Editorial
Finding Clues to Protect Against Coronary Atherosclerosis via Traditional Risk Factors
2023 Volume 30 Issue 5 Pages 434-436
Details
2023 Volume 30 Issue 5 Pages 434-436
See article vol. 30: 467-480
Coronary artery disease is one of the most important causes of death across the world1). Several researchers have tried to identify factors associated with this situation to combat this disease. Through this process, affected individuals who had suffered from coronary artery disease had been the target of interest, compared with the “controls” without coronary artery disease in almost all studies. Based on these studies investigating factors associated with coronary artery disease, researchers had identified that hypertension, diabetes, smoking, and low-density lipoprotein (LDL) cholesterol were significantly associated with this phenotype2). Now, we call these factors “risk factors,” and use them as risk scores to estimate their absolute lifetime risk of coronary artery disease in guidelines3). However, we recognize a portion of individuals without coronary artery disease despite multiple elements of “risk factors,” including hypertension, diabetes, smoking, and elevated LDL cholesterol. For a long period of time, these “supernormal” individuals had been ignored or just been considered as “controls” in most of the association studies. However, their antiatherosclerotic property against known risk factors can be considered an extreme phenotype, in contrast to the opposite phenotype of premature coronary artery disease. In fact, researchers had focused on the other side of the phenotype of premature coronary artery disease, and identified many important factors, genes, and pathways, such as the LDL receptor pathway leading to cause familial hypercholesterolemia (FH)4, 5). However, no prior study focused on individuals without coronary artery disease despite multiple elements of “risk factors,” although there are studies investigating the centenarians trying to find clues associated with longevity6). But, it is difficult to identify factors associated with longevity because too many different factors, including cancers, atherosclerosis, infections, and dementia, affect it. Thus, the authors performed an association study investigating genetic loci associated with protective properties for coronary artery disease using case (supernormal) and control (patients with coronary artery disease). Additionally, they assessed these genes based on eQTL7). They found several loci together with potential biological relevance.
It is almost always important to consider the extreme phenotypes when we perform association studies. In the case of coronary atherosclerosis, the worst phenotype is premature myocardial infarction. A typical example includes patients with homozygous FH whose function of LDL receptors is completely disrupted. They suffer from myocardial infarction as early as their childhood because of their extremely elevated LDL cholesterol level8). This indicates an important fact regarding LDL cholesterol, which is a causal factor for coronary atherosclerosis. Additionally, Do et al. performed an association study to find out genes associated with this extreme phenotype, and found that the LDL receptor was the top hit, as expected9). However, several studies have shown that “human-knockout” individuals with extremely low LDL cholesterol are quite cardioprotective, thereby supporting this notion10). There are other examples where phenotypic refinements led to the novel identifications in association studies. In this study, the authors defined “supernormal” as the extreme situation where coronary atherosclerosis is absent despite the accumulation of traditional risk factors, including hypertension, diabetes, LDL cholesterol, and smoking. The suggested pathways are likely to shield against the atherosclerotic process via known risk factors (Fig.1).
This scheme illustrates that the atherosclerotic process can be eased using unique shields identified in this study.
We now have a variety of therapeutic strategies for known risk factors, although there remains a so-called substantial residual risk for coronary atherosclerosis. We need to rethink the strategies to identify pathways leading to diseases. Alternatively, it would be a great idea to identify pathways that protect against the atherosclerotic process through analysis of individuals with “supernormal” phenotypes in any disease phenotype.
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