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340 results on '"Jaiswal, Siddhartha"'

1. Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate

Author

Mack, Taralynn M, Raddatz, Michael A, Pershad, Yash, Nachun, Daniel C, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O’Connell, Jeffrey R, Kenny, Eimear E, Loos, Ruth JF, Redline, Susan, Cade, Brian E, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Cho, Michael H, DeMeo, Dawn L, Levy, Daniel, Johnson, Andrew D, Mathias, Rasika A, Yanek, Lisa R, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Raffield, Laura M, Carson, April P, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Roden, Dan M, Kooperberg, Charles, Auer, Paul L, Desai, Pinkal, Blackwell, Thomas W, Smith, Albert V, Reiner, Alexander P, Jaiswal, Siddhartha, Weinstock, Joshua S, and Bick, Alexander G

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Hematology, Genetics, Biotechnology, Aging, Human Genome, Stem Cell Research, Precision Medicine, Aetiology, 2.1 Biological and endogenous factors, Cancer, Good Health and Well Being, Clinical sciences
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Published
2024

2. Determinants of mosaic chromosomal alteration fitness.

Author

Pershad, Yash, Mack, Taralynn, Poisner, Hannah, Jakubek, Yasminka, Stilp, Adrienne, Mitchell, Braxton, Lewis, Joshua, Boerwinkle, Eric, Loos, Ruth, Chami, Nathalie, Wang, Zhe, Barnes, Kathleen, Pankratz, Nathan, Fornage, Myriam, Redline, Susan, Psaty, Bruce, Bis, Joshua, Shojaie, Ali, Silverman, Edwin, Cho, Michael, Yun, Jeong, DeMeo, Dawn, Levy, Daniel, Johnson, Andrew, Mathias, Rasika, Taub, Margaret, Arnett, Donna, North, Kari, Raffield, Laura, Carson, April, Doyle, Margaret, Rich, Stephen, Guo, Xiuqing, Cox, Nancy, Roden, Dan, Franceschini, Nora, Desai, Pinkal, Reiner, Alex, Auer, Paul, Scheet, Paul, Jaiswal, Siddhartha, Weinstock, Joshua, Bick, Alexander, and Rotter, Jerome

Subjects
Humans, Mosaicism, Chromosome Aberrations, Clonal Hematopoiesis, Male, Female, Genome-Wide Association Study, Janus Kinase 2, Telomerase, Loss of Heterozygosity, Cross-Sectional Studies, Mutation, Middle Aged, Hematopoietic Stem Cells, Polymorphism, Single Nucleotide, Aged
Abstract

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Published
2024

4. Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate

Author

Mack, Taralynn M., Raddatz, Michael A., Pershad, Yash, Nachun, Daniel C., Taylor, Kent D., Guo, Xiuqing, Shuldiner, Alan R., O’Connell, Jeffrey R., Kenny, Eimear E., Loos, Ruth J. F., Redline, Susan, Cade, Brian E., Psaty, Bruce M., Bis, Joshua C., Brody, Jennifer A., Silverman, Edwin K., Yun, Jeong H., Cho, Michael H., DeMeo, Dawn L., Levy, Daniel, Johnson, Andrew D., Mathias, Rasika A., Yanek, Lisa R., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Raffield, Laura M., Carson, April P., Rotter, Jerome I., Rich, Stephen S., Manichaikul, Ani W., Gu, C. Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M. Benjamin, Roden, Dan M., Kooperberg, Charles, Auer, Paul L., Desai, Pinkal, Blackwell, Thomas W., Smith, Albert V., Reiner, Alexander P., Jaiswal, Siddhartha, Weinstock, Joshua S., and Bick, Alexander G.

Published
2024
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5. Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk.

Author

Yu, Zhi, Fidler, Trevor, Ruan, Yunfeng, Vlasschaert, Caitlyn, Nakao, Tetsushi, Uddin, Md, Mack, Taralynn, Niroula, Abhishek, Heimlich, J, Zekavat, Seyedeh, Gibson, Christopher, Griffin, Gabriel, Wang, Yuxuan, Peloso, Gina, Heard-Costa, Nancy, Levy, Daniel, Vasan, Ramachandran, Aguet, François, Ardlie, Kristin, Taylor, Kent, Rich, Stephen, Libby, Peter, Jaiswal, Siddhartha, Ebert, Benjamin, Bick, Alexander, Tall, Alan, Natarajan, Pradeep, and Rotter, Jerome

Subjects
Cardiology, Cardiovascular disease, Genetics, Mouse models, Population genetics, Humans, Animals, Mice, Cardiovascular Diseases, Clonal Hematopoiesis, Risk Factors, Inflammasomes, Hematopoiesis, Inflammation, Heart Disease Risk Factors, Mutation
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD-protective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.

Published
2023

6. The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Author

Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O’Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, and Consortium, NHLBI Trans-Omics for Precision Medicine

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Lung, Genetic Testing, Clinical Research, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Humans, Middle Aged, Hematopoiesis, Mutation, Germ-Line Mutation, Mutation, Missense, Phenotype, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Published
2023

7. 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

9. Abstract 4145859: Clonal Hematopoiesis of Indeterminate Potential Increases Mortality Risk in Coronary Artery Disease

Author

Von Scheidt, Moritz, Adkar, Shaunak, Krefting, Johannes, Hoermann, Gregor, Meggendorfer, Manja, Bauer, Sabine, Pugach, Irina, Friess, Christian, Ma, Angela, Hao, Ke, Steigerwald, Sophia, Kessler, Thorsten, Mokry, Michal, Bongiovanni, Dario, Fleig, Julia, Oldenbuettel, Lilith, Chen, Zhifen, Hecker, Judith S., Bassermann, Florian, Maegdefessel, Lars, Graw, Matthias, Ruusalepp, Arno, Hilgendorf, Ingo, Leuschner, Florian, Koenig, Wolfgang, Cremer, Sebastian, Leistner, David, Dimmeler, Stefanie, Zeiher, Andreas, Braun, Christian, Mitchell, Shaneice, Jaiswal, Siddhartha, Kovacic, Jason, Mann, Matthias, Kastrati, Adnan, Haferlach, Claudia, Haferlach, Torsten, Leeper, Nick, Björkegren, Johan, and Schunkert, Heribert

Published
2024
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10. Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Author

Uddin, MD Mesbah, Nguyen, Ngoc Quynh H, Yu, Bing, Brody, Jennifer A, Pampana, Akhil, Nakao, Tetsushi, Fornage, Myriam, Bressler, Jan, Sotoodehnia, Nona, Weinstock, Joshua S, Honigberg, Michael C, Nachun, Daniel, Bhattacharya, Romit, Griffin, Gabriel K, Chander, Varuna, Gibbs, Richard A, Rotter, Jerome I, Liu, Chunyu, Baccarelli, Andrea A, Chasman, Daniel I, Whitsel, Eric A, Kiel, Douglas P, Murabito, Joanne M, Boerwinkle, Eric, Ebert, Benjamin L, Jaiswal, Siddhartha, Floyd, James S, Bick, Alexander G, Ballantyne, Christie M, Psaty, Bruce M, Natarajan, Pradeep, and Conneely, Karen N

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Cardiovascular, Stem Cell Research - Nonembryonic - Non-Human, Aging, Heart Disease - Coronary Heart Disease, Atherosclerosis, Human Genome, Hematology, Stem Cell Research, Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Cancer, Good Health and Well Being, Clonal Hematopoiesis, Coronary Artery Disease, DNA Methylation, Hematopoiesis, Hematopoietic Stem Cells, Humans
Abstract

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Published
2022

12. Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes

Author

Rauch, Philipp J., Gopakumar, Jayakrishnan, Silver, Alexander J., Nachun, Daniel, Ahmad, Herra, McConkey, Marie, Nakao, Tetsushi, Bosse, Marc, Rentz, Thiago, Vivanco Gonzalez, Nora, Greenwald, Noah F., McCaffrey, Erin F., Khair, Zumana, Gopakumar, Manu, Rodrigues, Kameron B., Lin, Amy E., Sinha, Eti, Fefer, Maia, Cohen, Drew N., Vromman, Amélie, Shvartz, Eugenia, Sukhova, Galina, Bendall, Sean, Angelo, Michael, Libby, Peter, Ebert, Benjamin L., and Jaiswal, Siddhartha

Published
2023
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13. Clonal hematopoiesis is associated with protection from Alzheimer’s disease

Author

Bouzid, Hind, Belk, Julia A., Jan, Max, Qi, Yanyan, Sarnowski, Chloé, Wirth, Sara, Ma, Lisa, Chrostek, Matthew R., Ahmad, Herra, Nachun, Daniel, Yao, Winnie, Beiser, Alexa, Bick, Alexander G., Bis, Joshua C., Fornage, Myriam, Longstreth, Jr., William T., Lopez, Oscar L., Natarajan, Pradeep, Psaty, Bruce M., Satizabal, Claudia L., Weinstock, Joshua, Larson, Eric B., Crane, Paul K., Keene, C. Dirk, Seshadri, Sudha, Satpathy, Ansuman T., Montine, Thomas J., and Jaiswal, Siddhartha

Published
2023
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14. Clonal Hematopoiesis Is Associated With Higher Risk of Stroke

Author

Bhattacharya, Romit, Zekavat, Seyedeh M, Haessler, Jeffrey, Fornage, Myriam, Raffield, Laura, Uddin, Mesbah, Bick, Alexander G, Niroula, Abhishek, Yu, Bing, Gibson, Christopher, Griffin, Gabriel, Morrison, Alanna C, Psaty, Bruce M, Longstreth, William T, Bis, Joshua C, Rich, Stephen S, Rotter, Jerome I, Tracy, Russell P, Correa, Adolfo, Seshadri, Sudha, Johnson, Andrew, Collins, Jason M, Hayden, Kathleen M, Madsen, Tracy E, Ballantyne, Christie M, Jaiswal, Siddhartha, Ebert, Benjamin L, Kooperberg, Charles, Manson, JoAnn E, Whitsel, Eric A, Program, NHLBI Trans-Omics for Precision Medicine, Natarajan, Pradeep, and Reiner, Alexander P

Subjects
Epidemiology, Health Sciences, Human Genome, Prevention, Brain Disorders, Neurosciences, Stroke, Genetics, Aging, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Clonal Hematopoiesis, DNA Methyltransferase 3A, DNA-Binding Proteins, Dioxygenases, Female, Hemorrhagic Stroke, Humans, Incidence, Ischemic Stroke, Male, Middle Aged, Prevalence, Repressor Proteins, Risk, NHLBI Trans-Omics for Precision Medicine Program, brain ischemia, cardiovascular diseases, clonal hematopoiesis, humans, prospective studies, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences, Allied health and rehabilitation science
Abstract

Background and purposeClonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.MethodsWe utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke.ResultsCHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke.ConclusionsCHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

Published
2022

15. Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative

Author

Love, Shelly-Ann M., Collins, Jason M., Anthony, Kurtis M., Buchheit, Sophie F., Butler, Eboneé N., Bey, Ganga S., Gondalia, Rahul, Hayden, Kathleen M., Zannas, Anthony S., Bick, Alexander G., Manson, JoAnn E., Desai, Pinkal M., Natarajan, Pradeep, Bhattacharya, Romit, Jaiswal, Siddhartha, Barac, Ana, Reiner, Alex, Kooperberg, Charles, Stewart, James D., and Whitsel, Eric A.

Published
2024
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16. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Author

Weinstock, Joshua S., Gopakumar, Jayakrishnan, Burugula, Bala Bharathi, Uddin, Md Mesbah, Jahn, Nikolaus, Belk, Julia A., Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn M., Luna, Sofia E., Prothro, Katherine P., Mitchell, Shaneice R., Laurie, Cecelia A., Broome, Jai G., Taylor, Kent D., Guo, Xiuqing, Sinner, Moritz F., von Falkenhausen, Aenne S., Kääb, Stefan, Shuldiner, Alan R., O’Connell, Jeffrey R., Lewis, Joshua P., Boerwinkle, Eric, Barnes, Kathleen C., Chami, Nathalie, Kenny, Eimear E., Loos, Ruth J. F., Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald M., Redline, Susan, Cade, Brian E., Psaty, Bruce M., Bis, Joshua C., Brody, Jennifer A., Silverman, Edwin K., Yun, Jeong H., Qiao, Dandi, Palmer, Nicholette D., Freedman, Barry I., Bowden, Donald W., Cho, Michael H., DeMeo, Dawn L., Vasan, Ramachandran S., Yanek, Lisa R., Becker, Lewis C., Kardia, Sharon L. R., Peyser, Patricia A., He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Arnett, Donna K., Irvin, Marguerite R., Tiwari, Hemant, Cutler, Michael J., Knight, Stacey, Muhlestein, J. Brent, Correa, Adolfo, Raffield, Laura M., Gao, Yan, de Andrade, Mariza, Rotter, Jerome I., Rich, Stephen S., Tracy, Russell P., Konkle, Barbara A., Johnsen, Jill M., Wheeler, Marsha M., Smith, J. Gustav, Melander, Olle, Nilsson, Peter M., Custer, Brian S., Duggirala, Ravindranath, Curran, Joanne E., Blangero, John, McGarvey, Stephen, Williams, L. Keoki, Xiao, Shujie, Yang, Mao, Gu, C. Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Marcus, Gregory M., Kane, John P., Pullinger, Clive R., Shoemaker, M. Benjamin, Darbar, Dawood, Roden, Dan M., Albert, Christine, Kooperberg, Charles, Zhou, Ying, Manson, JoAnn E., Desai, Pinkal, Johnson, Andrew D., Mathias, Rasika A., Blackwell, Thomas W., Abecasis, Goncalo R., Smith, Albert V., Kang, Hyun M., Satpathy, Ansuman T., Natarajan, Pradeep, Kitzman, Jacob O., Whitsel, Eric A., Reiner, Alexander P., Bick, Alexander G., and Jaiswal, Siddhartha

Published
2023
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17. 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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18. Clonal hematopoiesis associated with epigenetic aging and clinical outcomes

Author

Nachun, Daniel, Lu, Ake T, Bick, Alexander G, Natarajan, Pradeep, Weinstock, Joshua, Szeto, Mindy D, Kathiresan, Sekar, Abecasis, Goncalo, Taylor, Kent D, Guo, Xiuqing, Tracy, Russ, Durda, Peter, Liu, Yongmei, Johnson, Craig, Rich, Stephen S, Van Den Berg, David, Laurie, Cecilia, Blackwell, Tom, Papanicolaou, George J, Correa, Adolfo, Raffield, Laura M, Johnson, Andrew D, Murabito, Joanne, Manson, JoAnn E, Desai, Pinkal, Kooperberg, Charles, Assimes, Themistocles L, Levy, Daniel, Rotter, Jerome I, Reiner, Alex P, Whitsel, Eric A, Wilson, James G, Horvath, Steve, Jaiswal, Siddhartha, and Consortium, the NHLBI Trans‐Omics for Precision Medicine

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Aging, Heart Disease, Cardiovascular, Patient Safety, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Clonal Hematopoiesis, Epigenomics, Humans, Risk Factors, Treatment Outcome, clonal hematopoiesis, epigenomics, heart disease, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p 0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p

Published
2021

20. Abstract 13052: Clonal Hematopoiesis of Indeterminate Potential Predicts Incident Cardiac Arrhythmias

Author

Schuermans, Art, Vlasschaert, Caitlyn, Nauffal, Victor, Uddin, Md Mesbah, Nakao, Tetsushi, Niroula, Abhishek, Klarqvist, Marcus D, Weeks, Lachelle D, Lin, Amy E, Saadatagah, Seyedmohammad, Lannery, Kim, Wong, Megan, Hornsby, Whitney, Lubitz, Steven A, Ballantyne, Christie M, Jaiswal, Siddhartha, Bick, Alexander G, Ellinor, Patrick T, Natarajan, Pradeep, and Honigberg, Michael C

Published
2023
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21. TET2-mutant clonal hematopoiesis and risk of gout

Author

Agrawal, Mridul, Niroula, Abhishek, Cunin, Pierre, McConkey, Marie, Shkolnik, Veronica, Kim, Peter G., Wong, Waihay J., Weeks, Lachelle D., Lin, Amy E., Miller, Peter G., Gibson, Christopher J., Sekar, Aswin, Schaefer, Inga-Marie, Neuberg, Donna, Stone, Richard M., Bick, Alexander G., Uddin, Md Mesbah, Griffin, Gabriel K., Jaiswal, Siddhartha, Natarajan, Pradeep, Nigrovic, Peter A., Rao, Deepak A., and Ebert, Benjamin L.

Published
2022
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22. Association of clonal hematopoiesis with chronic obstructive pulmonary disease

Author

Miller, Peter G., Qiao, Dandi, Rojas-Quintero, Joselyn, Honigberg, Michael C., Sperling, Adam S., Gibson, Christopher J., Bick, Alexander G., Niroula, Abhishek, McConkey, Marie E., Sandoval, Brittany, Miller, Brian C., Shi, Weiwei, Viswanathan, Kaushik, Leventhal, Matthew, Werner, Lillian, Moll, Matthew, Cade, Brian E., Barr, R. Graham, Correa, Adolfo, Cupples, L. Adrienne, Gharib, Sina A., Jain, Deepti, Gogarten, Stephanie M., Lange, Leslie A., London, Stephanie J., Manichaikul, Ani, O'Connor, George T., Oelsner, Elizabeth C., Redline, Susan, Rich, Stephen S., Rotter, Jerome I., Ramachandran, Vasan, Yu, Bing, Sholl, Lynette, Neuberg, Donna, Jaiswal, Siddhartha, Levy, Bruce D., Owen, Caroline A., Natarajan, Pradeep, Silverman, Edwin K., van Galen, Peter, Tesfaigzi, Yohannes, Cho, Michael H., and Ebert, Benjamin L.

Published
2022
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23. 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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26. Abstract 15719: Proteomic Analyses Reveal Mechanistic Links Between Clonal Hematopoiesis of Indeterminate Potential and Coronary Artery Disease

Author

Yu, Zhi, Yu, Bing, Vromman, Amelie, Nguyen, Quynh H, Khetarpal, Sumeet, Honigberg, Michael, Lin, Amy E, Katz, Daniel H, Tahir, Usman A, Weinstock, Joshua S, Jaiswal, Siddhartha, Austin, Thomas, Ramachandran, Vasan S, Peloso, Gina, Manson, Joann E, Haring, Bernhard, Kooperberg, Charles, Reiner, Alex P, Bis, Joshua, Psaty, Bruce M, Correa, Adolfo, Lange, Leslie, Post, Wendy S, Rotter, Jerome I, Rich, Stephen S, Wilson, James, Ballantyne, Christie M, Coresh, Josef, Sankaran, Vijay, Libby, Peter, Bick, Alexander G, Ebert, Benjamin L, Gerszten, Robert E, and Natarajan, Pradeep

Published
2022
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29. Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative

Author

Anthony, Kurtis M., primary, Collins, Jason M., additional, Love, Shelly-Ann M., additional, Stewart, James D., additional, Buchheit, Sophie F., additional, Gondalia, Rahul, additional, Schwartz, Gary G., additional, Huang, David Y., additional, Meliker, Jaymie R., additional, Zhang, Zhenzhen, additional, Barac, Ana, additional, Desai, Pinkal, additional, Hayden, Kathleen M., additional, Honigberg, Michael C., additional, Jaiswal, Siddhartha, additional, Natarajan, Pradeep, additional, Bick, Alexander G., additional, Kooperberg, Charles, additional, Manson, JoAnn E., additional, Reiner, Alexander P., additional, and Whitsel, Eric A., additional

Published
2024
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30. Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study

Author

Ahn, Hyo-Jeong, primary, An, Hong Yul, additional, Ryu, Gangpyo, additional, Lim, Jiwoo, additional, Sun, Choonghyun, additional, Song, Han, additional, Choi, Su-Yeon, additional, Lee, Heesun, additional, Maurer, Taylor, additional, Nachun, Daniel, additional, Kwon, Soonil, additional, Lee, So-Ryoung, additional, Lip, Gregory Y H, additional, Oh, Seil, additional, Jaiswal, Siddhartha, additional, Koh, Youngil, additional, and Choi, Eue-Keun, additional

Published
2024
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31. Clonal Hematopoiesis Is Associated With Higher Risk of Stroke

Author

Bhattacharya, Romit, Zekavat, Seyedeh M., Haessler, Jeffrey, Fornage, Myriam, Raffield, Laura, Uddin, Md Mesbah, Bick, Alexander G., Niroula, Abhishek, Yu, Bing, Gibson, Christopher, Griffin, Gabriel, Morrison, Alanna C., Psaty, Bruce M., Longstreth, William T., Bis, Joshua C., Rich, Stephen S., Rotter, Jerome I., Tracy, Russell P., Correa, Adolfo, Seshadri, Sudha, Johnson, Andrew, Collins, Jason M., Hayden, Kathleen M., Madsen, Tracy E., Ballantyne, Christie M., Jaiswal, Siddhartha, Ebert, Benjamin L., Kooperberg, Charles, Manson, JoAnn E., Whitsel, Eric A., Natarajan, Pradeep, and Reiner, Alexander P.

Published
2021
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32. Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self

Author

Chowdhury, Roshni Roy, D’Addabbo, Jessica, Huang, Xianxi, Veizades, Stefan, Sasagawa, Koki, Louis, David M., Cheng, Paul, Sokol, Jan, Jensen, Annie, Tso, Alexandria, Shankar, Vishnu, Wendel, Ben Shogo, Bakerman, Isaac, Liang, Grace, Koyano, Tiffany, Fong, Robyn, Nau, Allison N., Ahmad, Herra, Gopakumar, Jayakrishnan, Wirka, Robert, Lee, Andrew S., Boyd, Jack, Woo, Y. Joseph, Quertermous, Thomas, Gulati, Gunsagar Singh, Jaiswal, Siddhartha, Chien, Yueh-Hsiu, Chan, Charles Kwok Fai, Davis, Mark M., and Nguyen, Patricia K.

Published
2022
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36. Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias

Author

Schuermans, Art, primary, Vlasschaert, Caitlyn, additional, Nauffal, Victor, additional, Cho, So Mi Jemma, additional, Uddin, Md Mesbah, additional, Nakao, Tetsushi, additional, Niroula, Abhishek, additional, Klarqvist, Marcus D R, additional, Weeks, Lachelle D, additional, Lin, Amy E, additional, Saadatagah, Seyedmohammad, additional, Lannery, Kim, additional, Wong, Megan, additional, Hornsby, Whitney, additional, Lubitz, Steven A, additional, Ballantyne, Christie, additional, Jaiswal, Siddhartha, additional, Libby, Peter, additional, Ebert, Benjamin L, additional, Bick, Alexander G, additional, Ellinor, Patrick T, additional, Natarajan, Pradeep, additional, and Honigberg, Michael C, additional

Published
2023
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37. Determinants of mosaic chromosomal alteration fitness

Author

Pershad, Yash, primary, Mack, Taralynn, additional, Poisner, Hannah, additional, Jakubek, Yasminka A, additional, Stilp, Adrienne M, additional, Mitchell, Braxton D, additional, Lewis, Joshua P, additional, Boerwinkle, Eric, additional, Loos, Ruth J, additional, Chami, Nathalie, additional, Wang, Zhe, additional, Barnes, Kathleen, additional, Pankratz, Nathan, additional, Fornage, Myriam, additional, Redline, Susan, additional, Psaty, Bruce M, additional, Bis, Joshua C, additional, Shojaie, Ali, additional, Silverman, Edwin K, additional, Cho, Michael H, additional, Yun, Jeong, additional, DeMeo, Dawn, additional, Levy, Daniel, additional, Johnson, Andrew, additional, Mathias, Rasika, additional, Taub, Margaret, additional, Arnett, Donna, additional, North, Kari, additional, Raffield, Laura M, additional, Carson, April, additional, Doyle, Margaret F, additional, Rich, Stephen S., additional, Rotter, Jerome I., additional, Guo, Xiuqing, additional, Cox, Nancy, additional, Roden, Dan M, additional, Franceschini, Nora, additional, Desai, Pinkal, additional, Reiner, Alex, additional, Auer, Paul L, additional, Scheet, Paul, additional, Jaiswal, Siddhartha, additional, Weinstock, Joshua S, additional, and Bick, Alexander G, additional

Published
2023
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40. Birth Weight Is Associated With Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Adulthood

Author

Schuermans, Art, primary, Nakao, Tetsushi, additional, Ruan, Yunfeng, additional, Koyama, Satoshi, additional, Yu, Zhi, additional, Uddin, Md Mesbah, additional, Haidermota, Sara, additional, Hornsby, Whitney, additional, Lewandowski, Adam J., additional, Bick, Alexander G., additional, Niroula, Abhishek, additional, Jaiswal, Siddhartha, additional, Ebert, Benjamin L., additional, Natarajan, Pradeep, additional, and Honigberg, Michael C., additional

Published
2023
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44. Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.

Author

Schuermans, Art, Vlasschaert, Caitlyn, Nauffal, Victor, Cho, So Mi Jemma, Uddin, Md Mesbah, Nakao, Tetsushi, Niroula, Abhishek, Klarqvist, Marcus D R, Weeks, Lachelle D, Lin, Amy E, Saadatagah, Seyedmohammad, Lannery, Kim, Wong, Megan, Hornsby, Whitney, Lubitz, Steven A, Ballantyne, Christie, Jaiswal, Siddhartha, Libby, Peter, Ebert, Benjamin L, and Bick, Alexander G

Subjects
ARRHYTHMIA, VENTRICULAR arrhythmia, CORONARY disease, CARDIAC magnetic resonance imaging, CORONARY artery disease, HEMATOPOIESIS
Abstract

Background and Aims Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias. Methods UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. Results This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04–1.18; P =.001] and 1.13 (95% CI 1.05–1.22; P =.001) for supraventricular arrhythmias, 1.09 (95% CI 1.01–1.19; P =.031) and 1.13 (95% CI 1.03–1.25; P =.011) for bradyarrhythmias, and 1.16 (95% CI, 1.00–1.34; P =.049) and 1.22 (95% CI 1.03–1.45; P =.021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07–1.59; P =.009) of being in the top quintile of myocardial fibrosis by CMR. Conclusions CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease

Author

Gumuser, Esra D., primary, Schuermans, Art, additional, Cho, So Mi Jemma, additional, Sporn, Zachary A., additional, Uddin, Md Mesbah, additional, Paruchuri, Kaavya, additional, Nakao, Tetsushi, additional, Yu, Zhi, additional, Haidermota, Sara, additional, Hornsby, Whitney, additional, Weeks, Lachelle D., additional, Niroula, Abhishek, additional, Jaiswal, Siddhartha, additional, Libby, Peter, additional, Ebert, Benjamin L., additional, Bick, Alexander G., additional, Natarajan, Pradeep, additional, and Honigberg, Michael C., additional

Published
2023
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48. Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis

Author

Weeks, Lachelle D., primary, Niroula, Abhishek, additional, Neuberg, Donna, additional, Wong, Waihay, additional, Lindsley, R. Coleman, additional, Luskin, Marlise R., additional, Berliner, Nancy, additional, Stone, Richard M., additional, DeAngelo, Daniel J., additional, Soiffer, Robert J., additional, Uddin, Md Mesbah, additional, Griffin, Gabriel, additional, Vlasschaert, Caitlyn, additional, Gibson, Christopher J., additional, Jaiswal, Siddhartha, additional, Bick, Alexander G., additional, Malcovati, Luca, additional, Natarajan, Pradeep, additional, and Ebert, Benjamin L., additional

Published
2023
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49. Supplementary Figures S1-S11 from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author

Beauchamp, Ellen M., primary, Leventhal, Matthew, primary, Bernard, Elsa, primary, Hoppe, Emma R., primary, Todisco, Gabriele, primary, Creignou, Maria, primary, Gallì, Anna, primary, Castellano, Cecilia A., primary, McConkey, Marie, primary, Tarun, Akansha, primary, Wong, Waihay, primary, Schenone, Monica, primary, Stanclift, Caroline, primary, Tanenbaum, Benjamin, primary, Malolepsza, Edyta, primary, Nilsson, Björn, primary, Bick, Alexander G., primary, Weinstock, Joshua S., primary, Miller, Mendy, primary, Niroula, Abhishek, primary, Dunford, Andrew, primary, Taylor-Weiner, Amaro, primary, Wood, Timothy, primary, Barbera, Alex, primary, Anand, Shankara, primary, Psaty, Bruce M., primary, Desai, Pinkal, primary, Cho, Michael H., primary, Johnson, Andrew D., primary, Loos, Ruth, primary, MacArthur, Daniel G., primary, Lek, Monkol, primary, Neuberg, Donna S., primary, Lage, Kasper, primary, Carr, Steven A., primary, Hellstrom-Lindberg, Eva, primary, Malcovati, Luca, primary, Papaemmanuil, Elli, primary, Stewart, Chip, primary, Getz, Gad, primary, Bradley, Robert K., primary, Jaiswal, Siddhartha, primary, and Ebert, Benjamin L., primary

Published
2023
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50. Data from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author

Beauchamp, Ellen M., primary, Leventhal, Matthew, primary, Bernard, Elsa, primary, Hoppe, Emma R., primary, Todisco, Gabriele, primary, Creignou, Maria, primary, Gallì, Anna, primary, Castellano, Cecilia A., primary, McConkey, Marie, primary, Tarun, Akansha, primary, Wong, Waihay, primary, Schenone, Monica, primary, Stanclift, Caroline, primary, Tanenbaum, Benjamin, primary, Malolepsza, Edyta, primary, Nilsson, Björn, primary, Bick, Alexander G., primary, Weinstock, Joshua S., primary, Miller, Mendy, primary, Niroula, Abhishek, primary, Dunford, Andrew, primary, Taylor-Weiner, Amaro, primary, Wood, Timothy, primary, Barbera, Alex, primary, Anand, Shankara, primary, Psaty, Bruce M., primary, Desai, Pinkal, primary, Cho, Michael H., primary, Johnson, Andrew D., primary, Loos, Ruth, primary, MacArthur, Daniel G., primary, Lek, Monkol, primary, Neuberg, Donna S., primary, Lage, Kasper, primary, Carr, Steven A., primary, Hellstrom-Lindberg, Eva, primary, Malcovati, Luca, primary, Papaemmanuil, Elli, primary, Stewart, Chip, primary, Getz, Gad, primary, Bradley, Robert K., primary, Jaiswal, Siddhartha, primary, and Ebert, Benjamin L., primary

Published
2023
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