Multi-omics approach to explore the effects of chronic low-grade inflammation marked by c-reactive protein
File(s)
Author(s)
Said, Saredo
Type
Thesis
Abstract
Chronic low-grade inflammation is linked to a multitude of chronic diseases and conditions. However, chronic low-grade inflammation has not been fully characterised, as there remains conflicting and inconclusive evidence from epidemiological studies. My thesis aimed to explore chronic inflammation using a multi-omic approach. Data from the UK Biobank and Airwave cohort was used. Within this thesis I report genome-wide association on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N= 575,531). I identify 266 independent loci, of which 211 were not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 x 10-6) and tissue expression analysis indicated a strong association of CRP related genes to the liver and whole blood gene expression.
Phenome-wide association identified 27 clinical outcomes associated with genetically determined CRP, including five phenotypes of the respiratory system, nine of the circulatory system, three musculoskeletal, three sense organs, one mental disorder, five endocrine/metabolic, and lastly one genitourinary. Mendelian randomisation analyses of chronic diseases supported a causal association with several outcomes, such as schizophrenia (beta (β) = -0.074, 95%, p = 7.83 x 10-6), chronic airway obstruction (β=0.330, p=7.94 x 10-4) and breast cancer (β = 0.044, p = 2.02 x 10-5). Metabolome-wide causal association MR analyses tested CRP associated genetic variants with 123 NMR platform measured metabolites and identified five with convincing evidence, including citrate (β=-0.13, p=1.6 x 10-5) and phenylalanine (β=0.13, p=1.3 x 10-5).
In combination these results provides insight into the genomic, phenotypic, metabolomic profile, and functional properties of CRP proxied systemic chronic low-grade inflammation. Results provide novel findings, which can be investigated further to understand the underlying molecular pathways of disease afflicted by systemic chronic low-grade inflammation. As CRP proxied chronic inflammation is modifiable, this may be of interest for therapeutic intervention.
Phenome-wide association identified 27 clinical outcomes associated with genetically determined CRP, including five phenotypes of the respiratory system, nine of the circulatory system, three musculoskeletal, three sense organs, one mental disorder, five endocrine/metabolic, and lastly one genitourinary. Mendelian randomisation analyses of chronic diseases supported a causal association with several outcomes, such as schizophrenia (beta (β) = -0.074, 95%, p = 7.83 x 10-6), chronic airway obstruction (β=0.330, p=7.94 x 10-4) and breast cancer (β = 0.044, p = 2.02 x 10-5). Metabolome-wide causal association MR analyses tested CRP associated genetic variants with 123 NMR platform measured metabolites and identified five with convincing evidence, including citrate (β=-0.13, p=1.6 x 10-5) and phenylalanine (β=0.13, p=1.3 x 10-5).
In combination these results provides insight into the genomic, phenotypic, metabolomic profile, and functional properties of CRP proxied systemic chronic low-grade inflammation. Results provide novel findings, which can be investigated further to understand the underlying molecular pathways of disease afflicted by systemic chronic low-grade inflammation. As CRP proxied chronic inflammation is modifiable, this may be of interest for therapeutic intervention.
Version
Open Access
Date Issued
2021-06
Date Awarded
2021-09
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Tzoulaki, Ioanna
Dehghan, Abbas
Pazoki, Raha
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Department of Epidemiology and Biostatistics
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)