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oai:figshare.com:article/32805272 2026-10-01T16:16:55Z portal_1172 item_type_8 month_year_10_2026

Investigating causality in the associations between cardiometabolic biomarkers and cancer risks Joshua Kenneth O'Neill (24292598) PUREID: 670449626 Genome-wide association study GWAS Mendelian randomisation MR polygenic risk score PRS cardiometabolic biomarkers bile acids fibrinogen P-selectin cancer lung cancer colorectal cancer colon cancer rectal cancer Cardiometabolic alterations, including dysregulated metabolic, inflammatory, and haemostatic processes are established contributors to cardiovascular and metabolic diseases. They are now being increasingly recognised for their potential role in cancer aetiology as well. Circulating biomarkers that capture these processes offer a valuable opportunity to investigate shared disease pathways and inform early detection and prevention strategies. However, disentangling correlation from causation remains a major challenge in observational research. This thesis leveraged genetic epidemiological methods, including genome-wide association studies (GWAS), Mendelian randomisation (MR), and polygenic risk scores (PRS), to evaluate the causal relevance of specific cardiometabolic biomarkers, namely bile acids, fibrinogen, and P-selectin, in relation to cancer risk.<br><br>GWAS were performed on 18 quantitative bile acid metabolite measures using data from two independent prospective cohorts of European decent: the European Prospective Investigation into Cancer and Nutrition (EPIC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Meta-analyses identified several genome-wide significant associations, including novel variants and loci not previously linked to circulating bile acid levels. Among the main findings, two significant variants mapped to protein-coding genes, PFKP and NAA35, with links to glycolytic and protein regulation. These findings then informed the selection of genetic instruments for downstream MR analyses.<br><br>Two-sample MR analyses provided evidence supporting a positive association between genetically predicted deoxycholic acid (DCA) levels and colorectal cancer (CRC) risk, particularly among males and for rectal cancer. This is consistent with experimental and epidemiological evidence implicating secondary bile acids in colorectal carcinogenesis. In contrast, MR analyses of genetically predicted plasma fibrinogen and soluble P-selectin did not support causal associations with lung cancer risk, despite strong observational evidence. Bi-directional MR suggested that elevated fibrinogen levels may reflect smoking exposure rather than a direct aetiological role.<br><br>Overall, this thesis demonstrates the value of genetic epidemiology in strengthening causal inference for circulating biomarkers in cancer. The findings highlight DCA as a potential modifiable risk factor for CRC and suggest a greater role for haemostatic biomarkers in risk prediction than causal intervention.<br><br><i>Thesis is embargoed until 31 July 2029.</i><br> 2026-10-01T16:16:55Z Text Thesis 10.17034/32805272.v1 https://figshare.com/articles/thesis/Investigating_causality_in_the_associations_between_cardiometabolic_biomarkers_and_cancer_risks/32805272 All Rights Reserved Open Access after 2029-07-31