Interplay between vitamin D and metabolic factors in colorectal cancer development: a molecular epidemiology approach

Abstract

Observational studies have reported that higher levels of serum vitamin D are associated with lower risk of colorectal cancer (CRC) and metabolic syndrome (MetS). Given the fact that MetS and its components are also associated with CRC, the potential causal pathways between vitamin D, MetS and its components, and CRC are not well understood. At the same time, observational studies have inherit limitations and can only assess association rather than causation. Alternatively, the Mendelian randomisation (MR) approach uses genetic variants as proxies for an environmental exposure and can be used to provide more robust evidence for potential causality. In this thesis I used a variety of methods to study the interlinked effects of vitamin D, MetS, and CRC. Mediation analysis was used to assess whether the association between vitamin D and CRC was mediated by MetS in the EPIC cohort. I further assessed the potential causal association between vitamin D and CRC using both individual and summary-level data in EPIC, UK Biobank, the GECCO consortium and data from the SUNLIGHT consortium. Moreover, I assessed the direction of potential causal relationship between vitamin D and MetS components using summary-level data from genetic consortia. Among the 2,300 participants in EPIC, MetS mediated ~18% of the association between vitamin D and CRC. No significant causal association between vitamin D and CRC was found for either the individual-level data in EPIC (OR: 1.03, 95%CI: 0.99 – 1.06), or for the larger studies using summary-level data in the UK Biobank (OR: 0.86, 95%CI: 0.68 – 1.08) or GECCO (OR: 0.92, 95%CI: 0.76 – 1.10). I also assessed the potential causal association between vitamin D and MetS components and found that a 1 standard deviation decrease in the natural log transformed 25-hydroxyvitamin D (25(OH)D) was associated with a 4% increase in HbA1c levels. The results also showed that high BMI and low levels of HDL cholesterol reduced the levels of 25(OH)D, and that high levels of HbA1c and SBP increased 25(OH)D levels. To conclude, no evidence for a causal association was found between vitamin D and CRC. Further research needs to be conducted to understand the inconsistency of results between observational and MR analyses of vitamin D and CRC. Moreover, evidence of causality was found between vitamin D and MetS components; however, present methods cannot reliably infer the directionality of these associations.