Clinical Aspects of Genetic and Non-Genetic Cardiovascular Risk Factors in Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is the most common monogenic metabolic disorder characterized by considerably elevated low-density lipoprotein cholesterol (LDL-C) levels leading to enhanced atherogenesis, early cardiovascular disease (CVD), and premature death. However, the wide phenotypic heterogeneity in FH makes the cardiovascular risk prediction challenging in clinical practice to determine optimal therapeutic strategy. Beyond the lifetime LDL-C vascular accumulation, other genetic and non-genetic risk factors might exacerbate CVD development. Besides the most frequent variants of three genes (LDL-R, APOB, and PCSK9) in some proband variants of other genes implicated in lipid metabolism and atherogenesis are responsible for FH phenotype. Furthermore, non-genetic factors, including traditional cardiovascular risk factors, metabolic and endocrine disorders might also worsen risk profile. Although some were extensively studied previously, others, such as common endocrine disorders including thyroid disorders or polycystic ovary syndrome are not widely evaluated in FH. In this review, we summarize the most important genetic and non-genetic factors that might affect the risk prediction and therapeutic strategy in FH through the eyes of clinicians focusing on disorders that might not be in the center of FH research. The review highlights the complexity of FH care and the need of an interdisciplinary attitude to find the best therapeutic approach in FH patients.

Automated summary

Familial hypercholesterolemia (FH) is a common monogenic metabolic disorder with wide phenotypic heterogeneity, posing challenges in cardiovascular risk prediction and therapeutic strategy determination. Beyond lifetime low-density lipoprotein cholesterol (LDL-C) accumulation, other genetic and non-genetic risk factors may exacerbate the development of the disease. This review summarizes the most important genetic and non-genetic factors that might affect the risk prediction and therapeutic strategy in FH, emphasizing the need for an interdisciplinary approach in finding the best treatment methods.