DNA testing for familial hypercholesterolemia: improving disease recognition and patient care.

Cardiovascular disease is the leading cause of death worldwide and, like most chronic diseases, it has major genetic and environmental components. Among patients with coronary heart disease onset before the age of 55, about 5% of cases are attributable to heterozygous familial hypercholesterolemia (FH), a disease following autosomal dominant inheritance. About 50% of individuals with FH die before the age of 60 due to myocardial infarction. The frequency of FH is estimated to be 1 : 500. FH is related to mutations in the low-density lipoprotein (LDL)-cholesterol LDL-receptor gene and apolipoprotein B (apoB) gene. The identification of individuals with FH has been based on lipid levels and segregation of lipid levels within the family. However, phenotypes are overlapping and family history is not always informative. Therefore, a DNA-based genetic test for FH appears to offer the best alternative. The DNA test gives a simple yes/no answer. The FH test is a definitive tool for the identification of affected family members. The approach of targeted family genetic screening to find new patients is faster and more reliable compared with a biochemical form of screening. Early identification and efficient treatment of such patients is important and highly cost effective. There is evidence to suggest that the nature of the LDL-receptor (LDLR) mutation influences the degree of cholesterol lowering achieved by HMG-CoA reductase inhibitors (statins). The observed differences in the LDL-cholesterol (LDL-C) responses to these drugs among the various LDLR gene mutations are not yet completely understood. The relationships shown between LDLR mutation types and lipid levels, and the response of lipid levels to HMG-CoA reductase inhibitor treatment, will have to be investigated within the framework of pharmacogenetic studies. The variables, which are important in determining the overall atherosclerosis risk, are the result of combined activity in a dynamic network of numerous genes and environment. Candidate genes for atherosclerosis need to be further tested and validated. Future research should be directed at determining the significance of such targets, which patients with FH are at particularly high risk of premature cardiovascular disease, and which environmental factors are effective in modulating this risk. Genetics-based diagnostics will complement identification of FH while improving cardiovascular risk prediction, prevention of disease and treatment efficacy.