scholarly journals Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis

2022 ◽  
Author(s):  
Siddhartha P. Kar ◽  
Pedro M. Quiros ◽  
Muxin Gu ◽  
Tao Jiang ◽  
Ryan Langdon ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
European Ancestry ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Stem Cell Migration ◽  
Damage Repair ◽  
Genome Wide ◽  
Whole Exome ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

Clonal hematopoiesis (CH) is one of the most extensively studied somatic mutational phenomena, yet its causes and consequences remain poorly understood. We identify 10,924 individuals with CH amongst 200,453 whole-exome sequenced UK Biobank participants and use their linked genome-wide DNA genotypes to map the landscape of inherited predisposition to CH at unprecedented scale. We increase the number of European-ancestry genome-wide significant (P<5x10-8) germline associations with CH from four to 14 and identify one new transcriptome-wide significant (P<3.2x10-6) association. Genes at new loci implicate DNA damage repair (PARP1, ATM, and CHEK2), hematopoietic stem cell migration/homing (CD164), and myeloid oncogenesis (SETBP1) in CH development. Several associations were CH-subtype specific and, strikingly, variants at TCL1A and CD164 had opposite associations with DNMT3A- versus TET2-mutant CH, mirroring recently reported differences in lifelong behavior of these two most common CH subtypes and proposing important roles for these loci in CH pathogenesis. Using Mendelian randomization, we show, amongst other findings, that smoking and longer leukocyte telomere length are causal risk factors for CH and demonstrate that genetic predisposition to CH increases risks of myeloproliferative neoplasia, several non-hematological malignancies, atrial fibrillation, and blood epigenetic age acceleration.

scholarly journals A meta-analysis of genome-wide association studies of epigenetic age acceleration

PLoS Genetics ◽  
2019 ◽  
Vol 15 (11) ◽  
pp. e1008104 ◽  
Author(s):  
Jude Gibson ◽  
Tom C. Russ ◽  
Toni-Kim Clarke ◽  
David M. Howard ◽  
Robert F. Hillary ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

scholarly journals Effect of tobacco smoking on the epigenetic age of human respiratory organs

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaohui Wu ◽  
Qingsheng Huang ◽  
Ruheena Javed ◽  
Jiayong Zhong ◽  
Huan Gao ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Lung Tissue ◽  
Tobacco Consumption ◽  
Epigenetic Clock ◽  
Buccal Cells ◽  
Genome Wide ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Powerful Incentive ◽  
Airway Cells

Abstract Background Smoking leads to the aging of organs. However, no studies have been conducted to quantify the effect of smoking on the aging of respiratory organs and the aging-reversing ability of smoking cessation. Results We collected genome-wide methylation datasets of buccal cells, airway cells, esophagus tissue, and lung tissue from non-smokers, smokers, and ex-smokers. We used the “epigenetic clock” method to quantify the epigenetic age acceleration in the four organs. The statistical analyses showed the following: (1) Smoking increased the epigenetic age of airway cells by an average of 4.9 years and lung tissue by 4.3 years. (2) After smoking ceased, the epigenetic age acceleration in airway cells (but not in lung tissue) slowed to a level that non-smokers had. (3) The epigenetic age acceleration in airway cells and lung tissue showed no gender difference. Conclusions Smoking can accelerate the epigenetic age of human respiratory organs, but the effect varies among organs and can be reversed by smoking cessation. Our study provides a powerful incentive to reduce tobacco consumption autonomously.

scholarly journals Alcohol consumption and methylation-based measures of biological age

2021 ◽  
Author(s):  
Jacob K Kresovich ◽  
Alexandra M Martinez Lopez ◽  
Emma L Garval ◽  
Zongli Xu ◽  
Alexandra J White ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Consumption ◽  
Biological Age ◽  
Average Lifetime ◽  
Epigenetic Clock ◽  
Genome Wide ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
The Mean ◽  
Average Consumption

Abstract Epigenetic age acceleration is considered a measure of biological aging based on genome-wide patterns of DNA methylation. Although age acceleration has been associated with incidence of diseases and death, less is known about how it is related to lifestyle behaviors. Among 2,316 women, we evaluate associations between self-reported alcohol consumption and various metrics of epigenetic age acceleration. Recent average alcohol consumption was defined as the mean number of drinks consumed per week within the past year; lifetime average consumption was estimated as the mean number of drinks per year drinking. Whole blood genome-wide DNA methylation was measured with HumanMethylation450 BeadChips and used to assess four epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge) and their corresponding metrics of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, GrimAgeAccel). Although alcohol consumption showed little association with most age acceleration metrics, both lifetime and recent average consumption measures were positively associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.30 years, 95% CI: 0.11, 0.48, p=0.002; recent, per additional 5 drinks/week: β=0.19 years, 95% CI: 0.01, 0.37, p=0.04). In a mutually adjusted model, only average lifetime alcohol consumption remained associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.27 years, 95% CI: 0.04, 0.50, p=0.02; recent, per 5 additional drinks/week: β=0.05 years, 95% CI: -0.16, 0.26, p=0.64). Although alcohol use does not appear to be strongly associated with biological age measured by most epigenetic clocks, lifetime average consumption is associated with higher biological age assessed by the GrimAge epigenetic clock.

scholarly journals Whole exome sequencing reveals a novel LRBA mutation and clonal hematopoiesis in a common variable immunodeficiency patient presented with hemophagocytic lymphohistiocytosis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yanling Ren ◽  
Feng Xiao ◽  
Fei Cheng ◽  
Xin Huang ◽  
Jianhu Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Common Variable Immunodeficiency ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Great Promise ◽  
Hematopoietic Stem ◽  
Genetic Method ◽  
Clonal Hematopoiesis ◽  
Whole Exome ◽  
Common Variable

AbstractCommon variable immunodeficiency (CVID) was a kind of primary immunodeficiency disorders with heterogeneous phenotype and genotype. Lipopolysaccharide-responsive and beige-like anchor (LRBA) mutation was identified as disease associated in CVID, advanced genetic method will help to detect atypical cases. We report a case of adult patient manifested as hemophagocytic lymphohistiocytosis (HLH), bone marrow examination suggested prosperity to MDS, manifested as increased immature myeloid cells and dysplastic hematopoiesis. Whole exome sequencing (WES) identified a novel heterogeneous c.1876T > C (p.W626R) mutation in LRBA and four somatic mutations: ASXL1 (c.1967dupA); PTPN11 (c.226G > A), U2AF1 (c.101C > T and c.470A > G), among which ASXL1 was a high-risk marker of clonal hematopoiesis. Combined with her recurrent severe infections and immune abnormalities such as hypoimmunoglobulinemia, the patient was diagnosed with CVID. Subsequent hematopoietic stem cell transplantation saved her from severe cytopenia and immune deficiency. This case report highlights the great promise of utilization of WES for diagnosing rare disease with atypical manifestations and guiding further treatment.

scholarly journals Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

2019 ◽  
Author(s):  
Sisi Chen ◽  
Qiang Wang ◽  
Hao Yu ◽  
Maegan L. Capitano ◽  
Sasidhar Vemula ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Epigenetic Mechanism ◽  
Mutant P53 ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Induced Stress ◽  
Epigenetic Regulator ◽  
Radiation Induced

AbstractClonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. We discovered that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Further, genetic and pharmacological inhibition of EZH2 decrease the repopulating potential of p53 mutant HSPCs. Thus, we have uncovered an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

scholarly journals A meta-analysis of genome-wide association studies of epigenetic age acceleration

2019 ◽  
Author(s):  
Jude Gibson ◽  
Tom C. Russ ◽  
Toni-Kim Clarke ◽  
David M. Howard ◽  
Kathryn L. Evans ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Biological Mechanisms ◽  
Age Related ◽  
Genome Wide ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

Abstract‘Epigenetic age acceleration’ is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC,TPMT) and immune system pathways (TRIM59,EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3,MANBA,TRIM46), with metabolic functions (UBE2D3,MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father’s age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.Author SummaryDNA methylation, a type of epigenetic process, is known to vary with age. Methylation levels at specific sites across the genome can be combined to form estimates of age known as ‘epigenetic age’. The difference between epigenetic age and chronological age is referred to as ‘epigenetic age acceleration’, with positive values indicating that a person is biologically older than their years. Understanding why some people seem to age faster than others could shed light on the biological processes behind age-related decline; however, the mechanisms underlying differential rates of epigenetic ageing are largely unknown. Here, we investigate genetic determinants of two commonly used epigenetic age acceleration measures, based on the Horvath and Hannum epigenetic clocks. We report novel genetic variants and genes associated with epigenetic age acceleration, and highlight differences in the genetic factors influencing these two measures. We identify ten genetic variants and 21 genes associated with Horvath-based epigenetic age acceleration, and one variant and 12 genes associated with the Hannum-based measure. There were no genome-wide significant variants or genes in common between the Horvath-based and Hannum-based measures, supporting the hypothesis that they represent different aspects of ageing. Our results suggest a partial genetic basis underlying some previously reported phenotypic associations.

scholarly journals Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review

2020 ◽  
Vol 9 (8) ◽  
pp. 2480 ◽  
Author(s):  
Veronica Papa ◽  
Luisa Marracino ◽  
Francesca Fortini ◽  
Paola Rizzo ◽  
Gianluca Campo ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Blood Cells ◽  
Hematological Malignancies ◽  
Inflammatory Responses ◽  
Significant Proportion ◽  
Selective Advantage ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Disease Mechanisms ◽  
Increased Risk

Some random mutations can confer a selective advantage to a hematopoietic stem cell. As a result, mutated hematopoietic stem cells can give rise to a significant proportion of mutated clones of blood cells. This event is known as “clonal hematopoiesis.” Clonal hematopoiesis is closely associated with age, and carriers show an increased risk of developing blood cancers. Clonal hematopoiesis of indeterminate potential is defined by the presence of clones carrying a mutation associated with a blood neoplasm without obvious hematological malignancies. Unexpectedly, in recent years, it has emerged that clonal hematopoiesis of indeterminate potential carriers also have an increased risk of developing cardiovascular disease. Mechanisms linking clonal hematopoiesis of indeterminate potential to cardiovascular disease are only partially known. Findings in animal models indicate that clonal hematopoiesis of indeterminate potential-related mutations amplify inflammatory responses. Consistently, clinical studies have revealed that clonal hematopoiesis of indeterminate potential carriers display increased levels of inflammatory markers. In this review, we describe progress in our understanding of clonal hematopoiesis in the context of cancer, and we discuss the most recent findings linking clonal hematopoiesis of indeterminate potential and cardiovascular diseases.

scholarly journals Causal effects of senescence through intrinsic epigenetic age acceleration on age-related diseases: a Mendelian randomization study

2020 ◽  
Author(s):  
F. Gatto ◽  
P. Ueda
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Effects ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Epigenetic Age ◽  
Increased Risk ◽  
Epigenetic Age Acceleration ◽  
Artery Disease

AbstractOlder age is associated with many diseases. However, it is unclear whether the biological mechanisms underpinning senescense (biological ageing) is a cause of age-related diseases (ARDs). In this Mendelian randomization study, we examined the causal effects of intrinsic epigenetic age acceleration (IEAA) - a process assumed downstream of senescence - on the occurrence of ARDs. In a metanalysis of 18 genome-wide association studies (GWAS) spanning 12 ARDs in ~27 million people of European ancestry (median per GWAS: 17’008 cases vs. 40’940 controls), IEAA-associated SNPs did not significantly increase the risk of ARDs as a group (odds-ratio (OR) = 0.99) nor of any individual ARD (OR range: 0.87-1.04). However, one SNP, rs2736099 on TERT, was significantly associated with 8 of 10 ARDs with increased risk for lung and ovarian cancer, atrial fibrillation, and benign prostatic hyperplasia and lower risk for Alzheimer’s disease, rheumatoid arthritis, cardiovascular artery disease and breast cancer. No associations between rs2736099 and known ARD risk factors were found strengthening the causal role of rs2736099-associated senescence. While IEAA was not found as a unifying cause of ARDs, senescence seems to cause some ARDs while preventing others through a mechanism only partially affecting IEAA and associated with rs2736099.

scholarly journals Internalizing Symptoms Associate with the Pace of Epigenetic Aging in Childhood

2019 ◽  
Author(s):  
Marieke S. Tollenaar ◽  
Roseriet Beijers ◽  
Elika Garg ◽  
T.T. Thao Nguyen ◽  
David T.S. Lin ◽  
...  
Keyword(s):  
Internalizing Symptoms ◽  
Psychiatric Symptoms ◽  
Externalizing Symptoms ◽  
Biological Aging ◽  
Genome Wide ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Buccal Epithelial Cells ◽  
Epigenetic Age Acceleration ◽  
Internalizing And Externalizing

AbstractChildhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide DNA methylation. EAA was estimated using the Horvath clock. Internalizing symptoms at ages 2.5 and 4 years significantly predicted higher EAA at age 6, which in turn was significantly associated with internalizing symptoms from ages 6 to 10 years. Similar trends for externalizing symptoms did not reach significance. These findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.

scholarly journals Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sisi Chen ◽  
Qiang Wang ◽  
Hao Yu ◽  
Maegan L. Capitano ◽  
Sasidhar Vemula ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Epigenetic Mechanism ◽  
Mutant P53 ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Induced Stress ◽  
Epigenetic Regulator ◽  
Radiation Induced

AbstractClonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

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