Synergies of genetic factors and infectious agents in the aetiology of disease
Atherosclerosis is a multifactorial disease, and while many traditional risk factors have been identified, a significant number of patients do not fit the known profiles. Genetic variability may provide a partial explanation for these discrepancies. One of the major advances of the past decade is the identification of inflammation as a key player in atherogenesis, and the demonstration that polymorphisms in several genes that modulate the inflammatory response can importantly influence the atherosclerosis process.
Recent attention has focused on the potential role of infectious agents in the development of atherosclerosis. Animal data have demonstrated that specific bacterial and viral infections can increase atherosclerotic lesion size. The data in humans are more ambiguous. Results from many seroepidemiologic studies indicate that different pathogens are associated with an increased risk of coronary artery disease (CAD), while other studies do not find these associations. Recently, enthusiasm for the hypothesis that infectious agents contribute to CAD has diminished, as several trials have failed to demonstrate protection from coronary events following antibiotic treatment. Significant design limitations, such as targeting only bacterial agents even though many viruses have also been associated with an increased risk of CAD, may have contributed to these negative findings.
Indeed, we had further postulated that if infection is causally linked to atherosclerosis, it is unlikely that this effect would be limited to a single pathogen. We reasoned that the more infections one contracts, the greater the level of inflammation, and the greater the propensity for atherosclerosis to be initiated or to progress. Thus, we proposed the concept of “pathogen burden,” and demonstrated that increasing pathogen burden was associated with increasing CAD risk.
We hypothesize that the role of infection in atherogenesis is also governed by the genetic makeup of the individual, and that the propensity for infection contributing to atherosclerosis in an individual is in part related to a genetically-determined predisposition to develop chronic inflammatory or immune responses to certain infectious agents.