The plasma level of
LDL cholesterol is clinically important and genetically complex.
LDL cholesterol levels are in large part determined by the activity of
LDL receptors (LDLR) in the liver. Autosomal dominant familial hypercholesterolaemia (FH) - with its high
LDL cholesterol levels,
xanthomas, and premature
atherosclerosis - is caused by mutations in either the LDLR or in
APOB - the
protein in
LDL recognised by the LDLR. A third, rare form - autosomal recessive hypercholesterolaemia - arises from mutations in the gene encoding an adaptor
protein involved in the internalisation of the LDLR. A fourth variant of inherited hypercholesterolaemia was recently found to be associated with missense mutations in PCSK9, which encodes a
serine protease that degrades LDLR. Whereas the gain-of-function mutations in PCSK9 are rare, a spectrum of more frequent loss-of-function mutations in PCSK9 associated with low
LDL cholesterol levels has been identified in selected populations and could protect against
coronary heart disease. Heterozygous familial hypobetalipoproteinaemia (FHBL) - with its low
LDL cholesterol levels and resistance to
atherosclerosis - is caused by mutations in
APOB. In contrast to other inherited forms of severe hypocholesterolaemia such as abetalipoproteinaemia - caused by mutations in MTP - and homozygous FHBL, a deficiency of PCSK9 appears to be benign. Rare variants of NPC1L1, the gene encoding the putative intestinal
cholesterol receptor, have shown more modest effects on plasma
LDL cholesterol than PCSK9 variants, similar in magnitude to the effect of common
APOE variants. Taken together, these findings indicate that heritable variation in plasma
LDL cholesterol is conferred by sequence variation in various loci, with a small number of common and multiple rare gene variants contributing to the phenotype.