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Genomics of lipid metabolism: Identification of genetic determinants of lipid metabolites and the effect of perturbations of lipid levels on coronary heart disease risk factors

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cam.restrictionthesis_access_open
cam.supervisorWood, Angela M
cam.supervisorButterworth, Adam S
cam.supervisorDanesh, John
cam.supervisor.orcidWood, Angela [0000-0002-7937-304X]
cam.supervisor.orcidButterworth, Adam [0000-0002-6915-9015]
cam.supervisor.orcidDanesh, John [0000-0003-1158-6791]
cam.thesis.fundingfalse
dc.contributor.authorHarshfield, EL
dc.contributor.orcidHarshfield, Eric [0000-0001-8767-0928]
dc.date.accessioned2018-07-05T08:44:05Z
dc.date.available2018-07-05T08:44:05Z
dc.date.issued2018-07-20
dc.date.submitted2017-09-22
dc.date.updated2018-07-04T14:43:47Z
dc.description.abstractBackground: Coronary heart disease (CHD) is one of the leading causes of death worldwide, and global mortality rates are expected to continue to rise over the coming decades. In Pakistan in particular, chronic diseases are responsible for 50% of the total disease burden. Circulating lipids are strongly and linearly associated with risk of CHD; however, despite considerable efforts to demonstrate causality, available evidence is conflicting and insufficient. Study of the underlying metabolic pathways implicated in the association between lipids and CHD would help to disentangle and elucidate these complex relationships. Objectives: The primary objectives of this dissertation were to (1) identify the genetic determinants of lipid metabolites and (2) advance understanding of the effect of perturbations in lipid metabolite levels on CHD and its risk factors. Methods: Direct infusion high-resolution mass spectrometry was performed on 5662 participants from the Pakistan Risk of Myocardial Infarction Study to obtain signals for 444 known lipid metabolites. Correlations and associations of the lipids with smoking, physical activity, circulating biomarkers, and other CHD risk factors were assessed. Genome-wide analyses were conducted to analyse the association of each lipid with over 6.7 million imputed single nucleotide polymorphisms. Functional annotation and Gaussian Graphical Modelling were used to link the variants associated with each lipid to the most likely mediating gene, discern the underlying metabolic pathways, and provide a visual representation of the genetic determinants of human metabolism. Mendelian randomisation was also implemented to examine the causal effect of lipids on risk of CHD. Results: The lipids were highly correlated with each other and with levels of major circulating lipids, and they exhibited significant associations with several CHD risk factors. There were 254 lipids that had significant associations with one or more genetic variants and 355 associations between lipids and variants, with a total of 89 sentinel variants from 23 independent loci. The analyses described in this dissertation resulted in the discovery of four novel loci, identified novel relationships between genetic variants and lipids, and revealed new biological insights into lipid metabolism. Conclusion: Analyses of lipid metabolites in large epidemiological studies can contribute to enhanced understanding of mechanisms for CHD development and identification of novel causal pathways and new therapeutic targets.
dc.identifier.doi10.17863/CAM.25158
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/277818
dc.language.isoen
dc.publisher.collegeSt John's College
dc.publisher.departmentDepartment of Public Health and Primary Care
dc.publisher.institutionUniversity of Cambridge
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectgenetics
dc.subjectepidemiology
dc.subjectlipidomics
dc.subjectmetabolomics
dc.subjectcoronary heart disease
dc.subjectcardiovascular disease
dc.subjectmass spectrometry
dc.subjectlipids
dc.subjectMendelian randomisation
dc.subjectgenome-wide association study
dc.titleGenomics of lipid metabolism: Identification of genetic determinants of lipid metabolites and the effect of perturbations of lipid levels on coronary heart disease risk factors
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.type.qualificationtitlePhD in Epidemiology
pubs.funder-project-idBritish Heart Foundation (None)
rioxxterms.versionofrecord10.17863/CAM.25158

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