Familial hypercholesterolemia (FH) is a hereditary disease characterized by elevated LDL-C levels, premature atherosclerosis, and increased early cardiovascular morbidity and mortality. It is one of the most prevalent hereditary diseases (around 1:300 in most populations) and has been recognized by the WHO as a global health problem.
FH is responsible for approximately 9% of heart attacks in individuals under 65 years of age and up to 20% of heart attacks in individuals under 45 years of age. A timely diagnosis and the initiation of effective therapies to reduce LDL-C can significantly delay the onset of cardiovascular events and even normalize life expectancy.
Between 20% and 40% of patients diagnosed with clinically defined FH do not show a causal mutation in the classic FH candidate genes. It is estimated that in more than 80% of patients with a negative genetic diagnosis, the polygenic explanation is the most likely cause of their hypercholesterolemia (polygenic FH). Polygenic FH is due to the sum of the effects of several genetic defects (common polymorphisms that affect several loci) where each of them slightly increases LDL-C.
For greater complexity, polygenic and monogenic causes of FH are not mutually exclusive entities, but rather interact (even in patients with monogenic FH there may be a polygenic contribution).
Characterizing the genetic component of FH can have important consequences for both the patient and the family. The application of polygenic risk scores is useful to refine the diagnosis and prediction of future cardiovascular risk.