Lipoproteins constitute a set of proteins and lipids, organized to facilitate the transport of lipids through blood plasma. Elevated or decreased levels of these lipoproteins may be related to genetic alterations in 40% to 60% of cases.1 This fact explains why it is common to find lipid abnormalities in several members of the same family. The elevated levels of these composite organic biomolecules are responsible for approximately 50% of the attributable risk for the development of atherosclerotic cardiovascular diseases,2,3 a process in which other phenotypes with a hereditary component also participate, such as diabetes, obesity and metabolic syndrome. Population studies of genetic association identified more than one hundred genes that could have a direct impact on lipid levels.3 These genes affect plasma levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c), as well as of triglycerides, being capable of establishing complex phenotypes. However, among these genes identified in the association studies, there is a previously known and well-characterized group of genes responsible for the development of monogenic dyslipidemias. In such cases, the variant in a single gene clearly explains the phenotype. It is noteworthy that even when isolated, these mutations determine diseases considered rare and the impact produced by variants of these genes tend to be high, resulting in extreme values of lipid levels. Considering that cardiovascular atherosclerotic disease is a process that starts in childhood and progresses throughout life,4 the early identification of risk factors is very important. In this sense, the diagnosis of phenotypes determined by monogenic diseases of lipid metabolism deserves special attention, considering that, when they produce extreme phenotypes, they can be associated with the development of early atherosclerosis of rapid progression. In fact, genetic studies using Next-Generation Sequencing (NGS), carried out in patients with early acute myocardial infarction (AMI) (that occurring before 50 years of age in men and 60 in women) have determined that the presence of rare genetic variants in the LDLR gene resulted in a 4-fold higher risk of this event in their carriers. On the other hand, the rare variants in the APOA5 gene, associated with high triglyceride levels, resulted in a 3-fold higher risk. Moreover, approximately 2% of the cases were carriers of a clearly pathogenic mutation in LDLR, suggesting that these patients had a diagnosis of familial hypercholesterolemia.2 In a broader sense, it is estimated that approximately 5% of AMIs in patients aged < 60 years may be due to familial hypercholesterolemia, a figure that can increase up to 20% when acute coronary events affect individuals younger than 45 years.5 It is noteworthy that even in the case of monogenic diseases, mutations identified in many of the genes frequently responsible for these diseases show significant variability in phenotypic expression and the associated risk, either in carriers from the same family or among carriers of the same mutation that belong to different populations.6-9 Occasionally, this fact may hinder or delay diagnosis in patients to whom only clinical criteria are applied, since in those circumstances, lipid levels may overlap those observed in the general population. The great variability in clinical expression in patients with a certain variant is due to the effect of other factors, which would act as modifiers for the expression of the accountable mutation, a fact that has been demonstrated in several occasions. Incidentally, this is the case of variants in genes such as ApoB, PCSK9, LRP1 and Lp(a), as well as in carriers with mutations in LDLR diagnosed with familial hypercholesterolemia, just to name a few examples.6-11 The participation of genetic variants as phenotypic expression modifiers is explained by the fact that the genes involved can be independently associated, being capable of promoting an increase or decrease in the lipoprotein levels that they affect. In other words, the interactions of their effects attenuate or increase lipid levels, as well as the associated risk in carriers. Similarly, certain variants may influence not only the phenotypic expression, but also the response to drug treatment, determining that the intervention be or not effective in its goal of reducing the associated risk.6,7
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Open Access
Feb 29, 2024
Nurfadillah Rusli + 4
