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Open accessJournal ArticleDOI: 10.1161/JAHA.120.018789

Healthy Lifestyle and Clonal Hematopoiesis of Indeterminate Potential: Results From the Women's Health Initiative.

02 Mar 2021-Journal of the American Heart Association (Ovid Technologies (Wolters Kluwer Health))-Vol. 10, Iss: 5
Abstract: Background Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship bet...

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Journal ArticleDOI: 10.1001/JAMACARDIO.2021.1678
01 Sep 2021-JAMA Cardiology
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.

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Topics: Sample collection (52%), Population (51%), Cohort study (50%)

3 Citations


Journal ArticleDOI: 10.1016/J.YJMCC.2021.07.004
Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of a clonally expanded hematopoietic stem cell caused by a leukemogenic mutation in individuals without evidence of hematologic malignancy, dysplasia, or cytopenia. CHIP is associated with a 0.5-1.0% risk per year of leukemia. Remarkably, it confers a two-fold increase in cardiovascular risk independent of traditional risk factors. Roughly 80% of patients with CHIP have mutations in epigenetic regulators DNMT3A, TET2, ASXL1, DNA damage repair genes PPM1D, TP53, the regulatory tyrosine kinase JAK2, or mRNA spliceosome components SF3B1, and SRSF2. CHIP is associated with a pro-inflammatory state that has been linked to coronary artery disease, myocardial infarction, and venous thromboembolic disease, as well as prognosis among those with aortic stenosis and heart failure. Heritable and acquired risk factors are associated with increased CHIP prevalence, including germline variation, age, unhealthy lifestyle behaviors (i.e. smoking, obesity), inflammatory conditions, premature menopause, HIV and exposure to cancer therapies. This review aims to summarize emerging research on CHIP, the mechanisms underlying its important role in propagating inflammation and accelerating cardiovascular disease, and new studies detailing the role of associated risk factors and co-morbidities that increase CHIP prevalence.

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Topics: Disease (52%)

2 Citations


Journal ArticleDOI: 10.1007/S11883-021-00966-9
Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor that develops as aging hematopoietic stem cells (HSCs) acquire somatic mutations which confer a clonal survival advantage in their progeny. These cells confer increased leukemogenic risk but confer a greater absolute risk of cardiovascular disease—which appears to be mediated through altered inflammatory pathways. Here we review the evidence the risk of cardiovascular disease conferred by CHIP. We also review the evidence regarding risk factors associated with CHIP. The most recent evidence suggests that CHIP is associated with increased cardiovascular risk beyond atherosclerosis, which has been established in multiple studies, but also in heart failure and aortic valve stenosis. Additionally, the list of conditions associated with CHIP continues to grow including germline genetics, smoking, cancer therapies, radiation exposure, premature menopause, and unhealthy diet. CHIP is a cardiovascular risk factor of increasingly recognized importance, and new data continues to emerge about the risks it confers, which will need more prospective validation. Although risk factors for CHIP are being identified, relatively little is known about the mechanisms by which CHIP develops, which requires further study.

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Topics: Risk factor (54%)

1 Citations


Open accessPosted ContentDOI: 10.1101/2021.05.12.443095
09 Jul 2021-bioRxiv
Abstract: Aging is associated with clonal hematopoiesis (CH) caused by somatic mutations in blood cell progenitors. Mutations with ≥2% variant allele frequency (VAF), known as clonal hematopoiesis of indeterminate potential (CHIP) mutations, have been linked to risk of hematological malignancies and cardiovascular disease. Using an ultrasensitive single-molecule molecular inversion probe (smMIP) sequencing assay, we identified clonal hematopoiesis driver mutations (CHDMs) in a set of established CH driver genes in individuals with obesity from the Swedish Obese Subjects study. In cross-sectional setting, with samples from 1050 individuals, we identified 273 candidate CHDMs in 216 individuals, with a VAF ranging from 0.01% to 31.15% and with clone sizes and prevalence increasing with age. Longitudinal analysis over 20 years in 40 individuals showed that small clones may grow over time and become CHIP. Greater speed of clone growth was associated with insulin resistance (R=0.04, P=0.025) and low circulating levels of high-density lipoprotein-cholesterol (R=-0.68, P=1.74E-05), suggesting that dysfunctional metabolism may accelerate expansion of CH.

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Topics: Clone (cell biology) (51%)

1 Citations


Open accessPosted ContentDOI: 10.1101/2021.05.12.443095
van Deuren, Andersson-Assarsson1, Kristensson1, Steehouwer2  +12 moreInstitutions (3)
13 May 2021-bioRxiv
Abstract: Aging is associated with clonal hematopoiesis (CH) caused by somatic mutations in blood cell progenitors. Mutations with [≥]2% variant allele frequency (VAF), known as clonal hematopoiesis of indeterminate potential (CHIP) mutations, have been linked to risk of hematological malignancies and cardiovascular disease. Using an ultrasensitive single-molecule molecular inversion probe (smMIP) sequencing assay, we identified clonal hematopoiesis driver mutations (CHDMs) in a set of established CH driver genes in individuals with obesity from the Swedish Obese Subjects study. In cross-sectional setting, with samples from 1050 individuals, we identified 273 candidate CHDMs in 216 individuals, with a VAF ranging from 0.01% to 31.15% and with clone sizes and prevalence increasing with age. Longitudinal analysis over 20 years in 40 individuals showed that small clones may grow over time and become CHIP. Greater speed of clone growth was associated with insulin resistance (R=0.04, P=0.025) and low circulating levels of high-density lipoprotein-cholesterol (R=-0.68, P=1.74E-05), suggesting that dysfunctional metabolism may accelerate expansion of CH.

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Topics: Clone (cell biology) (54%)

1 Citations


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51 results found


Journal ArticleDOI: 10.1097/00005650-199206000-00002
01 Jun 1992-Medical Care
Abstract: A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.

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Topics: Health services research (58%), Health equity (58%), Health policy (58%) ... read more

31,597 Citations


Journal ArticleDOI: 10.1001/JAMA.289.19.2560
21 May 2003-JAMA
Abstract: "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" provides a new guideline for hypertension prevention and management. The following are the key messages(1) In persons older than 50 years, systolic blood pressure (BP) of more than 140 mm Hg is a much more important cardiovascular disease (CVD) risk factor than diastolic BP; (2) The risk of CVD, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension; (3) Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent CVD; (4) Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β-blockers, calcium channel blockers); (5) Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease); (6) If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy with 2 agents, 1 of which usually should be a thiazide-type diuretic; and (7) The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated. Motivation improves when patients have positive experiences with and trust in the clinician. Empathy builds trust and is a potent motivator. Finally, in presenting these guidelines, the committee recognizes that the responsible physician's judgment remains paramount.

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Topics: Prehypertension (64%), Systolic hypertension (56%), Blood pressure (56%) ... read more

24,313 Citations


Open accessJournal ArticleDOI: 10.1001/JAMA.288.3.321
17 Jul 2002-JAMA
Abstract: Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

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Topics: Women's Health Initiative (65%), Transdermal estrogen (57%), Breast cancer (55%) ... read more

13,961 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA1408617
Abstract: Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)

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Topics: Hazard ratio (55%), Germline mutation (53%)

2,339 Citations


Journal ArticleDOI: 10.1002/HEC.4730020305
01 Oct 1993-Health Economics
Abstract: Recently, Ware and Sherbourne published a new short-form health survey, the MOS 36-Item Short-Form Health Survey (SF-36), consisting of 36 items included in long-form measures developed for the Medical Outcomes Study. The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, general mental health, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. The SF-36 items and scoring rules are distributed by MOS Trust, Inc. Strict adherence to item wording and scoring recommendations is required in order to use the SF-36 trademark. The RAND 36-Item Health Survey 1.0 (distributed by RAND) includes the same items as those in the SF-36, but the recommended scoring algorithm is somewhat different from that of the SF-36. Scoring differences are discussed here and new T-scores are presented for the 8 multi-item scales and two factor analytically-derived physical and mental health composite scores.

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Topics: SF-36 (59%), Health care (59%), Mental health (55%) ... read more

2,151 Citations


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