A commentary on “Genetic insights into lipid traits and atherosclerosis risk: a Mendelian randomization and polygenic risk score analysis”

Dear Editor, Atherosclerosis is characterized by lipid accumulation, endothelium malfunction, macrophage and lymphocyte infiltration, connective tissue hyperplasia, vascular smooth muscle cell proliferation, and the development of atherosclerotic plaques in arteries of all sizes[1,2]. It is the primary cause of several severe arterial occlusive diseases, including carotid artery stenosis, ischemic stroke, coronary artery disease, peripheral arterial disease, and retinal artery occlusion. It causes the arterial wall to thicken and lose its flexibility. Zhang et al[3] investigated the causative relationships between atherosclerosis risk and four lipid characteristics (LDL, HDL, total cholesterol, and triglycerides) utilizing Mendelian randomization and polygenic risk score analysis. The study’s findings exhibited that while higher TG, TC, and LDL levels were connected to an increased risk of atherosclerosis, higher levels of HDL were linked to a lower risk. In the discovery cohort, HDL levels were inversely linked to atherosclerotic cardiovascular disease, indicating a possible preventive function for HDL; nevertheless, in the replication cohort, this correlation did not achieve statistical significance. Notably, shared SNPs were eliminated and collinearity among lipid characteristics was controlled for using multivariable Mendelian randomization. As a consequence, independent estimations of causative impacts of TC were produced. These estimates were different from those found in studies using univariable Mendelian randomization. This disparity may indicate that the multivariable Mendelian randomization study eliminated the positive causative effects of TG and LDL on atherosclerotic cardiovascular disease, emphasizing the protective role of HDL as the negative correlation of TC primary driver. The precise pathogenic process driving atherosclerosis remains unclear. However, abundant evidence suggests that genetic traits are a major factor in the pathophysiology of atherosclerosis. First, prior research on family-based associations has shown that the heritability of atherosclerosis ranges from 40% to 60%. Furthermore, a favorable family history has been demonstrated to be a powerful independent risk factor for diseases linked to atherosclerosis. Second, recent genome-wide association studies have linked nearly 60 genetic loci to atherosclerosis susceptibility, and screening for common causal variants in asymptomatic family members has been shown to be an economical method of predicting atherosclerosis risk. Thirdly, analogous phenotypes of human atherosclerosis have been successfully induced in rabbits and mice using genetically modified technology, and preclinical research on atherosclerotic diseases already makes extensive use of these animal models. Together, these results suggest that genetic predisposition to atherosclerosis plays a critical role in the development and incidence of the disease. To obtain a more thorough knowledge of the relationship between atherosclerosis and lipid characteristics, future research should examine the various functions of lipid metabolic pathways and take into account additional possible regulatory elements. Furthermore, in order to more thoroughly understand the molecular mechanisms of the disease, these results need be confirmed in larger-scale, multi-center trials due to the absence of spatial transcriptomics data and independent cohort validation. This study was conducted in compliance with the Transparency in the Reporting of Artificial Intelligence – the TITAN guideline[4]. Ethical approval Not applicable. Consent Not applicable.