Which genetic mutations elevate low-density lipoprotein cholesterol (LDLc) levels?

Updated: Apr 09, 2021
  • Author: Nainesh K Gandhi, MD, MSE; Chief Editor: Keith K Vaux, MD  more...
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Single variants that dramatically elevate LDLc plasma concentrations (ie, LDLc >200-400 mg/dL) or the FH (familial hypercholesterolemia) phenotype can be divided into 3 main mutations involving genes coding for (1) the LDL receptor (LDLR; cytogenetic location, 19p13.2); (2) apolipoprotein B (APOB; cytogenetic location, 2p24-p23); and (3) proprotein convertase subtilisin/kexin type 9 (PCSK9; cytogenetic location, 1p32.3). The vast majority of markedly elevated LDLc phenotypes (>95%) are due to these mutations. Much less common are mutations of LDLRAP1, which yields the autosomal recessive hypercholesterolemia (ARH).

The FH phenotype can be divided into heterozygous and homozygous FH, with a prevalence of 1 in 300-500 and 1 in 1 million, respectively. [4] In some population groups, such as French Canadians and Dutch Afrikaners, the prevalence is as high as 1 in 100. [4] The clinical syndrome of heterozygous FH is characterized by elevated LDLc plasma concentration; premature coronary heart disease (CHD) in the third, fourth, or fifth decade of life; or a family history of CHD, family history of FH, and tendon xanthomata. Usually, this phenotype is due to a single LDL receptor gene (LDLR) mutation, and a combination of these factors is often present, which strongly suggests that FH should be considered as a diagnosis. As mentioned, homozygous FH is much more rare, will be caused by at least 2 LDLR mutations, and will have most, if not all, of these characteristics at a much earlier age, with markedly elevated LDLc plasma concentrations.

LDL receptor mutations account for greater than 90% of the variants of the FH phenotype, and PCSK9 mutations account for approximately 2%. Gain-of-function PCSK9 activity leads to greater degradation of the LDL receptor, yielding less available LDL receptor, and increased LDLc plasma concentrations. [4, 9, 10]

There are several mutations that are known to cause loss of function in PCSK9, including the following: C679X nonsense mutations, C142X mutations, and the R46L missense mutation. These mutations have been associated with significantly lower LDLc concentrations and a reduction in incident CHD events (in some studies, up to 50%). [11, 12] These observations have led to the development of PCSK9 inhibitors, many of which are monoclonal antibodies directed at PCSK9. With these agents, in combination with statins, some studies have shown reductions in LDLc greater than 70%. [13, 14, 15]

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