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

Aug 09, 2022 11:55 CST Updated Aug 15, 16:28

AstraZeneca

Biopharmaceutical Manufacturer

University of Bristol

The University of Bristol is one of the most popular and successful universities in the UK, ranked 23rd in the world in the 2024 QS World University Rankings. The University of Bristol is renowned worldwide for “combining academic excellence and innovation with a spirit of independence and forward-thinking.” Former British Prime Minister Winston Churchill served as Chancellor of the University of Bristol for 36 years. The current Chancellor is Sir Paul Nurse, former President of the Royal Society and Nobel laureate. As of 2018, the University of Bristol had produced 13 Nobel laureates and has always been at the forefront of global research.

University of Cambridge

The University of Cambridge is a research university located in the city of Cambridge, Cambridgeshire, United Kingdom. It is the second-oldest university in the English-speaking world and the fourth-oldest surviving university globally.The University of Cambridge operates as a collegiate federal institution composed of constituent Colleges, Schools, Faculties, and Departments. It comprises 31 constituent Colleges, more than 150 Departments, and other affiliated institutions. The constituent Colleges enjoy a high degree of autonomy and function as semi-independent entities, each with its own governance framework, responsible for student admissions and the arrangement of student activities. Over time, the current constituent Colleges have reduced their involvement in teaching and research, which are now primarily the responsibility of the Departments. The Schools and Faculties serve as the overarching administrative bodies.

Wellcome Sanger Institute

The Wellcome Sanger Institute, formerly known as The Sanger Center and the Wellcome Trust Sanger Institute, is a non-profit UK-based genomics and genetics research institution primarily funded by the Wellcome Trust. As one of the world’s most prominent centers for genomic discovery and research, it leads ambitious global collaborations that lay the foundation for further scientific inquiry and transformative healthcare innovations. Its success is built upon the expertise and accumulated knowledge of its team, with the institute dedicated to advancing the research and development of next-generation genomics while sharing its discoveries and technologies.

Clonal Hematopoiesis (CH) is a common aging-related biological state that predisposes individuals to malignant hematological disorders or cardiovascular diseases. In the blood, certain mutations can confer self-renewal capacity to hematopoietic stem cells (HSCs), and their excessive proliferation leads to clonal hematopoiesis. CH has no obvious clinical symptoms, but with age, this condition becomes ubiquitous and serves as a risk factor for developing blood cancer and other age-related diseases. In fact, although CH is defined by its association with somatic mutations, its development is influenced by both non-mutational factors and heritable genomes.

Recently, a joint research team composed of the University of Bristol, the University of Cambridge, the Sanger Institute, the Asturias Health Research Institute in Spain, and AstraZeneca conducted a whole-genome analysis of 200,453 individuals, providing new insights into cognitive CH. The studyReveals multiple new germline loci associated with CH, including loci that interact with specific CH subtypes, while also uncovering causal relationships between CH and various pathological states across organ systems, providing evidence for the causal links between smoking, telomere length, and CH risk.The research findings have been published online inNature GeneticsThe article, titled "Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis," was published in the journal.

The article has been published inNature GeneticsUp

Main Research Content and Results

CH in the Representation of UKB

To identify individuals with CH, researchers analyzed blood whole-exome sequencing (WES) data from 200,453 participants of diverse ancestry from the UK Biobank (UKB), aged between 38 and 72 years. Additionally, the researchers called somatic mutations in 43 CH genes based on the data, filtering them according to a defined list of CH driver variants, identifying 11,697 mutations in 10,924 individuals, showing a pattern consistent with previous reports (Fig. 1a). Moreover, the data showed,The increase in CH prevalence varies among different driver genes (Figure 1b), with both females and males being similarly affected overall.But there are significant gene-level differences between the sexes (Fig. 1c), reflecting gender-specific differences in the frequency and prevalence of related gene levels in myeloid malignancies. Meanwhile, the research team also demonstrated that the aforementioned genetic changes are not only associated with blood cancers but also related to other tumors such as lung cancer, prostate cancer, and ovarian cancer.

Figure 1. Representation of CH in UKB. Source:Nature Genetics

The Association between CH and Multiple Traits/Diseases

To determine the association between CH and certain traits or diseases, the researchers conducted a logistic regression analysis with CH as the outcome in a cohort of 200,453 participants. The study revealed that CH is associated with factors such as age, chronic inflammatory stimulation, and smoking.The incidence of CH increases with age, with an annual increase of approximately 6.7% in risk, and the widespread presence of hypertension is associated with the CH state.Smokers and individuals with a history of smoking have a higher probability of developing CH, and this association applies to different phenotypes of CH, especiallyASXL1Mutations in CH. By analyzing complete blood counts and biochemical parameters, the researchers identified both known and previously unreported factors associated with CH. They found that CH status is associated with low-density lipoprotein cholesterol levels, whereJAK2CH with splicing regulator mutations was the most significant. (Fig. 2a)

Figure 2. Associations between CH and various traits/diseases. Source:Nature Genetics

Researchers also conducted a phenome-wide association study (PheWAS) on acute diseases and foundPatients with CH have a higher incidence of myeloid malignancies, and the risk of other hematologic and non-hematologic tumors, including lymphoma, lung cancer, and kidney cancer, is also significantly increased.. Unlike previous studies that linked CH with ischemic cardiovascular disease (CVD), this study did not find a significant association between CH and ischemic CVD, but rather an association between CH and heart failure and atrial fibrillation. The research team believes,CH accelerates the biological aging process and influences the risk of developing atrial fibrillation.(Figure 2b)

Germinal gene loci associated with CH risk

Researchers have mapped based on the genetic data of 200,453 participantsGenetic Susceptibility Atlas, the European ancestry populationThe number of CH-related germline mutations increased from 4 to 14., revealing the heterogeneity in the correlation between CH driver genes and clonal size, and uncovering potential new CH susceptibility genes through functional annotation, includingCD164、ATMAndSETBP1. Research has proven,GWAS signals of CH are enriched in the unique epigenetic markers of the hematopoietic system, particularly in the open chromatin regions of hematopoietic stem/progenitor cells.New Gene Loci and DNA Damage Repair (PARP1、ATM、CHEK2), Hematopoietic Stem Cell Migration/Homing (CD164) and bone marrow tumor occurrence (SETBP1) related to. Some of these associations are CH subtype-specific, includingTCL1AAndCD164Variant ofDNMT3A-AndTET2-Mutations in CH (the two most common CH subtypes) are negatively correlated.

Figure 3. Manhattan plot showing genome-wide associations between common germline variants and five CH traits. Source:Nature Genetics

Causal Risk Factors for CH

Researchers used Mendelian randomization to analyze the potential causal relationship between CH and presumed risk factors and outcomes, and the results showed that,Smoking and longer leukocyte telomere length are causal risk factors for CH, and the genetic susceptibility of CH increases the risk of myeloproliferative neoplasms, non-hematological malignancies, atrial fibrillation, and hematological epigenetic aging.Analysis shows that the use of two-sample Mendelian randomization prevented potential reverse causality caused by clonal hematopoiesis selection pressure induced by cancer treatment. The above results suggest that the genetic susceptibility of CH may be a biomarker for the development of other cancers.

Conclusion

Research Team Analyzes Genetic Data from 200,453 UK Biobank Participants in One of the Largest Studies of Its KindThe research team analyzed genetic data from 200,453 UK Biobank participants, making it one of the largest projects of its kind. The study uncovered genes and mechanisms involved in abnormal clonal expansion of blood cells, which could help guide advancements in treating related cancers to avoid or delay health consequences caused by clonal hematopoiesis. The findings thoroughly elucidate the genetic predisposition to CH and provide insights into the impact of CH on human health and aging, supporting the prevention and early detection of cancers, including leukemia.

References:

1.Caroline J. Watson et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis[J]. Science, 2020, 367(6485): 1449-1454.

2.Jaiswal Siddhartha and Ebert Benjamin L. Clonal hematopoiesis in human aging and disease[J]. Science (New York, N.Y.), 2019, 366(6465): eaan4673-eaan4673.

3.Genovese Giulio et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence[J]. The New England journal of medicine, 2014, 371(26): 2477-87.