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The causes and consequences of clonal haematopoiesis

The causes and consequences of clonal haematopoiesis
The causes and consequences of clonal haematopoiesis
Introduction: Over the past decade, the availability of large population studies has allowed a detailed exploration of the relationship between genetics and clinical phenotypes. Clonal haematopoiesis (CH) is the expansion of blood cells with genetic features that are often observed in patients with haematological malignancies, particularly myeloid neoplasms. CH is a common finding in elderly individuals and associated with an elevated risk of developing haematological malignancies, cardiovascular diseases, and all-cause mortality. My study has four main aims. First, to characterise the inherited and environmental risk factors associated with myeloid CH. Second, to characterise the impact of myeloid CH on the risk of developing chronic inflammation-related diseases. Third, to investigate the utility of CH measures to predict the risk of myeloid malignancies. Fourth, to identify risk factors associated with age-related loss of the Y-chromosome (LOY) in men and its relationship to CH. Methods: The UK Biobank represents a unique genetic and phenotypic dataset of about 500,000 individuals with 94.6% white ethnicity. CH was defined in this study by the presence of mosaic chromosomal alterations (mCA) and/or somatic driver mutations. I utilised B-allele frequencies, and genotypic intensities from single nucleotide polymorphism array data (n = 486,941) to identify mCA, and diagnostic data to classify mCA according to their association with myeloid, lymphoid or neither of these diseases. Furthermore, I utilised whole exome sequencing data (WES, 1st release, n = 49,956; 2nd release, n=150,685) and publicly available databases to identify putative somatic driver mutations. LOY calls in men were provided by the UK Biobank from published data. Results: The frequency of myeloid CH increased per year of participant age and was associated with: two distinct germline predisposition signals within TERT, current smoking, and several blood features and clinical phenotypes indicative of chronic inflammation. Somatic loss-of-function mutations in ASXL1 were found to be strongly associated with current and past smoking status. Focusing on chronic kidney disease (CKD), myeloid CH was negatively associated with glomerular filtration rate (GFR) estimated from cystatin-C which is a marker of CKD but not with GFR estimated from creatinine which has previously been reported to be less informative. Furthermore, myeloid CH increased the risk of adverse outcomes, defined by a composite of all-cause mortality, myocardial infarction or stroke, in CKD cases compared to those without myeloid CH. Machine learning (ML) survival models which analysed high dimensional data including CH calls, blood counts and biochemistry markers were more predictive of myeloid malignancies in comparison to traditional regression-based models. Finally, LOY was significantly associated with CH and also with clonality inferred from non-CH somatic mutations. LOY was suggested to be causally associated with high levels of sex hormone binding globulin, and this relationship was linked to expression Quantitative Trait Locus (eQTL) associated with genes at the DLK1-MEG3 locus. Conclusion: This study demonstrates the wide scientific reach of CH and its broad impact on health outcomes. My results indicate that the type of CH, the identity of specific driver genes, inherited risk variants, and environmental factors are collectively determinants of the fitness of CH and influence the potential for development of myeloid neoplasms or non-malignant diseases. My findings also provide evidence that blood and serum measures hold additional information that helps to determine the clinical significance of CH.
University of Southampton
Dawoud, Ahmed Abdelrazek Zaky
23beaa7f-ab38-4ac3-9624-f37ab9110c2c
Dawoud, Ahmed Abdelrazek Zaky
23beaa7f-ab38-4ac3-9624-f37ab9110c2c
Cross, Nicholas
f87650da-b908-4a34-b31b-d62c5f186fe4
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c

Dawoud, Ahmed Abdelrazek Zaky (2023) The causes and consequences of clonal haematopoiesis. University of Southampton, Doctoral Thesis, 265pp.

Record type: Thesis (Doctoral)

Abstract

Introduction: Over the past decade, the availability of large population studies has allowed a detailed exploration of the relationship between genetics and clinical phenotypes. Clonal haematopoiesis (CH) is the expansion of blood cells with genetic features that are often observed in patients with haematological malignancies, particularly myeloid neoplasms. CH is a common finding in elderly individuals and associated with an elevated risk of developing haematological malignancies, cardiovascular diseases, and all-cause mortality. My study has four main aims. First, to characterise the inherited and environmental risk factors associated with myeloid CH. Second, to characterise the impact of myeloid CH on the risk of developing chronic inflammation-related diseases. Third, to investigate the utility of CH measures to predict the risk of myeloid malignancies. Fourth, to identify risk factors associated with age-related loss of the Y-chromosome (LOY) in men and its relationship to CH. Methods: The UK Biobank represents a unique genetic and phenotypic dataset of about 500,000 individuals with 94.6% white ethnicity. CH was defined in this study by the presence of mosaic chromosomal alterations (mCA) and/or somatic driver mutations. I utilised B-allele frequencies, and genotypic intensities from single nucleotide polymorphism array data (n = 486,941) to identify mCA, and diagnostic data to classify mCA according to their association with myeloid, lymphoid or neither of these diseases. Furthermore, I utilised whole exome sequencing data (WES, 1st release, n = 49,956; 2nd release, n=150,685) and publicly available databases to identify putative somatic driver mutations. LOY calls in men were provided by the UK Biobank from published data. Results: The frequency of myeloid CH increased per year of participant age and was associated with: two distinct germline predisposition signals within TERT, current smoking, and several blood features and clinical phenotypes indicative of chronic inflammation. Somatic loss-of-function mutations in ASXL1 were found to be strongly associated with current and past smoking status. Focusing on chronic kidney disease (CKD), myeloid CH was negatively associated with glomerular filtration rate (GFR) estimated from cystatin-C which is a marker of CKD but not with GFR estimated from creatinine which has previously been reported to be less informative. Furthermore, myeloid CH increased the risk of adverse outcomes, defined by a composite of all-cause mortality, myocardial infarction or stroke, in CKD cases compared to those without myeloid CH. Machine learning (ML) survival models which analysed high dimensional data including CH calls, blood counts and biochemistry markers were more predictive of myeloid malignancies in comparison to traditional regression-based models. Finally, LOY was significantly associated with CH and also with clonality inferred from non-CH somatic mutations. LOY was suggested to be causally associated with high levels of sex hormone binding globulin, and this relationship was linked to expression Quantitative Trait Locus (eQTL) associated with genes at the DLK1-MEG3 locus. Conclusion: This study demonstrates the wide scientific reach of CH and its broad impact on health outcomes. My results indicate that the type of CH, the identity of specific driver genes, inherited risk variants, and environmental factors are collectively determinants of the fitness of CH and influence the potential for development of myeloid neoplasms or non-malignant diseases. My findings also provide evidence that blood and serum measures hold additional information that helps to determine the clinical significance of CH.

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Published date: 2023

Identifiers

Local EPrints ID: 473368
URI: http://eprints.soton.ac.uk/id/eprint/473368
PURE UUID: 72257587-4076-4e41-9b9e-f455a396d3ad
ORCID for Ahmed Abdelrazek Zaky Dawoud: ORCID iD orcid.org/0000-0003-0164-7773
ORCID for Nicholas Cross: ORCID iD orcid.org/0000-0001-5481-2555
ORCID for William Tapper: ORCID iD orcid.org/0000-0002-5896-1889

Catalogue record

Date deposited: 17 Jan 2023 17:34
Last modified: 17 Mar 2024 02:54

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Contributors

Author: Ahmed Abdelrazek Zaky Dawoud ORCID iD
Thesis advisor: Nicholas Cross ORCID iD
Thesis advisor: William Tapper ORCID iD

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