The role of one-carbon metabolism in health and disease: A genetic epidemiology perspective

Abstract

The overarching aim of this thesis is to provide mechanistic and aetiological insight into the existing evidence that links one-carbon metabolism (OCM) variability with healthy ageing and disease. There is increased urgency in the field of research to understand the distribution and determinants of human common diseases, as healthcare costs and the burden of complex diseases are on the rise. This thesis supports the view that understanding the inter-individual variability in levels of key OCM vitamins is a fundamental building block in redressing malnutrition/ nutrient deficiency in population groups, and in preventing disease.At the crossroads of genetics and epidemiology is genetic epidemiology, which examines the role of genetic factors in disease aetiology. Throughout the decades, the advancement of human health has been highlighted by the ability to move from a molecular perspective of understanding pathways of disease aetiology to extrapolating the implications of the latter to broader public health ventures. The thesis itself is a smaller-scale visual of how this works, as it builds up from a molecular-scale stance to a more public health viewpoint that may potentially lead to improved understanding of the genetic architecture of disease, improved diagnosis of specific markers, and targeted disease treatments.More specifically, the significance of this work is that it informs on (1) the genetic determinants of variability in key OCM metabolites and cofactors, which in turn informs on (2) the development of novel diagnostic and prognostic tools that predict vitamin B12 deficiency in healthy adults and in pregnancy; (3) a mechanism of gene-nutrient interaction leading to site-specific changes in DNA methylation patterns in humans – a molecular outcome of OCM-, that have also been associated with disease risk; (4) the effects of OCM- associated genetic variants on risk of ischaemic stroke, and finally; (5) how can we deploy/ translate findings from genetic research in the field of nutrition to aid in the development of public health recommendations