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Author

Romit Bhattacharya

Other affiliations: Broad Institute
Bio: Romit Bhattacharya is an academic researcher from Harvard University. The author has contributed to research in topics: Risk factor & Cohort study. The author has an hindex of 3, co-authored 9 publications receiving 36 citations. Previous affiliations of Romit Bhattacharya include Broad Institute.

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Journal ArticleDOI
TL;DR: In this paper, expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 2.7 × 10-4).
Abstract: Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

73 citations

Journal ArticleDOI
08 Nov 2021-Stroke
TL;DR: In this paper, a novel age-related risk factor for cardiovascular disease-related morbidity and mortality, called clonal hematopoiesis of indeterminate potential (CHIP), was proposed.
Abstract: Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease–related morbidity and mortality. The association of CHIP...

46 citations

Journal ArticleDOI
TL;DR: Obesity is independently associated with pulmonary hypertension and PH is associated with greater mortality; this is modified by obesity such that obese patients with precapillary PH have lower mortality compared with nonobese counterparts.
Abstract: Background Experimental studies support a link between obesity and pulmonary hypertension (PH), yet clinical studies have been limited. This study sought to determine the association of obesity and...

33 citations

Journal ArticleDOI
TL;DR: In this article, the authors examined whether there is an association between diet quality and the prevalence of clonal hematopoiesis of indeterminate potential (CHIP), the expansion of somatic leukemogenic variations in hepatopoietic stem cells, has been associated with atherosclerotic cardiovascular disease.
Abstract: Importance Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of somatic leukemogenic variations in hematopoietic stem cells, has been associated with atherosclerotic cardiovascular disease. Because the inherited risk of developing CHIP is low, lifestyle elements such as dietary factors may be associated with the development and outcomes of CHIP. Objective To examine whether there is an association between diet quality and the prevalence of CHIP. Design, Setting, and Participants This retrospective cohort study used data from participants in the UK Biobank, an ongoing population-based study in the United Kingdom that examines whole-exome sequencing data and survey-based information on health-associated behaviors. Individuals from the UK Biobank were recruited between 2006 and 2010 and followed up prospectively with linkage to health data records through May 2020. The present study included 44 111 participants in the UK Biobank who were age 40 to 70 years, had data available from whole-exome sequencing of blood DNA, and were free of coronary artery disease (CAD) or hematologic cancer at baseline. Exposures Diet quality was categorized as unhealthy if the intake of healthy elements (fruits and vegetables) was lower than the median of all survey responses, and the intake of unhealthy elements (red meat, processed food, and added salt) was higher than the median. Diets were classified as healthy if the intake of healthy elements was higher than the median, and the intake of unhealthy elements was lower than the median. The presence of CHIP was detected by data from whole-exome sequencing of blood DNA. Main Outcomes and Measures The primary outcome was CHIP prevalence. Multivariable logistic regression analysis was used to examine the association between diet quality and the presence of CHIP. Multivariable Cox proportional hazards models were used to assess the association of incident events (acute coronary syndromes, coronary revascularization, or death) in each diet quality category stratified by the presence of CHIP. Results Among 44 111 participants (mean [SD] age at time of blood sample collection, 56.3 [8.0] years; 24 507 women [55.6%]), 2271 individuals (5.1%) had an unhealthy diet, 38 552 individuals (87.4%) had an intermediate diet, and 3288 individuals (7.5%) had a healthy diet. A total of 2507 individuals (5.7%) had CHIP, and the prevalence of CHIP decreased as diet quality improved from unhealthy (162 of 2271 participants [7.1%]) to intermediate (2177 of 38 552 participants [5.7%]) to healthy (168 of 3288 participants [5.1%];P = .003 for trend). Compared with individuals without CHIP who had an intermediate diet, the rates of incident cardiovascular events progressively decreased among those with CHIP who had an unhealthy diet (hazard ratio [HR], 1.52; 95% CI, 1.04-2.22) and those with CHIP who had a healthy diet (HR, 0.99; 95% CI, 0.62-1.58) over a median of 10.0 years (interquartile range, 9.6-10.4 years) of follow-up. Conclusions and Relevance This cohort study suggests that an unhealthy diet quality may be associated with a higher prevalence of CHIP and higher rates of adverse cardiovascular events and death independent of CHIP status.

31 citations

Journal ArticleDOI
TL;DR: In this article, the authors used a linked electronic health records and insurer claims dataset from a large health system from a recent pragmatic trial to quantify adherence barriers for patients with poorly controlled cardiometabolic condition, identify patient characteristics associated with having multiple barriers, and determine its impact on adherence.
Abstract: Adherence to medications remains poor despite numerous efforts to identify and intervene upon nonadherence. One potential explanation is the limited focus of many interventions on one barrier. Little is known about the prevalence and impact of having multiple barriers in contemporary practice. Our objective was to quantify adherence barriers for patients with poorly controlled cardiometabolic condition, identify patient characteristics associated with having multiple barriers, and determine its impact on adherence. We used a linked electronic health records and insurer claims dataset from a large health system from a recent pragmatic trial. Barriers to medication taking before the start of the intervention were elicited by clinical pharmacists using structured interviews. We used multivariable modified Poisson regression models to examine the association between patient factors and multiple barriers and multivariable linear regression to evaluate the relation between multiple barriers and claims-based adherence. Of the 1,069 patients (mean: 61 years of age) in this study, 25.1% had multiple barriers to adherence; the most common co-occurring barriers were forgetfulness and health beliefs (31%, n = 268). Patients with multiple barriers were more likely to be non-white (relative risk [RR] 1.57, 95% confidence interval [CI] 1.21 to 1.74), be single/unpartnered (RR 1.36, 95% CI 1.06 to 1.74), use tobacco (RR 1.54, 95% CI 1.13 to 2.11), and have poor glycemic control (RR 1.77, 95% CI 1.31 to 2.39) versus those with 0 or 1 barrier. Each additional barrier worsened average adherence by 3.1% (95% CI −4.6%, −1.5%). In conclusion, >25% of nonadherent patients present with multiple barriers to optimal use, leading to meaningful differences in adherence. These findings should inform quality improvement interventions aimed at nonadherence.

11 citations


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TL;DR: In this article, a review of the evidence for obesity cardiomyopathy is presented, examining putative responsible mechanisms, and discusses therapeutic options for this disorder, which develops independent of hypertension, coronary heart disease, and other heart diseases.
Abstract: The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy," which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.

103 citations

Journal ArticleDOI
TL;DR: In this article, the authors performed an integrated analysis of gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), and found that myeloid and lymphoid gene mutations were associated with risk of lineage-specific malignancy.
Abstract: Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies. Genomic analyses in the UK Biobank show that clonal hematopoiesis of indeterminate potential in the lymphoid lineage is associated with a higher risk of developing lymphoid malignancies

79 citations

Journal ArticleDOI
TL;DR: The authors analyzed genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14.
Abstract: Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.

67 citations

Journal ArticleDOI
TL;DR: In this paper, the authors show that acquired somatic mutations in hematopoietic stem and progenitor cells are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival.
Abstract: Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation. Clonal haematopoiesis (CH) has been associated with altered inflammatory profiles and increased risk of cardiovascular and malignant diseases. Here, the authors analyze patient data from two different cohorts and show that CH is associated with severe infections and severe Covid19.

56 citations

Journal ArticleDOI
TL;DR: A review of the cellular and molecular mechanisms underlying ageing in the regenerative regions of different tissues as well as potential rejuvenation strategies is presented in this paper , focusing primarily on brain, muscle and blood tissues.
Abstract: Most adult organs contain regenerative stem cells, often organized in specific niches. Stem cell function is critical for tissue homeostasis and repair upon injury, and it is dependent on interactions with the niche. During ageing, stem cells decline in their regenerative potential and ability to give rise to differentiated cells in the tissue, which is associated with a deterioration of tissue integrity and health. Ageing-associated changes in regenerative tissue regions include defects in maintenance of stem cell quiescence, differentiation ability and bias, clonal expansion and infiltration of immune cells in the niche. In this Review, we discuss cellular and molecular mechanisms underlying ageing in the regenerative regions of different tissues as well as potential rejuvenation strategies. We focus primarily on brain, muscle and blood tissues, but also provide examples from other tissues, such as skin and intestine. We describe the complex interactions between different cell types, non-cell-autonomous mechanisms between ageing niches and stem cells, and the influence of systemic factors. We also compare different interventions for the rejuvenation of old regenerative regions. Future outlooks in the field of stem cell ageing are discussed, including strategies to counter ageing and age-dependent disease. Stem cell function declines during ageing, resulting in the loss of tissue integrity and health deterioration. Ageing is associated with defects in the maintenance of stem cell quiescence and cell differentiation ability, clonal expansion and infiltration of immune cells in the niche. This Review discusses the mechanisms underlying ageing in stem cells and their niches, and potential rejuvenation strategies.

48 citations