Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c.
Based on evidence from epidemiological studies regarding the relationship between cholesterol and cardiovascular disease (CVD) , cholesterol, with nucleic acids and glucose, is one of the most cited organic molecules in the scientific literature and household conversations. A high plasma cholesterol level alone is not usually accompanied by clinical manifestations, but persistent hypercholesterolemia is strongly associated with an elevated risk of developing highly prevalent diseases like CVD—which includes myocardial infarction (MI), ischemic stroke, and peripheral vascular disease (PVD) —and high blood pressure . Hypercholesterolemia is negatively associated with other diseases, such as intracerebral hemorrhage , but the relationship between diabetes and cholesterol is controversial . CVD is one of the leading causes of death in industrialized countries; for example, in Spain, where the prevalence of CVD is lower than in other Western countries , according to the Spanish National Statistics Institute, the leading causes of death in 2018 were ischemic heart disease in men and ischemic stroke in women . Notably, hypercholesterolemia is a modifiable risk factor, so early diagnosis is crucial for decreasing cardiovascular morbimortality, and cholesterol-lowering treatments have been shown to dramatically reduce CVD risk in hypercholesterolemic subjects .
Cholesterol is a structural component of animal cell membranes, influencing membrane fluidity and cell signaling . It is the precursor of steroid hormones, bile acids, fats, and lipophilic vitamins, but it also has a regulatory function in multiple processes, such as in the immune system, gene transcription, enzyme functions, protein degradation, signal transduction, and apoptosis . Its multiple functions are due to its peculiar three-part structure, which has opposing hydrophilic and hydrophobic ends, and an extremely rigid four-ring central component .
Both a lack or excess of cholesterol can be dangerous for cells because the balance between membrane fluidity and rigidity in many cases determines important aspects of cell functions . In humans, a limited ability to catabolize excess cholesterol can lead to serious health consequences, so scientific interest has focused mainly on mechanisms for regulating the uptake and synthesis of cholesterol, rather than eliminating it.
|Gene||Chromosome||Phenotype 1||Type||Inheritance 2||OMIM|
Linkage studies and/or exome sequencing in ADH-affected families have suggested other putative loci for ADH (Table 1). Linkage analysis in an ADH kindred without LDLR, APOB and PCSK9 mutations, identified the gene for signal transducing adaptor family member 1 (STAP1)—a docking protein—as a candidate for ADH , initially describing it as FH4 (OMIM #604298). However, studies in Spanish families with a clinical diagnosis of ADH showed incomplete or lack of STAP1 mutations cosegregation with the ADH phenotype [44,45]. A recent study failed to find STAP1 associated with plasma LDL-c in mice or humans , so its exclusion from candidate genes has been proposed.
Autosomal recessive cholesteryl ester storage disease (CESD) is caused by mutations of the lysosomal acid lipase (LIPA) gene. One study associated a homozygous splice junction mutation of the LIPA gene with the ARH phenotype in a Dutch family , but another study of patients with a clinical diagnosis of FH detected an enrichment of heterozygous (but not homozygous) LIPA mutations [48,49].
Cytochrome P450 family 7 subfamily A member 1 (CYP7A1)—also known as cholesterol 7-alpha monooxygenase—is the rate-limiting enzyme that catalyzes the first step of the transformation of cholesterol into bile acids . A homozygous CYP7A1 frameshift mutation was associated with high levels of LDL-c in a UK family , and a promoter CYP7A1 gene variant has been reported to influence the LDL-c-lowering response to atorvastatin, modulated by the APOE genotype .
The APOE mutation p.Leu167del was associated with ADH in a large French family . This APOE variant was previously associated with splenomegaly, thrombocytopenia, and the Fredrickson HLP2B (familial combined hyperlipidemia) and HLP3 (dysbetalipoproteinemia) phenotypes , both characterized by mixed hyperlipidemia. A study of ADH subjects with this mutation showed that VLDLs carrying mutant APOE caused hypercholesterolemia by down-regulating LDLR expression in hepatocytes .
ABCG5 and ABCG8 loss-of-function mutations are associated with sitosterolemia (OMIM #618666/#210250)—an autosomal recessive disease characterized by elevated plant-sterol plasma levels. Although sitosterolemia shares clinical features with ADH, such as the presence of tendon xanthomas and CVD risk, cholesterol plasma levels in affected subjects are typically normal or moderately elevated in adulthood . A common ABCG5/8 polymorphism was associated with plasma lipid concentrations in ADH and influenced CVD risk [57,58]. More recent studies reported a significantly higher frequency of carriers of pathogenic or likely-pathogenic ABCG5/8 mutations in mutation-negative ADH patients compared to the reference population [59,60,61,62]. However, although ABCG5/8 mutations may contribute to hypercholesterolemia in mutation carriers, it has not been proven to be sufficient to cause an ADH phenotype .
Patatin-like phospholipase domain containing 5 (PNPLA5) belongs to a patatin-like phospholipase family, which plays a key role in the hydrolysis of triglycerides and the regulation of adipocyte differentiation . Exome sequencing of individuals with extreme LDL-c levels showed an association of rare PNPLA5 variants with mainly high, but also low, plasma LDL-c levels .
Recently, a study has described the role of cyclase-associated protein 1 (CAP1) in cholesterol metabolism . CAP1 is a binding partner of PCSK9 and plays an important role in LDLR catabolism by directing LDLR–PCSK9 complex to lysosomal degradation. To my knowledge, no studies have been performed to detect CAP1 variants associated with plasma LDL-c levels.
Finally, it is noteworthy that patients diagnosed with ADH have elevated plasma levels of lipoprotein (Lp)(a)—an LDL-like particle with apolipoprotein(a) covalently bonding to apoB . In the absence of hypertriglyceridemia, plasma LDL-c concentrations are usually calculated using the Friedewald formula , rather than by direct detection; thus, Lp(a) particles could be responsible for an increased likelihood of high LDL-c diagnosis, since the cholesterol within Lp(a) contributes to the estimated LDL-c. A recent study showed that the presence of Lp(a) cholesterol misclassified a significant number of samples submitted for lipid testing as high LDL-c . Lp(a) is an independent CVD risk factor, and 90% of circulating Lp(a) plasma levels are genetically determined , so studies must consider a possible interference of Lp(a) if plasma LDL-c concentrations are not directly measured.