Hereditary polygenic hypercholesterolemiaE78.0

Hereditary (familial) polygenic hypercholesterolemia results from the combination of various genetic defects and the interaction of exogenous factors. Either mutations are present in genes not yet identified as relevant to the disease or it is a polygenic or oligogenic hypercholesterolemia (Tada H et al. 2019). See also Familial hypercholesterolemia, autosomal dominant.

For the German population a frequency of heterozygous hereditary hypercholesterolemia of 1/ 500 is assumed. For Denmark and Norway, prevalence rates of 1/200 to 1/300 are reported.

The age of manifestation of cardiovascular complications can vary greatly in this form of hypercholesterolemia. An early manifestation is possible (sporadic < 30 years of age; early onset of myocardial infarction) if other risk factors such as elevated lipoprotein(a), low HDL cholesterol or a high polygenic score are present (Khera AV et al. 2019). However, cardiovascular complications can also manifest themselves after the age of 50 or older.

Clinically, the focus is on premature atherosclerotic diseases. Familial (non-monogenetic) hypercholesterolemia illustrates a causal relationship between elevated LDL-cholesterol (LDL-C) and vascular disease (Hovingh GK et al. 2013).

Still mild to moderate hypercholesterolemia (cholesterol levels between 200 and 400mg/dl); plasma triglycerides normal, arcus corneae; tendinous and cutaneous xanthomas are typical, externally visible signs of abnormal cholesterol storage; xanthelasma; very high risk of CHD.

Human genetic exclusion of a monogenetic hyperchoesterinemia. If the detection of a disease-causing mutation could not be made, the diagnosis is made on the basis of the clinical characteristics. Increasingly, however, in the case of non-monogenetic hereditary hypercholesterolemia, a more genetic score (oligogenic/polygenic) allows statements to be made about a potential risk of CHD (Tada H et al. 2019).

It is concluded that there is an 8-fold increase in the risk of CHD compared to persons not exposed to hereditary factors. However, the risk of CHD is significantly lower with polygenic (oligogenic) hypercholesterolemia than with monogenic forms (Sharifi M et al. 2019). Patients with familial hypercholesterolemia in whom xanthomas occur have a 3-fold higher risk of CHD than those without xanthomas.

In most European countries, hereditary (familial) hypercholesterolemia is diagnosed in only 15% of cases, typically after a heart attack at a young age or when myocardial infarction is a family history. In this respect, routine laboratory tests are recommended (Klose G et al. (2014).

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The full costs for a genetic diagnosis are only incurred once by the index patient, because a relevant mutation once identified can be searched for in relatives.

1. Berberich AJ et al (2019) The complex molecular genetics of familial hypercholesterolaemia. Nat Rev Cardiol 16:9-20.
2. Hooper AJ et al (2018) The Present and the Future of Genetic Testing in Familial Hypercholesterolemia: Opportunities and Caveats. Curr Atheroscler Rep 20:31.
3. Hovingh GK et al (2013) Diagnosis and treatment of familial hypercholesterolemia. Eur Heart J 34: 962-971.
4. Khera AV et al (2019) Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. Circulation 139:1593-1602.
5. Klose G et al (2014) Familial hypercholesterolemia: developments in diagnosis and treatment. Dtsch Arztebl Int 111: 523-529.
6. Miname MH et al (2019) Subclinical coronary atherosclerosis and cardiovascular risk stratification in heterozygous familial hypercholesterolemia patients undergoing statin treatment. Curr Opin Lipidol 30:82-87.
7. Sharifi M et al (2019) Polygenic Hypercholesterolemia and Cardiovascular Disease Risk. Curr Cardiol Rep 21:43.
8. Tada H et al (2018) Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease. J Clin Lipidol 12:1436-1444.
9. Tada H et al (2019) Monogenic, polygenic, and oligogenic familial hypercholesterolemia. Curr Opin Lipidol doi: 10.1097/QCO.0000000000000000000563.