael F., Fornwalt, Brandon K., and Arany, Zoltan

Published
2019
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14. Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy

Author

De Jong, Hannah N., primary, Dewey, Frederick E., additional, Cordero, Pablo, additional, Victorio, Rachelle A., additional, Kirillova, Anna, additional, Huang, Yong, additional, Madhvani, Roshni, additional, Seo, Kinya, additional, Werdich, Andreas A., additional, Lan, Feng, additional, Orcholski, Mark, additional, Liu, W. Robert, additional, Erbilgin, Ayca, additional, Wheeler, Matthew T., additional, Chen, Rui, additional, Pan, Stephen, additional, Kim, Young M., additional, Bommakanti, Krishna, additional, Marcou, Cherisse A., additional, Bos, J. Martijn, additional, Haddad, Francois, additional, Ackerman, Michael, additional, Vasan, Ramachandran S., additional, MacRae, Calum, additional, Wu, Joseph C., additional, de Jesus Perez, Vinicio, additional, Snyder, Michael, additional, Parikh, Victoria N., additional, and Ashley, Euan A., additional

Published
2022
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15. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease

Author

Abul-Husn, Noura S., Cheng, Xiping, Li, Alexander H., Xin, Yurong, Schurmann, Claudia, Stevis, Panayiotis, Liu, Yashu, Kozlitina, Julia, Stender, Stefan, Wood, Craig G., Stepanchick, Ann N., Still, Matthew D., McCarthy, Shane, OʼDushlaine, Colm, Packer, Jonathan S., Balasubramanian, Suganthi, Gosalia, Nehal, Esopi, David, Kim, Sun Y., Mukherjee, Semanti, Lopez, Alexander E., Fuller, Erin D., Penn, John, Chu, Xin, Luo, Jonathan Z., Mirshahi, Uyenlinh L., Carey, David J., Still, Christopher D., Feldman, Michael D., Small, Aeron, Damrauer, Scott M., Rader, Daniel J., Zambrowicz, Brian, Olson, William, Murphy, Andrew J., Borecki, Ingrid B., Shuldiner, Alan R., Reid, Jeffrey G., Overton, John D., Yancopoulos, George D., Hobbs, Helen H., Cohen, Jonathan C., Gottesman, Omri, Teslovich, Tanya M., Baras, Aris, Mirshahi, Tooraj, Gromada, Jesper, and Dewey, Frederick E.

Published
2018
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17. Abstract 14753: Loss of Function ABCC8 Mutations Are Associated With Pulmonary Arterial Hypertension

Author

Bohnen, Michael S, Ma, Lijiang, Zhu, Na, Qi, Hongjian, McClenaghan, Conor, Gonzaga-Jauregui, Claudia, Dewey, Frederick E, Overton, John D, Reid, Jeffrey G, Shuldiner, Alan R, Baras, Aris, Sampson, Kevin J, Bleda, Marta, Hadinnapola, Charaka, Haimel, Matthias, Bogaard, Harm J, Church, Colin, Coghlan, Gerry, Corris, Paul A, Eyries, Mélanie, Gibbs, J. Simon R, Girerd, Barbara, Houweling, Arjan C, Humbert, Marc, Kiely, David G, Lawrie, Allan, MacKenzie Ross, Rob V, Martin, Jennifer M, Montani, David, Peacock, Andrew J, Pepke-Zaba, Joanna, Soubrier, Florent, Suntharalingam, Jay, Toshner, Mark, Treacy, Carmen M, Trembath, Richard C, Vonk Noordegraaf, Anton, Wharton, John, Wilkins, Martin R, Wort, Stephen J, Yates, Katherine, Gräf, Stefan, Morrell, Nicholas W, Krishnan, Usha, Rosenzweig, Erika B, Shen, Yufeng, Nichols, Colin G, Kass, Robert S, and Chung, Wendy K

Published
2017

20. Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

Author

Zhu, Na, Welch, Carrie L., Wang, Jiayao, Allen, Philip M., Gonzaga-Jauregui, Claudia, Ma, Lijiang, King, Alejandra K., Krishnan, Usha, Rosenzweig, Erika B., Ivy, D. Dunbar, Austin, Eric D., Hamid, Rizwan, Pauciulo, Michael W., Lutz, Katie A., Nichols, William C., Reid, Jeffrey G., Overton, John D., Baras, Aris, Dewey, Frederick E., Shen, Yufeng, and Chung, Wendy K.

Published
2018
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22. Supplement to: Inactivating variants in ANGPTL4 and risk of coronary artery disease.

Author

Dewey, Frederick E., Gusarova, Viktoria, OʼDushlaine, Colm, Gottesman, Omri, Trejos, Jesus, Hunt, Charleen, Van Hout, Cristopher V., Habegger, Lukas, Buckler, David, Lai, Ka-Man V., Leader, Joseph B., Murray, Michael F., Ritchie, Marylyn D., Kirchner, Lester H., Ledbetter, David H., Penn, John, Lopez, Alexander, Borecki, Ingrid B., Overton, John D., Reid, Jeffrey G., Carey, David J., Murphy, Andrew J., Yancopoulos, George D., Baras, Aris, Gromada, Jesper, and Shuldiner, Alan R.

Published
2016

23. Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease

Author

Khera, Amit V., Won, Hong-Hee, Peloso, Gina M., O’Dushlaine, Colm, Liu, Dajiang, Stitziel, Nathan O., Natarajan, Pradeep, Nomura, Akihiro, Emdin, Connor A., Gupta, Namrata, Borecki, Ingrid B., Asselta, Rosanna, Duga, Stefano, Merlini, Piera Angelica, 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, Hartzel, Dustin N., Samani, Nilesh J., Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Lander, Eric S., Rader, Daniel J., Danesh, John, Ardissino, Diego, Gabriel, Stacey, Willer, Cristen, Abecasis, Gonçalo R., Saleheen, Danish, Dewey, Frederick E., and Kathiresan, Sekar

Published
2017
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24. Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease

Author

Dewey, Frederick E., Gusarova, Viktoria, OʼDushlaine, Colm, Gottesman, Omri, Trejos, Jesus, Hunt, Charleen, Van Hout, Cristopher V., Habegger, Lukas, Buckler, David, Lai, Ka-Man V., Leader, Joseph B., Murray, Michael F., Ritchie, Marylyn D., Kirchner, Lester H., Ledbetter, David H., Penn, John, Lopez, Alexander, Borecki, Ingrid B., Overton, John D., Reid, Jeffrey G., Carey, David J., Murphy, Andrew J., Yancopoulos, George D., Baras, Aris, Gromada, Jesper, and Shuldiner, Alan R.

Published
2016
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25. Clinical assessment incorporating a personal genome

Author

Ashley, Euan A, Butte, Atul J, Wheeler, Matthew T, Chen, Rong, Klein, Teri E, Dewey, Frederick E, Dudley, Joel T, Ormond, Kelly E, Pavlovic, Aleksandra, Morgan, Alexander A, Pushkarev, Dmitry, Neff, Norma F, Hudgins, Louanne, Gong, Li, Hodges, Laura M, Berlin, Dorit S, Thorn, Caroline F, Sangkuhl, Katrin, Hebert, Joan M, Woon, Mark, Sagreiya, Hersh, Whaley, Ryan, Knowles, Joshua W, Chou, Michael F, Thakuria, Joseph V, Rosenbaum, Abraham M, Zaranek, Alexander Wait, Church, George M, Greely, Henry T, Quake, Stephen R, and Altman, Russ B

Published
2010
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30. Age-adjusted modification of the Duke Treadmill Score nomogram

Author

Rafie, Amir H. Sadrzadeh, Dewey, Frederick E., Myers, Jonathan, and Froelicher, Victor F.

Subjects
Exercise equipment industry, Health
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2008.01.025 Byline: Amir H. Sadrzadeh Rafie (a), Frederick E. Dewey (b), Jonathan Myers (c), Victor F. Froelicher (c) Abstract: The Duke Treadmill Score (DTS) is an established clinical tool for risk stratification of patients referred for exercise testing, but it does not consider age. We aimed to determine if age could improve the prognostic power of the DTS and if so, to modify the DTS nomogram to include age. Author Affiliation: (a) Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford , CA (b) Stanford University School of Medicine, Stanford, CA (c) VA Palo Alto Health Care System, Palo Alto, CA Article History: Received 10 November 2007; Accepted 22 January 2008

Published
2008

37. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program

Author

Klarin, Derek, Damrauer, Scott M, Cho, Kelly, Sun, Yan V, Teslovich, Tanya M, Honerlaw, Jacqueline, Gagnon, David R, DuVall, Scott L, Li, Jin, Peloso, Gina M, Chaffin, Mark, Small, Aeron M, Huang, Jie, Tang, Hua, Lynch, Julie A, Ho, Yuk-Lam, Liu, Dajiang J, Emdin, Connor A, Li, Alexander H, Huffman, Jennifer E, Lee, Jennifer S, Natarajan, Pradeep, Chowdhury, Rajiv, Saleheen, Danish, Vujkovic, Marijana, Baras, Aris, Pyarajan, Saiju, Di Angelantonio, Emanuele, Neale, Benjamin M, Naheed, Aliya, Khera, Amit V, Danesh, John, Chang, Kyong-Mi, Abecasis, Gonçalo, Willer, Cristen, Dewey, Frederick E, Carey, David J, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato, John, Gaziano, J Michael, O'Donnell, Christopher J, Tsao, Philip S, Kathiresan, Sekar, Rader, Daniel J, Wilson, Peter WF, Assimes, Themistocles L, Gagnon, David R [0000-0002-6367-3179], Chaffin, Mark [0000-0002-1234-5562], Emdin, Connor A [0000-0002-2385-8259], Huffman, Jennifer E [0000-0002-9672-2491], Vujkovic, Marijana [0000-0003-4924-5714], Neale, Benjamin M [0000-0003-1513-6077], Willer, Cristen [0000-0001-5645-4966], Kathiresan, Sekar [0000-0002-6724-032X], Assimes, Themistocles L [0000-0003-2349-0009], and Apollo - University of Cambridge Repository

Subjects
Male, Genotype, Black People, Hispanic or Latino, Middle Aged, Lipid Metabolism, Lipids, Polymorphism, Single Nucleotide, White People, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Ethnicity, Humans, Female, Aged, Genome-Wide Association Study, Veterans
Abstract

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

Published
2018

38. Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease

Author

Khera, Amit V, Won, Hong-Hee, Peloso, Gina M, O'Dushlaine, Colm, Liu, Dajiang, Stitziel, Nathan O, Natarajan, Pradeep, Nomura, Akihiro, Emdin, Connor A, Gupta, Namrata, Borecki, Ingrid B, Asselta, Rosanna, Duga, Stefano, Merlini, Piera Angelica, 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, Hartzel, Dustin N, Samani, Nilesh J, Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Lander, Eric S, Rader, Daniel J, Danesh, John, Ardissino, Diego, Gabriel, Stacey, Willer, Cristen, Abecasis, Gonçalo R, Saleheen, Danish, Dewey, Frederick E, Kathiresan, Sekar, Myocardial Infarction Genetics Consortium, DiscovEHR Study Group, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Heterozygote, Genotype, Lipoproteins, Coronary Artery Disease, Middle Aged, Lipoprotein Lipase, Cross-Sectional Studies, Case-Control Studies, Mutation, Odds Ratio, Humans, Female, Age of Onset, Triglycerides
Abstract

IMPORTANCE: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. OBJECTIVE: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. EXPOSURES: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. MAIN OUTCOMES AND MEASURES: Circulating lipid levels and CAD. RESULTS: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. CONCLUSIONS AND RELEVANCE: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

Published
2018
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39. Rare Protein-Truncating Variants in APOB , Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease

Author

Peloso, Gina M., primary, Nomura, Akihiro, additional, Khera, Amit V., additional, Chaffin, Mark, additional, Won, Hong-Hee, additional, Ardissino, Diego, additional, Danesh, John, additional, Schunkert, Heribert, additional, Wilson, James G., additional, Samani, Nilesh, additional, Erdmann, Jeanette, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Saleheen, Danish, additional, McCarthy, Shane, additional, Teslovich, Tanya M., additional, Leader, Joseph B., additional, Lester Kirchner, H., additional, Marrugat, Jaume, additional, Nohara, Atsushi, additional, Kawashiri, Masa-aki, additional, Tada, Hayato, additional, Dewey, Frederick E., additional, Carey, David J., additional, Baras, Aris, additional, and Kathiresan, Sekar, additional

Published
2019
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40. Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development

Author

Nielsen, Jonas B., Fritsche, Lars G., Zhou, Wei, Teslovich, Tanya M., Holmen, Oddgeir L., Gustafsson, Stefan, Gabrielsen, Maiken E., Schmidt, Ellen M., Beaumont, Robin, Wolford, Brooke N., Lin, Maoxuan, Brummett, Chad M., Preuss, Michael H., Refsgaard, Lena, Bottinger, Erwin P., Graham, Sarah E., Surakka, Ida, Chu, Yunhan, Skogholt, Anne Heidi, Dalen, Havard, Boyle, Alan P., Oral, Hakan, Herron, Todd J., Kitzman, Jacob, Jalife, Jose, Svendsen, Jesper H., Olesen, Morten S., Njolstad, Inger, Lochen, Maja-Lisa, Baras, Aris, Gottesman, Omri, Marcketta, Anthony, O'Dushlaine, Colm, Ritchie, Marylyn D., Wilsgaard, Tom, Loos, Ruth J. F., Frayling, Timothy M., Boehnke, Michael, Ingelsson, Erik, Carey, David J., Dewey, Frederick E., Kang, Hyun M., Abecasis, Goncalo R., Hveem, Kristian, Willer, Cristen J., Nielsen, Jonas B., Fritsche, Lars G., Zhou, Wei, Teslovich, Tanya M., Holmen, Oddgeir L., Gustafsson, Stefan, Gabrielsen, Maiken E., Schmidt, Ellen M., Beaumont, Robin, Wolford, Brooke N., Lin, Maoxuan, Brummett, Chad M., Preuss, Michael H., Refsgaard, Lena, Bottinger, Erwin P., Graham, Sarah E., Surakka, Ida, Chu, Yunhan, Skogholt, Anne Heidi, Dalen, Havard, Boyle, Alan P., Oral, Hakan, Herron, Todd J., Kitzman, Jacob, Jalife, Jose, Svendsen, Jesper H., Olesen, Morten S., Njolstad, Inger, Lochen, Maja-Lisa, Baras, Aris, Gottesman, Omri, Marcketta, Anthony, O'Dushlaine, Colm, Ritchie, Marylyn D., Wilsgaard, Tom, Loos, Ruth J. F., Frayling, Timothy M., Boehnke, Michael, Ingelsson, Erik, Carey, David J., Dewey, Frederick E., Kang, Hyun M., Abecasis, Goncalo R., Hveem, Kristian, and Willer, Cristen J.

Abstract

Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

Published
2018
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41. Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Zekavat, Seyedeh M., Murray, Michael F, Lander, Eric Steven, Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V., Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A., Klarin, Derek, Natarajan, Pradeep, 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., 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., 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., Kathiresan, Sekar, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Zekavat, Seyedeh M., Murray, Michael F, Lander, Eric Steven, Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V., Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A., Klarin, Derek, Natarajan, Pradeep, 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., 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., 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

Abstract

Rationale: Therapies 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. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We 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<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). Conclusions: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.

Published
2018

42. Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance

Author

Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V., Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A., Klarin, Derek, Natarajan, Pradeep, 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., 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., 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., Kathiresan, Sekar, Zekavat, Seyedeh M., Murray, Michael F, Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Zekavat, Seyedeh M., Murray, Michael F, and Lander, Eric Steven

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

Rationale: Therapies 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. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We 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

43. Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension

Author

Bohnen, Michael S., primary, Ma, Lijiang, additional, Zhu, Na, additional, Qi, Hongjian, additional, McClenaghan, Conor, additional, Gonzaga-Jauregui, Claudia, additional, Dewey, Frederick E., additional, Overton, John D., additional, Reid, Jeffrey G., additional, Shuldiner, Alan R., additional, Baras, Aris, additional, Sampson, Kevin J., additional, Bleda, Marta, additional, Hadinnapola, Charaka, additional, Haimel, Matthias, additional, Bogaard, Harm J., additional, Church, Colin, additional, Coghlan, Gerry, additional, Corris, Paul A., additional, Eyries, Mélanie, additional, Gibbs, J. Simon R., additional, Girerd, Barbara, additional, Houweling, Arjan C., additional, Humbert, Marc, additional, Guignabert, Christophe, additional, Kiely, David G., additional, Lawrie, Allan, additional, MacKenzie Ross, Rob V., additional, Martin, Jennifer M., additional, Montani, David, additional, Peacock, Andrew J., additional, Pepke-Zaba, Joanna, additional, Soubrier, Florent, additional, Suntharalingam, Jay, additional, Toshner, Mark, additional, Treacy, Carmen M., additional, Trembath, Richard C., additional, Vonk Noordegraaf, Anton, additional, Wharton, John, additional, Wilkins, Martin R., additional, Wort, Stephen J., additional, Yates, Katherine, additional, Gräf, Stefan, additional, Morrell, Nicholas W., additional, Krishnan, Usha, additional, Rosenzweig, Erika B., additional, Shen, Yufeng, additional, Nichols, Colin G., additional, Kass, Robert S., additional, and Chung, Wendy K., additional

Published
2018
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44. Exome Sequencing–Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants

Author

Manickam, Kandamurugu, primary, Buchanan, Adam H., additional, Schwartz, Marci L. B., additional, Hallquist, Miranda L. G., additional, Williams, Janet L., additional, Rahm, Alanna Kulchak, additional, Rocha, Heather, additional, Savatt, Juliann M., additional, Evans, Alyson E., additional, Butry, Loren M., additional, Lazzeri, Amanda L., additional, Lindbuchler, D’Andra M., additional, Flansburg, Carroll N., additional, Leeming, Rosemary, additional, Vogel, Victor G., additional, Lebo, Matthew S., additional, Mason-Suares, Heather M., additional, Hoskinson, Derick C., additional, Abul-Husn, Noura S., additional, Dewey, Frederick E., additional, Overton, John D., additional, Reid, Jeffrey G., additional, Baras, Aris, additional, Willard, Huntington F., additional, McCormick, Cara Z., additional, Krishnamurthy, Sarath B., additional, Hartzel, Dustin N., additional, Kost, Korey A., additional, Lavage, Daniel R., additional, Sturm, Amy C., additional, Frisbie, Lauren R., additional, Person, T. Nate, additional, Metpally, Raghu P., additional, Giovanni, Monica A., additional, Lowry, Lacy E., additional, Leader, Joseph B., additional, Ritchie, Marylyn D., additional, Carey, David J., additional, Justice, Anne E., additional, Kirchner, H. Lester, additional, Faucett, W. Andrew, additional, Williams, Marc S., additional, Ledbetter, David H., additional, and Murray, Michael F., additional

Published
2018
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45. Profiling and Leveraging Relatedness in a Precision Medicine Cohort of 92,455 Exomes

Author

Staples, Jeffrey, primary, Maxwell, Evan K., additional, Gosalia, Nehal, additional, Gonzaga-Jauregui, Claudia, additional, Snyder, Christopher, additional, Hawes, Alicia, additional, Penn, John, additional, Ulloa, Ricardo, additional, Bai, Xiaodong, additional, Lopez, Alexander E., additional, Van Hout, Cristopher V., additional, O’Dushlaine, Colm, additional, Teslovich, Tanya M., additional, McCarthy, Shane E., additional, Balasubramanian, Suganthi, additional, Kirchner, H. Lester, additional, Leader, Joseph B., additional, Murray, Michael F., additional, Ledbetter, David H., additional, Shuldiner, Alan R., additional, Yancoupolos, George D., additional, Dewey, Frederick E., additional, Carey, David J., additional, Overton, John D., additional, Baras, Aris, additional, Habegger, Lukas, additional, and Reid, Jeffrey G., additional

Published
2018
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46. A Protein-TruncatingHSD17B13Variant and Protection from Chronic Liver Disease

Author

Abul-Husn, Noura S., primary, Cheng, Xiping, additional, Li, Alexander H., additional, Xin, Yurong, additional, Schurmann, Claudia, additional, Stevis, Panayiotis, additional, Liu, Yashu, additional, Kozlitina, Julia, additional, Stender, Stefan, additional, Wood, G. Craig, additional, Stepanchick, Ann N., additional, Still, Matthew D., additional, McCarthy, Shane, additional, O’Dushlaine, Colm, additional, Packer, Jonathan S., additional, Balasubramanian, Suganthi, additional, Gosalia, Nehal, additional, Esopi, David, additional, Kim, Sun Y., additional, Mukherjee, Semanti, additional, Lopez, Alexander E., additional, Fuller, Erin D., additional, Penn, John, additional, Chu, Xin, additional, Luo, Jonathan Z., additional, Mirshahi, Uyenlinh L., additional, Carey, David J., additional, Still, Christopher D., additional, Feldman, Michael D., additional, Small, Aeron, additional, Damrauer, Scott M., additional, Rader, Daniel J., additional, Zambrowicz, Brian, additional, Olson, William, additional, Murphy, Andrew J., additional, Borecki, Ingrid B., additional, Shuldiner, Alan R., additional, Reid, Jeffrey G., additional, Overton, John D., additional, Yancopoulos, George D., additional, Hobbs, Helen H., additional, Cohen, Jonathan C., additional, Gottesman, Omri, additional, Teslovich, Tanya M., additional, Baras, Aris, additional, Mirshahi, Tooraj, additional, Gromada, Jesper, additional, and Dewey, Frederick E., additional

Published
2018
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47. Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

Author

Nielsen, Jonas B., primary, Thorolfsdottir, Rosa B., additional, Fritsche, Lars G., additional, Zhou, Wei, additional, Skov, Morten W., additional, Graham, Sarah E., additional, Herron, Todd J., additional, McCarthy, Shane, additional, Schmidt, Ellen M., additional, Sveinbjornsson, Gardar, additional, Surakka, Ida, additional, Mathis, Michael R., additional, Yamazaki, Masatoshi, additional, Crawford, Ryan D., additional, Gabrielsen, Maiken E., additional, Skogholt, Anne Heidi, additional, Holmen, Oddgeir L., additional, Lin, Maoxuan, additional, Wolford, Brooke N., additional, Dey, Rounak, additional, Dalen, Håvard, additional, Sulem, Patrick, additional, Chung, Jonathan H., additional, Backman, Joshua D., additional, Arnar, David O., additional, Thorsteinsdottir, Unnur, additional, Baras, Aris, additional, O’Dushlaine, Colm, additional, Holst, Anders G., additional, Wen, Xiaoquan, additional, Hornsby, Whitney, additional, Dewey, Frederick E., additional, Boehnke, Michael, additional, Kheterpal, Sachin, additional, Lee, Seunggeun, additional, Kang, Hyun M., additional, Holm, Hilma, additional, Kitzman, Jacob, additional, Shavit, Jordan A., additional, Jalife, José, additional, Brummett, Chad M., additional, Teslovich, Tanya M., additional, Carey, David J., additional, Gudbjartsson, Daniel F., additional, Stefansson, Kari, additional, Abecasis, Goncalo R., additional, Hveem, Kristian, additional, and Willer, Cristen J., additional

Published
2018
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48. Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development

Author

Nielsen, Jonas B., primary, Fritsche, Lars G., additional, Zhou, Wei, additional, Teslovich, Tanya M., additional, Holmen, Oddgeir L., additional, Gustafsson, Stefan, additional, Gabrielsen, Maiken E., additional, Schmidt, Ellen M., additional, Beaumont, Robin, additional, Wolford, Brooke N., additional, Lin, Maoxuan, additional, Brummett, Chad M., additional, Preuss, Michael H., additional, Refsgaard, Lena, additional, Bottinger, Erwin P., additional, Graham, Sarah E., additional, Surakka, Ida, additional, Chu, Yunhan, additional, Skogholt, Anne Heidi, additional, Dalen, Håvard, additional, Boyle, Alan P., additional, Oral, Hakan, additional, Herron, Todd J., additional, Kitzman, Jacob, additional, Jalife, José, additional, Svendsen, Jesper H., additional, Olesen, Morten S., additional, Njølstad, Inger, additional, Løchen, Maja-Lisa, additional, Baras, Aris, additional, Gottesman, Omri, additional, Marcketta, Anthony, additional, O’Dushlaine, Colm, additional, Ritchie, Marylyn D., additional, Wilsgaard, Tom, additional, Loos, Ruth J.F., additional, Frayling, Timothy M., additional, Boehnke, Michael, additional, Ingelsson, Erik, additional, Carey, David J., additional, Dewey, Frederick E., additional, Kang, Hyun M., additional, Abecasis, Gonçalo R., additional, Hveem, Kristian, additional, and Willer, Cristen J., additional

Published
2018
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49. Genomic diagnostics within a medically underserved population: efficacy and implications

Author

Strauss, Kevin A., primary, Gonzaga-Jauregui, Claudia, additional, Brigatti, Karlla W., additional, Williams, Katie B., additional, King, Alejandra K., additional, Van Hout, Cristopher, additional, Robinson, Donna L., additional, Young, Millie, additional, Praveen, Kavita, additional, Heaps, Adam D., additional, Kuebler, Mindy, additional, Baras, Aris, additional, Reid, Jeffrey G., additional, Overton, John D., additional, Dewey, Frederick E., additional, Jinks, Robert N., additional, Finnegan, Ian, additional, Mellis, Scott J., additional, Shuldiner, Alan R., additional, and Puffenberger, Erik G., additional

Published
2018
Full Text
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