Low-density lipoprotein cholesterol (LDLc) is well established as a key causal factor in the development of atherosclerotic vascular disease, especially coronary heart disease (CHD). Although there is wide variability of LDLc levels within the population, several studies have demonstrated that LDLc levels in related individuals tend to be similar, indicating that the LDLc level is a heritable trait. [1, 2] Because of these findings, there has been considerable investigation into the genetics that determine the LDLc plasma concentration, which is part of the larger effort to improve the risk assessment of future cardiovascular disease in any given person.
The genetics of LDLc can be divided into 2 main groups: one where a clear pattern of inheritance (mendelian) is evident, and the other where an inheritance pattern is not easily deciphered. The syndrome of familial hypercholesterolemia (FH) falls into the first group, where clear single variant mutations that are inherited in a mendelian fashion (autosomal recessive or dominant pattern) profoundly alter the LDLc level. This is in contrast to other individuals with the FH phenotype, with no clear single gene mutation that can explain the alteration in LDLc. This is likely the more common scenario, in which there may be a collection of gene variants (single-nucleotide polymorphisms, or SNPs) that, together with traditional dietary and lifestyle factors, exert a compound effect similar to the classic gene mutations of FH.
To see complete information on the pathogenic role of LDLc in atherosclerosis, please click here. To also see more complete information about the syndrome of familial hypercholesterolemia, click here.
Single variant mutations
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.  In some population groups, such as French Canadians and Dutch Afrikaners, the prevalence is as high as 1 in 100.  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. [3, 4, 5]
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%). [6, 7] 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 >70%. [8, 9, 10]
The first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor approved in the United States was alirocumab (Praluent) in July 2015. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDLc.
Alirocumab’s approval was based on data from the pivotal phase 3 ODYSSEY program, which showed consistent, positive results for alirocumab compared to placebo and included current standard of care therapy (statins). The ODYSSEY LONG TERM trial evaluated alirocumab 150 mg SC every 2 weeks. Alirocumab reduced LDLc by 58%, as compared to placebo at week 24, when added to current standard of care, including maximally tolerated statins.  In ODYSSEY COMBO I, alirocumab 75 mg every 2 weeks as an adjunct to statins reduced LDLc by an additional 45%, compared with placebo at week 12.  At week 24 in the same trial, alirocumab reduced LDLc by an additional 44% compared with placebo. In this study, if additional LDLc lowering was required based on prespecified criteria at week 8, alirocumab was up-titrated to 150 mg at week 12 for the remainder of the trial. Eighty-three percent of patients remained on their initial 75-mg dose.
A second PCSK9 inhibitor, evolocumab (Repatha), was approved in August 2015. It is approved for adults as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic CVD who require additional lowering of LDLc. It is also approved for adults and adolescents with homozygous familial hypercholesterolemia (HoFH). Approval of evolocumab was based on the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER). During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels. [13, 14]
The other genetic mutation that has been associated with elevated levels of LDLc and the FH phenotype is in the ligand-binding domain of apo-B 100. Also called familial defective apolipoprotein B-100, clearance of LDL via the LDL receptor is impaired because of defective binding of apo-B 100 (on the LDL particle) to the LDL receptor. This mutation has an autosomal dominant inheritance and its prevalence is anywhere from 5-8% in those with the FH phenotype. [3, 15]
LDL particle size
LDL particle size has also been associated with increased CHD risk. Increased levels or percentage of small dense low-density lipoprotein cholesterol (sdLDLc) has been correlated with increased future CHD events in the ARIC study.  It is thought that increased sdLDLc leads to increased atherogenicity because of a higher LDL particle number or because of more available smaller LDL circulating particles. Elevated sdLDLc has been correlated with increased markers of inflammation, metabolic syndrome, and development of adverse lipid profiles. Many single nucleotide polymorphisms (SNPs) on multiple chromosomal loci and genetic variants in the PCSK7 gene have been implicated in abnormal levels of sdLDLc. 
Polygenic hypercholesterolemia, SNPs, and genotype scores
Some studies have introduced the classification of polygenic hypercholesterolemia, in which a person has the FH phenotype but none of the classic mutations that lead to heterozygous or homozygous familial hypercholesterolemia. One study, which examined a UK population, showed that in 40% of those with the FH phenotype, no mutations in LDLR, ApoB, or PCSK9 were found. [17, 18]
Given these findings, some have proposed the concept that less potent but more common LDLc-raising variants at specific loci across multiple genes may be playing a key role.  Based on GWA (genome-wide association) studies that utilize high-throughput genotyping techniques, many SNPs have been found to have significant associations with elevated LDLc. It is thought that an individual may carry multiple variants that work together to produce an FH-like phenotype. Some investigators have proposed utilizing a polygenic or genotype score, which tallies SNPs from multiple LDLc-raising alleles, to use in risk assessment. Interestingly, some studies have shown that higher genotype scores have correlated with higher CVD event rates. [18, 20, 21] However, much investigation is still needed to show the added value of such genotype scores, especially when considered in the context of the classic risk factors for atherosclerotic vascular disease and coronary heart disease.
Screening for FH and Genetic testing
Many studies have shown that FH is an underdiagnosed condition worldwide, despite the fact that there are effective ways to treat it and prevent long-term damage. The National Lipid Association guidelines in 2011 stressed the need, in the primary care setting, to identify familial hypercholesterolemia on the basis of clinical criteria and LDLc levels. These guidelines stated that genetic testing may be helpful if the diagnosis of FH is uncertain, but they also noted that a negative genetic test does not exclude FH, because up to 20% of patients will not be found to have a known mutation because of the limitations of current methods. 
If index cases are found and are highly suggestive of FH on the basis of clinical criteria, genetic testing is not necessary to confirm a primary mutation, but it may still be done, and cascade screening of relatives is recommended. Some studies have shown the cost-effectiveness of cascade screening of relatives utilizing this approach. [22, 23]
There is still controversy regarding universal screening of children for FH, with some believing that early identification can lead to early treatment and, as a result, reduction in total "cholesterol years." However, the long-term effects of statin therapy and the thresholds for initiation of treatment in young children are currently being debated. Groups such as the American Heart Association do not endorse universal screening, but they do state that cholesterol testing should be considered in children of parents with premature CHD and/or a history of elevated total cholesterol levels.