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7. 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

9. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Author

Nakao, Tetsushi, Bick, Alexander G, Taub, Margaret A, Zekavat, Seyedeh M, Uddin, Md M, Niroula, Abhishek, Carty, Cara L, Lane, John, Honigberg, Michael C, Weinstock, Joshua S, Pampana, Akhil, Gibson, Christopher J, Griffin, Gabriel K, Clarke, Shoa L, Bhattacharya, Romit, Assimes, Themistocles L, Emery, Leslie S, Stilp, Adrienne M, Wong, Quenna, Broome, Jai, Laurie, Cecelia A, Khan, Alyna T, Smith, Albert V, Blackwell, Thomas W, Codd, Veryan, Nelson, Christopher P, Yoneda, Zachary T, Peralta, Juan M, Bowden, Donald W, Irvin, Marguerite R, Boorgula, Meher, Zhao, Wei, Yanek, Lisa R, Wiggins, Kerri L, Hixson, James E, Gu, C Charles, Peloso, Gina M, Roden, Dan M, Reupena, Muagututi’a S, Hwu, Chii-Min, DeMeo, Dawn L, North, Kari E, Kelly, Shannon, Musani, Solomon K, Bis, Joshua C, Lloyd-Jones, Donald M, Johnsen, Jill M, Preuss, Michael, Tracy, Russell P, Peyser, Patricia A, Qiao, Dandi, Desai, Pinkal, Curran, Joanne E, Freedman, Barry I, Tiwari, Hemant K, Chavan, Sameer, Smith, Jennifer A, Smith, Nicholas L, Kelly, Tanika N, Hidalgo, Bertha, Cupples, L Adrienne, Weeks, Daniel E, Hawley, Nicola L, Minster, Ryan L, Deka, Ranjan, Naseri, Take T, de las Fuentes, Lisa, Raffield, Laura M, Morrison, Alanna C, Vries, Paul S, Ballantyne, Christie M, Kenny, Eimear E, Rich, Stephen S, Whitsel, Eric A, Cho, Michael H, Shoemaker, M Benjamin, Pace, Betty S, Blangero, John, Palmer, Nicholette D, Mitchell, Braxton D, Shuldiner, Alan R, Barnes, Kathleen C, Redline, Susan, Kardia, Sharon LR, Abecasis, Gonçalo R, Becker, Lewis C, Heckbert, Susan R, He, Jiang, Post, Wendy, Arnett, Donna K, Vasan, Ramachandran S, Darbar, Dawood, Weiss, Scott T, McGarvey, Stephen T, de Andrade, Mariza, Chen, Yii-Der Ida, Kaplan, Robert C, Meyers, Deborah A, Custer, Brian S, and Correa, Adolfo

Subjects
Cardiovascular, Genetics, Aging, Heart Disease, Heart Disease - Coronary Heart Disease, Human Genome, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Published
2022

12. Adverse Pregnancy Outcomes and Incident Heart Failure in the Women’s Health Initiative

Author

Hansen, Aleksander L, Søndergaard, Marc Meller, Hlatky, Mark A, Vittinghof, Eric, Nah, Gregory, Stefanick, Marcia L, Manson, JoAnn E, Farland, Leslie V, Wells, Gretchen L, Mongraw-Chaffin, Morgana, Gunderson, Erica P, Van Horn, Linda, Wild, Robert A, Liu, Buyun, Shadyab, Aladdin H, Allison, Matthew A, Liu, Simin, Eaton, Charles B, Honigberg, Michael C, and Parikh, Nisha I

Subjects
Pediatric, Prevention, Perinatal Period - Conditions Originating in Perinatal Period, Contraception/Reproduction, Preterm, Low Birth Weight and Health of the Newborn, Clinical Research, Cardiovascular, Aging, Nutrition, Infant Mortality, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Good Health and Well Being, Aged, Cohort Studies, Female, Heart Failure, Humans, Incidence, Longitudinal Studies, Middle Aged, Postmenopause, Pregnancy, Pregnancy Complications, Cardiovascular, Pregnancy Outcome, Risk Factors, United States, Women's Health
Abstract

ImportanceSome prior evidence suggests that adverse pregnancy outcomes (APOs) may be associated with heart failure (HF). Identifying unique factors associated with the risk of HF and studying HF subtypes are important next steps.ObjectiveTo investigate the association of APOs with incident HF overall and stratified by HF subtype (preserved vs reduced ejection fraction) among postmenopausal women in the Women's Health Initiative (WHI).Design, setting, and participantsIn 2017, an APO history survey was administered in the WHI study, a large multiethnic cohort of postmenopausal women. The associations of 5 APOs (gestational diabetes, hypertensive disorders of pregnancy [HDP], low birth weight, high birth weight, and preterm delivery) with incident adjudicated HF were analyzed. In this cohort study, the association of each APO with HF was assessed using logistic regression models and with HF subtypes using multinomial regression, adjusting for age, sociodemographic characteristics, smoking, randomization status, reproductive history, and other APOs. Data analysis was performed from January 2020 to September 2021.ExposuresAPOs (gestational diabetes, HDP, low birth weight, high birth weight, and preterm delivery).Main outcomes and measuresAll confirmed cases of women hospitalized with HF and HF subtype were adjudicated by trained physicians using standardized methods.ResultsOf 10 292 women (median [IQR] age, 60 [55-64] years), 3185 (31.0%) reported 1 or more APO and 336 (3.3%) had a diagnosis of HF. Women with a history of any APO had a higher prevalence of hypertension, diabetes, coronary heart disease, or smoking. Of the APOs studied, only HDP was significantly associated with HF with a fully adjusted odds ratio (OR) of 1.75 (95% CI, 1.22-2.50), and with HF with preserved ejection fraction in fully adjusted models (OR, 2.06; 95% CI, 1.29-3.27). In mediation analyses, hypertension explained 24% (95% CI, 12%-73%), coronary heart disease 23% (95% CI, 11%-68%), and body mass index 20% (95% CI, 10%-64%) of the association between HDP and HF.Conclusions and relevanceIn this large cohort of postmenopausal women, HDP was independently associated with incident HF, particularly HF with preserved ejection fraction, and this association was mediated by subsequent hypertension, coronary heart disease, and obesity. These findings suggest that monitoring and modifying these factors early in women presenting with HDP may be associated with reduced long-term risk of HF.

Published
2021

13. Polygenic prediction of preeclampsia and gestational hypertension

Author

Honigberg, Michael C., Truong, Buu, Khan, Raiyan R., Xiao, Brenda, Bhatta, Laxmi, Vy, Ha My T., Guerrero, Rafael F., Schuermans, Art, Selvaraj, Margaret Sunitha, Patel, Aniruddh P., Koyama, Satoshi, Cho, So Mi Jemma, Vellarikkal, Shamsudheen Karuthedath, Trinder, Mark, Urbut, Sarah M., Gray, Kathryn J., Brumpton, Ben M., Patil, Snehal, Zöllner, Sebastian, Antopia, Mariah C., Saxena, Richa, Nadkarni, Girish N., Do, Ron, Yan, Qi, Pe’er, Itsik, Verma, Shefali Setia, Gupta, Rajat M., Haas, David M., Martin, Hilary C., van Heel, David A., Laisk, Triin, and Natarajan, Pradeep

Published
2023
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14. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Author

Natarajan, Pradeep, Pampana, Akhil, Graham, Sarah E, Ruotsalainen, Sanni E, Perry, James A, de Vries, Paul S, Broome, Jai G, Pirruccello, James P, Honigberg, Michael C, Aragam, Krishna, Wolford, Brooke, Brody, Jennifer A, Antonacci-Fulton, Lucinda, Arden, Moscati, Aslibekyan, Stella, Assimes, Themistocles L, Ballantyne, Christie M, Bielak, Lawrence F, Bis, Joshua C, Cade, Brian E, Do, Ron, Doddapaneni, Harsha, Emery, Leslie S, Hung, Yi-Jen, Irvin, Marguerite R, Khan, Alyna T, Lange, Leslie, Lee, Jiwon, Lemaitre, Rozenn N, Martin, Lisa W, Metcalf, Ginger, Montasser, May E, Moon, Jee-Young, Muzny, Donna, O'Connell, Jeffrey R, Palmer, Nicholette D, Peralta, Juan M, Peyser, Patricia A, Stilp, Adrienne M, Tsai, Michael, Wang, Fei Fei, Weeks, Daniel E, Yanek, Lisa R, Wilson, James G, Abecasis, Goncalo, Arnett, Donna K, Becker, Lewis C, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Chang, Yi-Cheng, Chen, Yii-Der I, Choi, Won Jung, Correa, Adolfo, Curran, Joanne E, Daly, Mark J, Dutcher, Susan K, Ellinor, Patrick T, Fornage, Myriam, Freedman, Barry I, Gabriel, Stacey, Germer, Soren, Gibbs, Richard A, He, Jiang, Hveem, Kristian, Jarvik, Gail P, Kaplan, Robert C, Kardia, Sharon LR, Kenny, Eimear, Kim, Ryan W, Kooperberg, Charles, Laurie, Cathy C, Lee, Seonwook, Lloyd-Jones, Don M, Loos, Ruth JF, Lubitz, Steven A, Mathias, Rasika A, Martinez, Karine A Viaud, McGarvey, Stephen T, Mitchell, Braxton D, Nickerson, Deborah A, North, Kari E, Palotie, Aarno, Park, Cheol Joo, Psaty, Bruce M, Rao, DC, Redline, Susan, Reiner, Alexander P, Seo, Daekwan, Seo, Jeong-Sun, Smith, Albert V, Tracy, Russell P, Vasan, Ramachandran S, Kathiresan, Sekar, Cupples, L Adrienne, Rotter, Jerome I, Morrison, Alanna C, Rich, Stephen S, Ripatti, Samuli, and Willer, Cristen

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, FinnGen, Subcutaneous Tissue, Chromosomes, Human, X, Humans, Genetic Predisposition to Disease, Lipids, Eye Proteins, Nerve Tissue Proteins, Gene Expression Regulation, Genotype, Polymorphism, Single Nucleotide, Middle Aged, Female, Male, Genetic Loci, Genetic Association Studies, Whole Genome Sequencing, Phenomics, Cardiometabolic Risk Factors, Chromosomes, Human, X, Polymorphism, Single Nucleotide
Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Published
2021

20. Abstract 13711: Clonal Hematopoiesis Driven by TET2 and ASXL1 but Not DNMT3A is Associated With Interleukin 6 Levels, Cardiac Biomarkers, Cardiac Remodeling, and Risk of Atrial Fibrillation

Author

Saadatagah, Seyedmohammad, Naderian, Mohammadreza, Uddin, Md Mesbah, Dikilitas, Ozan, Schuermans, Art, Niroula, Abhishek, Selvin, Elizabeth, Hoogeveen, Ron C, Matsushita, Kuni, NAMBI, VIJAY, Yu, Bing, Chen, Lin Y, Bick, Alexander G, Ebert, Benjamin L, Honigberg, Michael C, Li, Na, Shah, Amil M, Natarajan, Pradeep, Kullo, Iftikhar J, and Ballantyne, Christie M

Published
2023
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21. 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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23. Association of T-cell subtypes with macrophage-specific arterial infiltration in people with HIV.

Author

Schnittman, Samuel R., Talathi, Ria, Wilks, Moses Q., Hedgire, Sandeep, Lu, Michael T., Fourman, Lindsay T., Alagpulinsa, David A., Stockman, Sara L., White, Kevin S., Wallis, Zoey K., Autissier, Patrick, Stanley, Takara L., Hang Lee, Honigberg, Michael C., El-Fakhri, Georges, Williams, Kenneth C., Zanni, Markella V., Grinspoon, Steven K., and Toribio, Mabel

Published
2024
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24. Colchicine prevents accelerated atherosclerosis in TET2-mutant clonal haematopoiesis.

Author

Zuriaga, María A, Yu, Zhi, Matesanz, Nuria, Truong, Buu, Ramos-Neble, Beatriz L, Asensio-López, Mari C, Uddin, Md Mesbah, Nakao, Tetsushi, Niroula, Abhishek, Zorita, Virginia, Amorós-Pérez, Marta, Moro, Rosa, Ebert, Benjamin L, Honigberg, Michael C, Pascual-Figal, Domingo, Natarajan, Pradeep, and Fuster, José J

Subjects
HIGH cholesterol diet, BONE marrow transplantation, BLOOD cells, INDIVIDUALIZED medicine, COLCHICINE, MYOCARDIAL infarction, ATHEROSCLEROSIS
Abstract

Background and Aims Somatic mutations in the TET2 gene that lead to clonal haematopoiesis (CH) are associated with accelerated atherosclerosis development in mice and a higher risk of atherosclerotic disease in humans. Mechanistically, these observations have been linked to exacerbated vascular inflammation. This study aimed to evaluate whether colchicine, a widely available and inexpensive anti-inflammatory drug, prevents the accelerated atherosclerosis associated with TET2-mutant CH. Methods In mice, TET2 -mutant CH was modelled using bone marrow transplantations in atherosclerosis-prone Ldlr −/− mice. Haematopoietic chimeras carrying initially 10% Tet2 −/− haematopoietic cells were fed a high-cholesterol diet and treated with colchicine or placebo. In humans, whole-exome sequencing data and clinical data from 37 181 participants in the Mass General Brigham Biobank and 437 236 participants in the UK Biobank were analysed to examine the potential modifying effect of colchicine prescription on the relationship between CH and myocardial infarction. Results Colchicine prevented accelerated atherosclerosis development in the mouse model of TET2 -mutant CH, in parallel with suppression of interleukin-1β overproduction in conditions of TET2 loss of function. In humans, patients who were prescribed colchicine had attenuated associations between TET2 mutations and myocardial infarction. This interaction was not observed for other mutated genes. Conclusions These results highlight the potential value of colchicine to mitigate the higher cardiovascular risk of carriers of somatic TET2 mutations in blood cells. These observations set the basis for the development of clinical trials that evaluate the efficacy of precision medicine approaches tailored to the effects of specific mutations linked to CH. [ABSTRACT FROM AUTHOR]

Published
2024
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25. 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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29. Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1

Author

Saadatagah, Seyedmohammad, primary, Naderian, Mohammadreza, additional, Uddin, Mesbah, additional, Dikilitas, Ozan, additional, Niroula, Abhishek, additional, Schuermans, Art, additional, Selvin, Elizabeth, additional, Hoogeveen, Ron C., additional, Matsushita, Kunihiro, additional, Nambi, Vijay, additional, Yu, Bing, additional, Chen, Lin Yee, additional, Bick, Alexander G., additional, Ebert, Benjamin L., additional, Honigberg, Michael C., additional, Li, Na, additional, Shah, Amil, additional, Natarajan, Pradeep, additional, Kullo, Iftikhar J., additional, and Ballantyne, Christie M., additional

Published
2024
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30. Coronary Microvascular Function Following Severe Preeclampsia

Author

Honigberg, Michael C., primary, Economy, Katherine E., additional, Pabón, Maria A., additional, Wang, Xiaowen, additional, Castro, Claire, additional, Brown, Jenifer M., additional, Divakaran, Sanjay, additional, Weber, Brittany N., additional, Barrett, Leanne, additional, Perillo, Anna, additional, Sun, Anina Y., additional, Antoine, Tajmara, additional, Farrohi, Faranak, additional, Docktor, Brenda, additional, Lau, Emily S., additional, DeFaria Yeh, Doreen, additional, Natarajan, Pradeep, additional, Sarma, Amy A., additional, Weisbrod, Robert M., additional, Hamburg, Naomi M., additional, Ho, Jennifer E., additional, Roh, Jason D., additional, Wood, Malissa J., additional, Scott, Nandita S., additional, and Di Carli, Marcelo F., additional

Published
2024
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31. LGBTQ Health Disparities

Author

Connors, Jeremy, Casares, Maria Carolina, Honigberg, Michael C., Davis, John A., Lehman, James R., editor, Diaz, Kristine, editor, Ng, Henry, editor, Petty, Elizabeth M., editor, Thatikunta, Meena, editor, and Eckstrand, Kristen, editor

Published
2020
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32. Distinction of lymphoid and myeloid clonal hematopoiesis

Author

Niroula, Abhishek, Sekar, Aswin, Murakami, Mark A., Trinder, Mark, Agrawal, Mridul, Wong, Waihay J., Bick, Alexander G., Uddin, Md Mesbah, Gibson, Christopher J., Griffin, Gabriel K., Honigberg, Michael C., Zekavat, Seyedeh M., Paruchuri, Kaavya, Natarajan, Pradeep, and Ebert, Benjamin L.

Published
2021
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33. Obesity-induced inflammation exacerbates clonal hematopoiesis

Author

Pasupuleti, Santhosh Kumar, Ramdas, Baskar, Burns, Sarah S., Palam, Lakshmi Reddy, Kanumuri, Rahul, Kumar, Ramesh, Pandhiri, Taruni Reddy, Dave, Utpal P., Yellapu, Nanda Kumar, Zhou, Xinyu, Zhang, Chi, Sandusky, George E., Yu, Zhi, Honigberg, Michael C., Bick, Alexander G., Griffin, Gabriel K., Niroula, Abhishek, Ebert, Benjamin L., Paczesny, Sophie, Natarajan, Pradeep, and Kapur, Reuben

Subjects
Obesity -- Complications and side effects, Hematopoiesis -- Health aspects -- Genetic aspects, Leukemia -- Risk factors -- Development and progression, Lymphomas -- Risk factors -- Development and progression, Multiple myeloma -- Risk factors -- Development and progression, Health care industry
Abstract

Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity., Introduction Clonal hematopoiesis of indeterminate potential (CHIP) is a newly-discovered condition that increases the risk of all-cause mortality and the development of hematologic malignancies (1, 2). The prevalence of CHIP [...]

Published
2023
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35. Association of Clonal Hematopoiesis With Incident Heart Failure

Author

Yu, Bing, Roberts, Mary B., Raffield, Laura M., Zekavat, Seyedeh Maryam, Nguyen, Ngoc Quynh H., Biggs, Mary L., Brown, Michael R., Griffin, Gabriel, Desai, Pinkal, Correa, Adolfo, Morrison, Alanna C., Shah, Amil M., Niroula, Abhishek, Uddin, Md Mesbah, Honigberg, Michael C., Ebert, Benjamin L., Psaty, Bruce M., Whitsel, Eric A., Manson, JoAnn E., Kooperberg, Charles, Bick, Alexander G., Ballantyne, Christie M., Reiner, Alex P., Natarajan, Pradeep, and Eaton, Charles B.

Published
2021
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36. Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations

Author

Ardissino, Maddalena, Slob, Eric A W, Reddy, Rohin K, Morley, Alec P, Schuermans, Art, Hill, Phoebe, Williamson, Catherine, Honigberg, Michael C, de Marvao, Antonio, Ng, Fu Siong, Ardissino, Maddalena, Slob, Eric A W, Reddy, Rohin K, Morley, Alec P, Schuermans, Art, Hill, Phoebe, Williamson, Catherine, Honigberg, Michael C, de Marvao, Antonio, and Ng, Fu Siong

Abstract

Aims: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. Methods and results: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30–5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33–3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16–1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. Conclusion: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.

Published
2024

40. Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia

Author

Schuermans, Art, primary, Truong, Buu, additional, Ardissino, Maddalena, additional, Bhukar, Rohan, additional, Slob, Eric A. W., additional, Nakao, Tetsushi, additional, Dron, Jacqueline S., additional, Small, Aeron M., additional, Cho, So Mi Jemma, additional, Yu, Zhi, additional, Hornsby, Whitney, additional, Antoine, Tajmara, additional, Lannery, Kim, additional, Postupaka, Darina, additional, Gray, Kathryn J., additional, Yan, Qi, additional, Butterworth, Adam S., additional, Burgess, Stephen, additional, Wood, Malissa J., additional, Scott, Nandita S., additional, Harrington, Colleen M., additional, Sarma, Amy A., additional, Lau, Emily S., additional, Roh, Jason D., additional, Januzzi, James L., additional, Natarajan, Pradeep, additional, and Honigberg, Michael C., additional

Published
2024
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42. Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

Author

Schuermans, Art, primary, Honigberg, Michael C., additional, Raffield, Laura M., additional, Yu, Bing, additional, Roberts, Mary B., additional, Kooperberg, Charles, additional, Desai, Pinkal, additional, Carson, April P., additional, Shah, Amil M., additional, Ballantyne, Christie M., additional, Bick, Alexander G., additional, Natarajan, Pradeep, additional, Manson, JoAnn E., additional, Whitsel, Eric A., additional, Eaton, Charles B., additional, and Reiner, Alexander P., additional

Published
2024
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43. 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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50. Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.

Author

Roh, Jason D., Castro, Claire, Yu, Andy, Rana, Sarosh, Shahul, Sajid, Gray, Kathryn J., Honigberg, Michael C., Ricke-Hoch, Melanie, Iwamoto, Yoshiko, Yeri, Ashish, Kitchen, Robert, Guerra, Justin Baldovino, Hobson, Ryan, Chaudhari, Vinita, Chang, Bliss, Sarma, Amy, Lerchenmüller, Carolin, Al Sayed, Zeina R., Diaz Verdugo, Carmen, and Xia, Peng

Abstract

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy. Editor's summary: Peripartum cardiomyopathy is a form of heart failure linked to preeclampsia. Roh et al. found that secreted proteins associated with senescence, a process linked to aging and cellular stress, were increased in sera from patients with peripartum cardiomyopathy or preeclampsia. Placentas from patients with preeclampsia also had elevated gene expression and tissue signatures of senescence. The most up-regulated senescence-associated secretory protein, activin A, was associated with worse heart function in human pregnancy cohorts that included patients with peripartum cardiomyopathy or preeclampsia. In a mouse model of peripartum cardiomyopathy with the peroxisome proliferator–activated receptor γ coactivator-1α gene deleted in cardiomyocytes, placentas also showed an amplified senescence phenotype. Treating these mice with the senolytic compound fisetin during mid to late pregnancy reduced placental senescence and improved heart function. Treatment with a monoclonal antibody directed against the activin type II receptor similarly improved heart function. These findings suggest that cardiovascular diseases of pregnancy could be targeted through reducing pathological cellular senescence in the placenta. —Brandon Berry [ABSTRACT FROM AUTHOR]

Published
2024
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