Se. Humphries et al., GENETIC TESTING FOR FAMILIAL HYPERCHOLESTEROLEMIA - PRACTICAL AND ETHICAL ISSUES, Quarterly Journal of Medicine, 90(3), 1997, pp. 169-181
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.