Apolipoprotein polymorphisms and familial hypercholesterolemia

The majority of apolipoproteins known to play a major role in lipid metabolism were identified over 20 years ago, and nine of them (APOA1, -A2, -A4, -B48, -B100, -C1, -C2, -C3 and -E) have long been known to be most relevant to the regulation of lipoproteins. Polymorphisms of genes encoding apolipoproteins influence plasma levels of high-density lipoproteins (HDL), very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) chylomicrons or triglycerides. Familial hypercholesterolemia (FH), an autosomal dominant disorder, is caused by mutations mainly located in the low-density lipoprotein receptor (LDLR) gene, or more rarely within the apolipoprotein B-100 gene or the gene encoding a secreted proteinase PSCK9. FH is characterized by elevated concentrations of LDL, deposition of LDL-derived cholesterol in tendons, skin xanthomas, and premature coronary artery disease. The frequency of heterozygotes is approximately one in 500 persons, placing FH among the most common inborn errors of metabolism. The risk of cardiovascular disease in these patients is influenced not only by the type of the mutations they carry, but also by the haplotype of lipid modifier genes, as is the case of apolipoproteins. In this review, we present current information that demonstrates the impact of apolipoprotein polymorphisms on the FH phenotype.