Familial hypercholesterolemia + statin PGx + polygenic FH + CV risk [12 genes]

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.

The prevalence of heterozygous familial hypercholesterolemia is around 1:3,000 in most populations.

The identification of pathogenic mutations confirms the diagnosis of FH according to current diagnostic criteria, such as the British Simon Broome registry, the Dutch Lipid Clinic Criteria or the widely used WHO-MEDPED criteria. for the diagnosis of this disease. Once the mutation is identified in the index case, it is important to begin family genetic screening, which should include members of pediatric age, in whom the benefit of early diagnosis and therapeutic intervention has been demonstrated. Recent epidemiological studies have shown that the genetic study of FH has a high cost-efficiency relationship, contributing to reducing long-term health expenditure. Currently, and in patients with high clinical suspicion, it constitutes a study indicated by multiple scientific communities and working groups on the subject at an international level, integrating population detection programs in various countries.

• The genes selected in this panel allow a diagnosis of FH, as well as differential diagnoses with other hereditary diseases whose biochemical alteration is hypercholesterolemia. These include sitosterolemia and lysosomal acid lipase (DLAL) deficiency.
• This study also allows us to evaluate the probability that FH is of polygenic etiology. It is estimated that more than 80% of patients with a definite clinical diagnosis of FH, but without an identified mutation, could have hypercholesterolemia of polygenic etiology. We used one of the most validated polygenic FH risk scores (Talmud et al., 2013) to predict LDL-C levels and the risk of atherosclerotic cardiovascular disease. Both patients with a negative genetic study and those with a positive genetic study (monogenic FH) can benefit from knowing their polygenic FH score. The application of this score is useful to refine the diagnosis and prediction of future cardiovascular risk. The score may also be useful in patients with variants of uncertain significance and a low polygenic FH score, where this VUS (for example, in a highly prevalent gene such as LDLR) may be the cause of the disease. In this case, the cosegregation study would start from a favorable hypothesis. Finally, those patients with a high polygenic FH score would require more aggressive lipid-lowering treatment, since their risk may be comparable to that of monogenic hypercholesterolemia.
• In these patients, who are most likely under treatment with statins, the pharmacogenetic study may be useful to know the probability of presenting any adverse event to these drugs. The potential development of adverse events could compromise adherence to these drugs. The pharmacogenetic study in these cases allows the type of statin or lipid-lowering treatment to be selected appropriately.
• The service offers the possibility of knowing the additional genetic risk of developing ischemic cardiovascular events in hypercholesterolemic patients. Hypercholesterolemia constitutes per se a known risk factor for the development of coronary heart disease. However, the identification of a high value in the genetic cardiovascular risk score has been shown to be an independent factor that could have an additive effect to traditional factors. Adequate control of modifiable risk factors such as hypercholesterolemia could considerably mitigate the overall risk.

Patients with suspected familial hypercholesterolemia considering current, duly validated clinical criteria, who are under treatment with statins and in whom it is desired to know the incremental risk of developing ischemic cardiovascular events.