Genetic, Epigenetic, and Metabolic Determinants of Disease Pathophysiology

Abstract

The classical concept of genetic determinism in pathophysiology is changing to an integrative, systems-based concept. This model acknowledges that disease does not occur due to solitary genetic malformations but as a result of the interplay between genetic susceptibility, epigenetic control, and metabolic mediators and is complex and multidirectional. Genetic variants create a threshold of risk, but their implementation is dynamically considered by epigenome, or a malleable layer of chemical modifications, sensitive to environmental influences such as diet, stress, and toxins. This epigenetic control, in its turn, regulates metabolic pathways, whose metabolites (e.g., acetyl-CoA, SAM) are also fed back to power and control the epigenetic machinery. This leads to self-reinforcing loops that may entrapping cells in pathological states and this is where such phenomena as metabolic memory in diabetes and long-term effects of early-life programming can be explained. This triad has a clinical redefinition of diagnostics and therapeutics. It broadens the biomarker repertoire to encompass epigenetic and metabolic biomarkers and develops interventions-not to a single malfunction but to the reconstruction of the whole system-based on epigenetic drugs and metabolic modulators as well as lifestyle medicine. The model also gives a singular account of comorbidities (e.g., obesity, diabetes and depression) and how conditions such as cancer steal these interactions. Finally, it places pathophysiology as the new product of a disrupted conversation between genome, epigenome, and metabolome, providing new opportunities to prevent and cure it.