Korean Circ J.  2021 Nov;51(11):899-907. 10.4070/kcj.2021.0239.

Role of Genetics in Preventive Cardiology: Focused on Dyslipidemia

• Lee SH

• KMID: 2522107
• DOI: http://doi.org/10.4070/kcj.2021.0239

Abstract

Dyslipidemia is a strong risk factor for cardiovascular disease as well as a major target for its prevention. Along with the progress in genetic research techniques and bioinformatics analysis, genetic knowledge helps manage individuals with dyslipidemia. Familial hypercholesterolemia, the most common monogenic lipid disorder, can be diagnosed clinically without confirming pathogenic mutations. However, it can be difficult to do so due to uncertain family history, and genetic testing is of vital importance in such cases. Conversely, recent studies have revealed that combination effect of rare and common variants is frequent in people with other extreme lipid phenotypes. Genetic characteristics are helpful for prediction and selection of patients with high risk for cardiovascular disease or poor response to lipid-lowering therapy. In the past decade, studies using new genetic techniques have identified novel associations among lipid metabolism-associated genes, intermediate lipid phenotypes, and cardiovascular health. Such findings shed light on new drug targets. With improvements in the platforms and processes for drug development, several recent clinical trials showed promising results regarding lipid control and potential cardiovascular disease prevention.

Keyword

Atherosclerosis; Genomics; Hypertriglyceridemia; Genetic therapy; Hypercholesterolemia

Figure

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  Figure 1 Flow of genetic testing for diagnosis of familial hypercholesterolemia. Any of the sequential or multi-gene testing methods can be used to identify pathogenic mutations. When novel mutations are found, their functionality can be examined through familial cosegregation, in silico analysis, or in vitro experiment assessing the function of low-density lipoprotein uptake.

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  Figure 2 Example of familial cosegregation of a potential pathogenic mutation. (A) Pedigree shows people whose DNA was examined. The proband (P05), proband's sister (P05-F01), proband's daughter (P05-F02), and proband's son (P05-F03) were included. (B) The cholesterol levels of the proband and his sister were compatible with FH, whereas his 2 children had normal levels. Sanger sequencing revealed the same heterozygous mutation in the proband and his sister, whereas no mutations were present in his children (from Han et al.6)). The study including this figure was approved by the Institutional Review Board of Severance Hospital, Seoul, Korea (No. 4-2008-0267) and the participants gave written informed consent.

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  Figure 3 The prevalence of rare and common variant carriers in populations with 3 extreme lipid phenotypes. (A) Carriers of APOB or PCSK9 variants in people with very low low-density lipoprotein cholesterol level (from Lee et al.8)). (B) Carriers of LPL, APOC2, GPIHBP1, APOA5, or LMF1 variants in people with very high triglyceride levels (from Lee et al.).9) (C) Carriers of CETP, LIPC, or SCARB1 variant in people with very high high-density lipoprotein cholesterol levels (from Lee et al.).10)

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  Figure 4 Achievement of expected LDL-C reduction through evolocumab treatment in patients with FH. Blue bars indicate LDL-C reduction following addition of evolocumab to the statin/ezetimibe regimen. Orange bars indicate the achievement of expected LDL-C reduction (adjusted lipid-lowering response) following addition of evolocumab to the statin/ezetimibe regimen. Differences in LDL-C reduction and adjusted response are observed according to mutation type, irrespective of disease homozygosity (From Kim et al.15)).CNV = copy number variation; FH = familial hypercholesterolemia; HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol.

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  Figure 5 LPL and other related proteins supporting or inhibiting this enzyme acting in endothelial cells (from Olivecrona with permission20)). In the last decade, some of these genes and their proteins have shown considerable influence on the risk of coronary artery disease, suggesting a causal effect.ANGPTL = angiopoietin-like protein; ECM = extracellular matrix; FFA = free fatty acid; HSPG = heparan sulfate proteoglycan; GPIHBP1 = glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1; LMF1 = lipase maturation factor 1; LPL = lipoprotein lipase; Sel1L = sel-1 suppressor of lin-12-like 1; TRL = triglyceride-rich lipoprotein.

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  Figure 6 Flow of target discovery and drug development based on recent genetic studies. Progress and cost reduction in genetic analysis and bioinformatics helped the identification of rare functional variants that would have been previously impossible. Improvement in production of gene-targeting therapeutics improved the success rate in drug development.Ab = antibody; ASO = antisense oligonucleotide; CV = cardiovascular; LOF = loss-of-function..

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