GENETIC TESTING FOR FAMILIAL HYPERCHOLESTEROLEMIA - PRACTICAL AND ETHICAL ISSUES

Coronary artery disease (CAD) has a strong genetic component, but is a lso greatly influenced by environmental factors such as diet and smoki ng, and disorders such as diabetes mellitus and hypertension. This int eraction makes prediction of CAD risk generally difficult. However, in familial hypercholesterolaemia (FH), risk of early CAD is considerabl y increased by the mutation of a single gene, and genetic testing may be appropriate. We summarize current knowledge concerning DNA-based te sts in the identification and management of FH, and propose specific r ecommendations for genetic testing and further research. The major val ue of DNA tests for FH is in genetic tracing programs to identify and treat affected individuals. DNA testing is appropriate for: (a) diagno sis of FH when physical signs or family history are equivocal or absen t (important given the increased risk of CAD associated with FH compar ed to other hypercholesterolaemias); (b) detection of a mutation causi ng FH in immediate family members (particularly children) where there is a family history of premature CAD. A positive DNA-based test for a mutation is especially useful in children, in whom plasma lipid levels may not be diagnostic. Current clinical practice is to test relatives for raised cholesterol. Testing for mutation carriers in distant rela tives, although feasible, is not currently recommended. Research proje cts should now be started to address two issues: (i) whether genetic t ests for FH better predict clinical outcome than does measurement of p lasma lipid levels; (ii) whether genetic testing for FH confers overal l benefit both to the patient and their relatives, and to the NHS. Ans wers to these questions will guide the subsequent development and impl ementation of genetic tests for CAD risk in general, if and when the c onsiderably more complex genetic causes of CAD are identified.