Inherited risk factors for heart disease is under intensive investigation and it’s likely that, as a result of the Human Genome Project, we’ll see a major expansion of our understanding of genetic causes over the next decade or two.
Researchers in this field commonly divide inherited risk factors into two major groups:
The first are due to a single major gene defect in which all affected people show signs of disease. This includes groups who have familial hypercholesterolaemia.
The other group of inherited risk factors are called subtle gene defects. People with these have a predisposition towards coronary artery disease (CAD), but are strongly affected by their context or environment.
The environment for subtle gene defects includes:
- Other gene variants in the affected person
- The presence of precipitating factors such as diabetes mellitus, obesity or an unhealthy diet
- Some medications such as certain types of oral contraceptive pills
- Excessive alcohol intake in some people
Major gene defects follow defined genetic rules. The subtle gene defects, on the other hand, are more unpredictable, and diagnosing risk in the individual is almost impossible at present.
What we will see is certain factors manifesting in families, such as the development of type 2 diabetes, obesity, high blood pressure and CAD in later life. But it can be very difficult to diagnose risk in an individual family member.
More commonly in such situations, it is assumed that all family members share the risk more or less equally.
Major gene defect
The major gene defect prominent in South Africa is known as familial hypercholesterolaemia (FH).
It is inherited in a dominant fashion, which means that the presence of only a single FH gene from one affected parent can produce the condition in the child who inherits it - that is, in an average of 50% of the offspring.
In a person with the gene for FH, cholesterol levels, mainly LDL cholesterol, are raised from birth making early diagnosis possible. However, clinical disease usually shows itself in adulthood.
As many as 85% of affected men have clinical CAD by the age of 60 years while women follow a decade later. Significant numbers show severe symptoms in their thirties or forties while a few affected individuals are healthy until their seventies or eighties.
The condition is surprisingly common among the Afrikaans population, with an incidence of around one in 75.
This is because the disease arrived in South Africa with one Huguenot couple and spread from them - a phenomenon known as the “founder effect”. The disease also occurs in all the other South African population groups with the lowest incidence in the black community.
Diagnosis can often be made clinically and from routine laboratory measurements, but molecular techniques now permit definite identification of affected individuals and, even more importantly, prenatal testing.
The genetic defect prevents LDL cholesterol from being effectively removed from the bloodstream by the LDL receptor. This also stimulates increased cholesterol synthesis in the body.
Much more rarely, an individual inherits an FH gene from two affected parents. This is called the homozygous condition and is much more severe, with CAD generally present by the age of 20. Unlike the more common single gene, or heterozygous form, it cannot be effectively treated by means of drugs alone and requires the facilities of a specialised lipid clinic.
Other major and subtle gene defects
Besides the receptor defects producing FH, a number of other major gene defects have been identified. All of these produce well-defined, clinically severe illnesses. They are fortunately uncommon or very rare since treatment is difficult in most cases.
Other than for FH, none of the other major gene defects can be regarded as a public health problem, although their impact on the patient and the family can be devastating.
The list of subtle gene variants is likely to become considerably longer than that of the major gene defects. Of those that are known, most are currently not fully defined at the molecular level. A number will undoubtedly turn out to be more than a single disorder.
The important point to remember is that subtle genetic influences can often be effectively treated indirectly – by vigorous lifestyle management, by stopping problematic medication or by treating the disorder that is causing the underlying genetic abnormality to show up.
For instance, obesity can result in significant dyslipidaemia in genetically predisposed individuals, but not in those less predisposed. Weight reduction alone may markedly improve the lipid profile and, along with it, a number of other risk factors in such persons.
There is suggestive evidence that, as for major gene defects, certain population groups harbour a higher prevalence of specific subtle gene variants than others. This, under suitable circumstances, may result in a high incidence of CAD.
- (The Heart and Stroke Foundation/Health24, updated July 2008)