A Comprehensive Review of the Genetics of Dyslipidemias and Risk of Atherosclerotic Cardiovascular Disease

Abstract

Dyslipidemias are often diagnosed based on an individual's lipid panel that may or may not include Lp(a) or apoB. But these values alone omit key information that can underestimate risk and misdiagnose disease, which leads to imprecise medical therapies that reduce efficacy with unnecessary adverse events. For example, knowing whether an individual's dyslipidemia is monogenic can granularly inform risk and create opportunities for precision therapeutics. This review explores the canonical and non-canonical causes of dyslipidemias and how they impact atherosclerotic cardiovascular disease (ASCVD) risk. This review emphasizes the multitude of genetic causes that cause primary hypercholesterolemia, hypertriglyceridemia, and low or elevated high-density lipoprotein (HDL)-cholesterol levels. Within each of these sections, this review will explore the evidence linking these genetic conditions with ASCVD risk. Where applicable, this review will summarize approved therapies for a particular genetic condition.

Keywords: Lp(a); atherosclerotic cardiovascular disease; dyslipidemia; genetics; hyperalphalipoproteinemia; hypercholesterolemia; hypertriglyceridemia; hypoalphalipoproteinemia.

Figure 1

This diagram shows the multitude of risk factors contributing to the ASCVD risk and a selection of genes contributing to these risk factors. The GBinsight Comprehensive Dyslipidemia and ASCVD genetics panel screens these genes to provide a comprehensive analysis of ASCVD risk in a single genetic test.

Figure 2

Infographic summarizing different conditions that cause primary dyslipidemias and their relative effect on ASCVD risk. When applicable, guidelines-based recommendations are suggested for the specific condition. Red upward-facing arrows represent increased ASCVD risk. Green downward-facing arrows represent relative cardioprotection. The number of arrows is proportional to relative risk of ASCVD for a given condition. When red and green arrows co-occur in the same condition, it indicates that ASCVD risk can be either higher or lower depending on the genetic cause(s). A high-resolution version of this figure can be downloaded at the following URL: https://www.gbhealthwatch.com/downloads/GBinsight%20Precision%20Medicine-poster1.pdf (accessed on 5 February 2025).