Dyslipidemias + statin PGx + polygenic FH + CV risk [31 genes]

Genetic hyperlipidemias are associated with a high predisposition to develop early atherosclerotic disease with a familial presentation, which is currently regarded as a major global health issue by the WHO. They have a high impact on cardiovascular risk, as they act from very early stages of life and constitute a factor for poor prognosis in affected patients. It has been estimated that approximately 9% of cardiac arrests in individuals younger than 65 years and up to 20% of cardiac arrests in individuals younger than 45 years are due to monogenic dyslipidemias, mainly familial hypercholesterolemia (FH). Moreover, some types of hyperlipidemia, such as severe hypertriglyceridemias, are a rare but well-documented cause of pancreatitis associated with a poor prognosis.

The nature of hyperlipidemias is very complex both at the clinical and at the genetic level. Polygenic forms of hyperlipidemia are much more common, and the manifestations of the disorder are largely influenced by environmental or secondary factors. In some forms of hyperlipidemia, the underlying genetic defect is often insufficient to cause hyperlipidemia unless additional environmental or genetic influences coexist. It is estimated that more than 60% of the variability in serum lipid levels is genetically determined, and most of this variation is due to polygenic influences. Monogenic forms of hyperlipidemia are less common and are usually clearly defined. Some of them follow a dominant inheritance pattern and are relatively common, while others are inherited in a recessive manner and are much rarer. This type of disorders is expressed independently of environmental influences.

The correct diagnosis of genetic hyperlipidemias is of great importance, since their prognosis and, therefore, the clinical management of the patient and of the family can substantially differ from those of non-genetic hyperlipidemias.

1. Heterozygous familial hypercholesterolemia: 1:250 for most populations.
2. Homozygous familial hypercholesterolemia: 1:240,000 (estimated)
3. Autosomal recessive familial hypercholesterolemia: <1:1,000,000
4. Polygenic familial hypercholesterolemia: 1:15 (estimated)
5. Sitosterolemia: <1:1,000,000
6. Lysosomal acid lipase deficiency: 1:177,000
7. Familial chylomicronemia syndrome: 1:250,000 (estimated).
8. Transient infantile hypertriglyceridemia: <1:1,000,000.
9. Multifactorial chylomicronemia syndrome (MCS): 1:600-1:1,000
10. Monogenic hypertriglyceridemias: 1:10-1:100
11. Familial dysbetalipoproteinemia: 1:10-1:1,000
12. Familial combined hyperlipidemia: 1:150
13. Pancreatic lipase deficiency: <1:1,000,000

This panel allows jointly assessing all the relevant genetic information for the management of a patient with clinical suspicion of hyperlipidemia.

• The application of polygenic risk scores is useful for refining the diagnosis and predicting future cardiovascular risk:
  • Polygenic FH risk score (polygenic FH PRS). We use one of the most widely validated scores, which includes 12 SNPs and stratifies patients based on their probability of having polygenic FH (Talmud et al., 2013). Patients with both a negative and a positive genetic test (monogenic FH) can benefit from knowing their polygenic FH score). Polygenic FH may have a more benign prognosis than monogenic FH and is not inherited following a Mendelian pattern. Nevertheless, polygenic FH is associated with a higher cardiovascular risk than non-genetic hypercholesterolemia, probably due to longer exposure times to higher cholesterol levels, and these patients could therefore require more aggressive hypolipidemic treatments. It can also be useful in patients carrying variants of uncertain significance (e.g. in a highly prevalent gene, such as LDLR) and with a low polygenic FH score, suggesting that these variants could be more likely to be causative of disease (in this case, cosegregation study would start from a positive hypothesis).
  • Genetic cardiovascular risk score (cardiovascular PRS). We use a widely validated score that includes 50 SNPs and allows assessing the genetic risk of incidence of coronary events during a 20-year follow-up period (Tada et al., 2015; Khera et al., 2016). However, the identification of high values for the cardiovascular genetic risk score has proven to be an independent factor from traditional risk factors.
    Determining the cardiovascular genetic risk can improve the prediction of the overall risk (only in combination with existing risk algorithms), allows implementing lifestyle changes, and could help improve treatment adherence.
• Pharmacogenetic testing provides orientation about the most suitable treatment for each patient, in case it is warranted by an underlying genetic cause and based on updated information from the main pharmacogenetic clinical practice guidelines and drug data sheets from regulatory authorities.

Aimed at patients with elevated levels of several lipoproteins (who do not show hypercholesterolemia or isolated hypertriglyceridemias) currently receiving or considering treatment with statins and whose incremental risk of developing ischemic cardiovascular events is of interest.