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1. Clonal haematopoiesis and risk of chronic liver disease.

Author

Dichtel, Laura, Griffin, Gabriel, Uddin, Md, Gibson, Christopher, Kovalcik, Veronica, Lin, Amy, McConkey, Marie, Vromman, Amelie, Sellar, Rob, Kim, Peter, Agrawal, Mridul, Weinstock, Joshua, Long, Michelle, Yu, Bing, Banerjee, Rajarshi, Nicholls, Rowan, Dennis, Andrea, Kelly, Matt, Loh, Po-Ru, McCarroll, Steve, Boerwinkle, Eric, Vasan, Ramachandran, Jaiswal, Siddhartha, Johnson, Andrew, Chung, Raymond, Corey, Kathleen, Levy, Daniel, Ballantyne, Christie, Ebert, Benjamin, Natarajan, Pradeep, Wong, Waihay, Emdin, Connor, Bick, Alexander, Zekavat, Seyedeh, Niroula, Abhishek, and Pirruccello, James

Subjects
Animals, Mice, Clonal Hematopoiesis, Hepatitis, Inflammation, Liver Cirrhosis, Non-alcoholic Fatty Liver Disease, Disease Susceptibility, Odds Ratio, Disease Progression
Abstract

Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P

Published
2023

2. Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease

Author

Khera, Amit V, Wang, Minxian, Chaffin, Mark, Emdin, Connor A, Samani, Nilesh J, Schunkert, Heribert, Watkins, Hugh, McPherson, Ruth, Erdmann, Jeanette, Elosua, Roberto, Boerwinkle, Eric, Ardissino, Diego, Butterworth, Adam S, Di Angelantonio, Emanuele, Naheed, Aliya, Danesh, John, Chowdhury, Rajiv, Krumholz, Harlan M, Sheu, Wayne H-H, Rich, Stephen S, Rotter, Jerome I, Chen, Yii-der Ida, Gabriel, Stacey, Lander, Eric S, Saleheen, Danish, and Kathiresan, Sekar

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Hypertension, Atherosclerosis, Heart Disease - Coronary Heart Disease, Cardiovascular, Human Genome, Genetics, Prevention, Heart Disease, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Coronary Artery Disease, Polymorphism, Genetic, Nitric Oxide, Cholesterol, Hypercholesterolemia, atherosclerosis, coronary artery disease, genetic association studies, nitric oxide synthase type III, precision medicine, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundA key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene (LDLR) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia.MethodsTo search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls.ResultsRare variants in LDLR were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene (NOS3), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in NOS3 was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80-3.26; P=5.50×10-9). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86-4.65]; P=5.00×10-6) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14-1.51]; P=2.00×10-4) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk.ConclusionsBeyond LDLR, we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.

Published
2022

3. Machine learning enables new insights into genetic contributions to liver fat accumulation

Author

Haas, Mary E, Pirruccello, James P, Friedman, Samuel N, Wang, Minxian, Emdin, Connor A, Ajmera, Veeral H, Simon, Tracey G, Homburger, Julian R, Guo, Xiuqing, Budoff, Matthew, Corey, Kathleen E, Zhou, Alicia Y, Philippakis, Anthony, Ellinor, Patrick T, Loomba, Rohit, Batra, Puneet, and Khera, Amit V

Subjects
Biological Sciences, Genetics, Chronic Liver Disease and Cirrhosis, Human Genome, Liver Disease, Digestive Diseases, Machine Learning and Artificial Intelligence, Biomedical Imaging, Prevention, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Metabolic and endocrine, Good Health and Well Being
Abstract

Excess liver fat, called hepatic steatosis, is a leading risk factor for end-stage liver disease and cardiometabolic diseases but often remains undiagnosed in clinical practice because of the need for direct imaging assessments. We developed an abdominal MRI-based machine-learning algorithm to accurately estimate liver fat (correlation coefficients, 0.97-0.99) from a truth dataset of 4,511 middle-aged UK Biobank participants, enabling quantification in 32,192 additional individuals. 17% of participants had predicted liver fat levels indicative of steatosis, and liver fat could not have been reliably estimated based on clinical factors such as BMI. A genome-wide association study of common genetic variants and liver fat replicated three known associations and identified five newly associated variants in or near the MTARC1, ADH1B, TRIB1, GPAM, and MAST3 genes (p < 3 × 10-8). A polygenic score integrating these eight genetic variants was strongly associated with future risk of chronic liver disease (hazard ratio > 1.32 per SD score, p < 9 × 10-17). Rare inactivating variants in the APOB or MTTP genes were identified in 0.8% of individuals with steatosis and conferred more than 6-fold risk (p < 2 × 10-5), highlighting a molecular subtype of hepatic steatosis characterized by defective secretion of apolipoprotein B-containing lipoproteins. We demonstrate that our imaging-based machine-learning model accurately estimates liver fat and may be useful in epidemiological and genetic studies of hepatic steatosis.

Published
2021

4. Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene–Environment Interaction Study

Author

Emdin, Connor A, Haas, Mary, Ajmera, Veeral, Simon, Tracey G, Homburger, Julian, Neben, Cynthia, Jiang, Lan, Wei, Wei-Qi, Feng, Qiping, Zhou, Alicia, Denny, Joshua, Corey, Kathleen, Loomba, Rohit, Kathiresan, Sekar, and Khera, Amit V

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Prevention, Obesity, Substance Misuse, Digestive Diseases, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Cancer, Stroke, Cardiovascular, Good Health and Well Being, Adult, Age Factors, Aged, Alcohol Drinking, Case-Control Studies, Comorbidity, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Liver Cirrhosis, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Risk Assessment, Risk Factors, Cirrhosis, Chronic Liver Disease, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsIn contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition.MethodsWe conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank.ResultsFive previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10-8) and the replication studies (P < .05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score-defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (Pinteraction < .001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (Pinteraction < .001).ConclusionsTwelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.

Published
2021

5. Clonal haematopoiesis and risk of chronic liver disease

Author

Wong, Waihay J., Emdin, Connor, Bick, Alexander G., Zekavat, Seyedeh M., Niroula, Abhishek, Pirruccello, James P., Dichtel, Laura, Griffin, Gabriel, Uddin, Md Mesbah, Gibson, Christopher J., Kovalcik, Veronica, Lin, Amy E., McConkey, Marie E., Vromman, Amelie, Sellar, Rob S., Kim, Peter G., Agrawal, Mridul, Weinstock, Joshua, Long, Michelle T., Yu, Bing, Banerjee, Rajarshi, Nicholls, Rowan C., Dennis, Andrea, Kelly, Matt, Loh, Po-Ru, McCarroll, Steve, Boerwinkle, Eric, Vasan, Ramachandran S., Jaiswal, Siddhartha, Johnson, Andrew D., Chung, Raymond T., Corey, Kathleen, Levy, Daniel, Ballantyne, Christie, Ebert, Benjamin L., and Natarajan, Pradeep

Published
2023
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6. Machine learning enables new insights into clinical significance of and genetic contributions to liver fat accumulation

Author

Haas, Mary E, Pirruccello, James P, Friedman, Samuel N, Emdin, Connor A, Ajmera, Veeral H, Simon, Tracey G, Homburger, Julian R, Guo, Xiuqing, Budoff, Matthew, Corey, Kathleen E, Zhou, Alicia Y, Philippakis, Anthony, Ellinor, Patrick T, Loomba, Rohit, Batra, Puneet, and Khera, Amit V

Subjects
Biological Sciences, Genetics, Networking and Information Technology R&D (NITRD), Chronic Liver Disease and Cirrhosis, Biomedical Imaging, Machine Learning and Artificial Intelligence, Human Genome, Prevention, Digestive Diseases, Liver Disease, 2.1 Biological and endogenous factors, Cardiovascular, Oral and gastrointestinal, Metabolic and endocrine, Good Health and Well Being
Abstract

Excess accumulation of liver fat – termed hepatic steatosis when fat accounts for > 5.5% of liver content – is a leading risk factor for end-stage liver disease and is strongly associated with important cardiometabolic disorders. Using a truth dataset of 4,511 UK Biobank participants with liver fat previously quantified via abdominal MRI imaging, we developed a machine learning algorithm to quantify liver fat with correlation coefficients of 0.97 and 0.99 in hold-out testing datasets and applied this algorithm to raw imaging data from an additional 32,192 participants. Among all 36,703 individuals with abdominal MRI imaging, median liver fat was 2.2%, with 6,250 (17%) meeting criteria for hepatic steatosis. Although individuals afflicted with hepatic steatosis were more likely to have been diagnosed with conditions such as obesity or diabetes, a prediction model based on clinical data alone without imaging could not reliably estimate liver fat content. To identify genetic drivers of variation in liver fat, we first conducted a common variant association study of 9.8 million variants, confirming three known associations for variants in the TM6SF2, APOE , and PNPLA3 genes and identifying five new variants associated with increased hepatic fat in or near the MARC1, ADH1B, TRIB1, GPAM and MAST3 genes. A polygenic score that integrated information from each of these eight variants was strongly associated with future clinical diagnosis of liver diseases. Next, we performed a rare variant association study in a subset of 11,021 participants with gene sequencing data available, identifying an association between inactivating variants in the APOB gene and substantially lower LDL cholesterol, but more than 10-fold increased risk of steatosis. Taken together, these results provide proof of principle for the use of machine learning algorithms on raw imaging data to enable epidemiologic studies and genetic discovery.

Published
2020

8. Author Correction: Clonal haematopoiesis and risk of chronic liver disease

Author

Wong, Waihay J., Emdin, Connor, Bick, Alexander G., Zekavat, Seyedeh M., Niroula, Abhishek, Pirruccello, James P., Dichtel, Laura, Griffin, Gabriel, Uddin, Md Mesbah, Gibson, Christopher J., Kovalcik, Veronica, Lin, Amy E., McConkey, Marie E., Vromman, Amelie, Sellar, Rob S., Kim, Peter G., Agrawal, Mridul, Weinstock, Joshua, Long, Michelle T., Yu, Bing, Banerjee, Rajarshi, Nicholls, Rowan C., Dennis, Andrea, Kelly, Matt, Loh, Po-Ru, McCarroll, Steve, Boerwinkle, Eric, Vasan, Ramachandran S., Jaiswal, Siddhartha, Johnson, Andrew D., Chung, Raymond T., Corey, Kathleen, Levy, Daniel, Ballantyne, Christie, Ebert, Benjamin L., and Natarajan, Pradeep

Published
2023
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9. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Author

Emdin, Connor A, Khera, Amit V, Chaffin, Mark, Klarin, Derek, Natarajan, Pradeep, Aragam, Krishna, Haas, Mary, Bick, Alexander, Zekavat, Seyedeh M, Nomura, Akihiro, Ardissino, Diego, Wilson, James G, Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J, Samani, Nilesh J, Baber, Usman, Erdmann, Jeanette, Gupta, Namrata, Danesh, John, Chasman, Daniel, Ridker, Paul, Denny, Joshua, Bastarache, Lisa, Lichtman, Judith H, D’Onofrio, Gail, Mattera, Jennifer, Spertus, John A, Sheu, Wayne H-H, Taylor, Kent D, Psaty, Bruce M, Rich, Stephen S, Post, Wendy, Rotter, Jerome I, Chen, Yii-Der Ida, Krumholz, Harlan, Saleheen, Danish, Gabriel, Stacey, and Kathiresan, Sekar

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Heart Disease - Coronary Heart Disease, Diabetes, Biotechnology, Obesity, Cardiovascular, Heart Disease, Human Genome, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Databases, Genetic, Diabetes Mellitus, Type 2, Disease, Gene Frequency, Genetic Testing, Genetic Variation, Humans, Phenotype, Proteins, Respiratory Hypersensitivity, United Kingdom
Abstract

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency

Published
2018

10. 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

11. 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

12. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author

Vreugdenhil, Anita, Alisi, Anna, Socha, Piotr, Jańczyk, Wojciech, Baumann, Ulrich, Rajwal, Sanjay, van Mourik, Indra, Lacaille, Florence, Dabbas, Myriam, Kelly, Deirdre A., Nobili, Valerio, Eiriksdottir, Gudny, Garcia, Melissa E., Gudnason, Vilmundur, Harris, Tamara B., Kim, Lauren J., Launer, Lenore J., Nalls, Michael A., Smith, Albert V., Clark, Jeanne M., Hernaez, Ruben, Kao, W.H. Linda, Mitchell, Braxton D., Shuldiner, Alan R., Yerges-Armstrong, Laura M., Borecki, Ingrid B., Carr, J. Jeffrey, Feitosa, Mary F., Wu, Jun, Butler, Johannah L., Fox, Caroline S., Hirschhorn, Joel N., Hoffmann, Udo, Hwang, Shih-Jen, Massaro, Joseph M., O'Donnell, Christopher J., Palmer, Cameron D., Sahani, Dushyant V., Speliotes, Elizabeth K., Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Banales, Jesus M., Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Ida Chen, Yii-Der, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, de Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., and Mann, Jake P.

Published
2021
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13. Blood pressure, atrial fibrillation and diabetes : evidence from observational and randomized analyses

Author

Emdin, Connor A., Rahini, Kazem, Woodward, Mark, and MacMahon, Stephen

Subjects
616.1
Abstract

The subgroup-specific relationships between blood pressure (BP), risk of atrial fibrillation (AF) and risk of diabetes are unclear. These two chronic diseases have key epidemiologic and clinical similarities, are difficult to examine through traditional cohort studies, and are of high clinical and public health importance. Using observational analyses of electronic health records and meta-analyses of randomized trials, the relationships between blood pressure, atrial fibrillation and diabetes are investigated in this thesis. First, I show that blood pressure is modestly associated with risk of atrial fibrillation in a population free of cardiovascular disease [HR 1.21 95% confidence interval 1.19, 1.22 per 20 mm Hg higher systolic blood pressure (SBP)]. While a non-significant effect of BP lowering on AF in non-heart failure populations is observed in a meta-analysis of randomized trials, this randomized estimate is similar in magnitude to the observational association, suggesting that BP lowering may modestly lower the risk of AF. Second, I show that elevated BP is associated with a higher risk of incident diabetes (HR 1.76 CI 1.56, 198 per 20 mm Hg higher SBP), although the causality of this finding is unclear. Third, I demonstrate in both observational and randomized analyses that the relationship between blood pressure and cardiovascular events appears to be modified by achieved BP in type 2 diabetes, with attenuated proportional reductions at achieved SBP less than 130 mm Hg. However, I also show that BP lowering to levels lower than those recommended in current guidelines (< 130 mm Hg SBP) may lower the risk of stroke, renal disease and retinopathy. These findings are of clinical and public health importance, as they suggest that BP lowering therapy can be used to reduce the risk of AF, that elevated BP may be a risk factor for incident diabetes, and that BP lowering in type 2 diabetes to lower levels than currently recommended in guidelines may further reduce the burden of cardiovascular disease in diabetic populations.

Published
2016

15. A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

Author

Gupta, Rajat M., Hadaya, Joseph, Trehan, Aditi, Zekavat, Seyedeh M., Roselli, Carolina, Klarin, Derek, Emdin, Connor A., Hilvering, Catharina R.E., Bianchi, Valerio, Mueller, Christian, Khera, Amit V., Ryan, Russell J.H., Engreitz, Jesse M., Issner, Robbyn, Shoresh, Noam, Epstein, Charles B., de Laat, Wouter, Brown, Jonathan D., Schnabel, Renate B., Bernstein, Bradley E., and Kathiresan, Sekar

Published
2017
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17. Referral for Specialist Follow-up and Its Association With Post-discharge Mortality Among Patients With Systolic Heart Failure (from the National Heart Failure Audit for England and Wales)

Author

Emdin, Connor A., Hsiao, Allan J., Kiran, Amit, Conrad, Nathalie, Salimi-Khorshidi, Gholamreza, Woodward, Mark, Anderson, Simon G., Mohseni, Hamid, McMurray, John J.V., Cleland, John G.F., Dargie, Henry, Hardman, Suzanna, McDonagh, Theresa, and Rahimi, Kazem

Published
2017
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32. Contributors

Author

Achenbach, Stephan, primary, Aragam, Krishna G., additional, Arnold, Suzanne V., additional, Bäck, Magnus, additional, Blaha, Michael J., additional, Blankenberg, Stefan, additional, Blumenthal, Roger S., additional, Camici, Paolo G., additional, Chung, Mina K., additional, Cigarroa, Joaquin E., additional, Crea, Filippo, additional, Davidson, Karina W., additional, De Schutter, Alban, additional, Di Carli, Marcelo F., additional, Douglas, Pamela S., additional, Ducrocq, Gregory, additional, Emdin, Connor A., additional, Emeruwa, Obi, additional, Enriquez, Jonathan R., additional, Fearon, William F., additional, Fordyce, Christopher B., additional, Gaziano, Thomas A., additional, Gersh, Bernard, additional, Gitsioudis, Gitsios, additional, Guo, Yuanlin, additional, Hachamovitch, Rory, additional, Hansson, Göran K., additional, Heinzman, Kristopher, additional, Henry, Timothy D., additional, Hussein, Ayman A., additional, Jensen, Jesper K., additional, Jolicoeur, E. Marc, additional, Kathiresan, Sekar, additional, Khattar, Rajdeep S., additional, Khera, Amit V., additional, Kosiborod, Mikhail, additional, Kwon, Lawrence, additional, Lavie, Carl J., additional, Lawlor, Matthew, additional, Marso, Steven P., additional, Martin, Seth S., additional, Marx, Nikolaus, additional, Mehta, Puja K., additional, Bairey Merz, C. Noel, additional, Michos, Erin D., additional, Milani, Richard V., additional, O’Donnell, Christopher J., additional, Opie, Lionel, additional, Parikh, Shailja V., additional, Prescott, Eva, additional, Reith, Sebastian, additional, Rimoldi, Ornella E., additional, Robinson, Jennifer G., additional, Rodgers, George, additional, Rohatgi, Anand, additional, Rosendorff, Clive, additional, Sahni, Sheila, additional, Sedehi, Daniel, additional, Senior, Roxy, additional, Steg, Philippe Gabriel, additional, Wasson, Lauren, additional, Watson, Karol E., additional, Wei, Janet, additional, Wilson, Peter W.F., additional, and Zeller, Tanja, additional

Published
2018
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34. Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling

Author

Emdin, Connor A., Khera, Amit V., Klarin, Derek, Natarajan, Pradeep, Zekavat, Seyedeh M., Nomura, Akihiro, Haas, Mary, Aragam, Krishna, Ardissino, Diego, Wilson, James G., Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J., Samani, Nilesh J., Baber, Usman, Erdmann, Jeanette, Gormley, Padhraig, Palotie, Aarno, Stitziel, Nathan O., Gupta, Namrata, Danesh, John, Saleheen, Danish, Gabriel, Stacey, and Kathiresan, Sekar

Published
2018
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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., and Kathiresan, Sekar

Published
2017
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45. Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease

Author

Ghodsian, Nooshin, primary, Abner, Erik, additional, Emdin, Connor A., additional, Gobeil, Émilie, additional, Taba, Nele, additional, Haas, Mary E., additional, Perrot, Nicolas, additional, Manikpurage, Hasanga D., additional, Gagnon, Éloi, additional, Bourgault, Jérôme, additional, St-Amand, Alexis, additional, Couture, Christian, additional, Mitchell, Patricia L., additional, Bossé, Yohan, additional, Mathieu, Patrick, additional, Vohl, Marie-Claude, additional, Tchernof, André, additional, Thériault, Sébastien, additional, Khera, Amit V., additional, Esko, Tõnu, additional, and Arsenault, Benoit J., additional

Published
2021
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