The genesis of the Framingham heart study in 1948 and the onset of the great era of cardiovascular core risk factor identification (e.g., high lipid levels) are credited with a precipitous decline in ischemic heart disease (IHD) mortality. Rather than lauding this triumph, some epidemiologists have mounted a substantial critique of “risk-factor” epidemiology in IHD, notwithstanding its documented public health value. This critique arises from quite different directions as described in the January 2022 issue of the journal Epidemiology.
Proponents of the social determinants of health argue that it is necessary to move far “above the skin” by examining larger social forces that give rise to the biologic markers conventional epidemiology has treated as causal factors in IHD. Conversely, supporters of the human genome project advocate probing yet further “beneath the skin” to demonstrate that the massive investment in genome-wide association studies and the coalescence of these findings into polygenic scores will open up new avenues for prevention. The two positions to some extent reflect the contrast between the reductionism attractive to molecular biologists and the holism to which social scientists are drawn.
The debate is enriched in the Epidemiology issue by inclusion of a study that brings together genetic and sociodemographic antecedents, providing a welcome attempt at integrating risk factors operating across different levels of organization. Sophisticated mathematical and statistical tools used in the study are indifferent to preconceived causal structures and they have the additional benefit of helping to constrain the prejudices of investigators. The commonality linking the two schools of thought represented is not often recognized. Both argue that it is a mistake to see conventional cardiovascular risk factors as causes. Both agree that they are mere biologic intermediaries determined by factors operating long before they are evident, whether those factors can be social forces or genetic differences.
Both schools also argue that it is necessary to go beyond conventional thinking about cardiovascular risk factors to understand fully the causes of IHD. As has often been noted, causality is not a straight line, but a messy matrix of interacting and intersecting factors operating at different times and at different levels. This consideration especially is true for IHD, which has no singular cause. Although this nexus frequently has been described as a web of causation, that metaphor does not do full justice to the complexity of influences operating on several levels.
Another paper appearing in the January 2022 issue of the journal Nature Genetics complements what is known about cardiovascular disease. Efforts to elucidate causal mechanisms, including large-scale sequencing studies, have resulted in thousands of genes being associated with cardiovascular and cardiometabolic diseases with varying degrees of evidence. The traditional reductionist paradigm, i.e., one disease–one target–one drug, or, if need be, a combination thereof, is insufficient to provide mechanistic explanations and enable actionable subtyping or endotyping of diseases for precision medicine.