Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review

Abstract

Hypercholesterolemia is a strong determinant of mortality and morbidity associated with cardiovascular diseases and a major contributor to the global disease burden. Mutations in four genes (LDLR, APOB, PCSK9 and LDLRAP1) account for the majority of cases with familial hypercholesterolemia. However, a substantial proportion of adults with hypercholesterolemia do not have a mutation in any of these four genes. This indicates the probability of having other genes with a causative or contributory role in the pathogenesis of hypercholesterolemia and suggests a polygenic inheritance of this condition. Here in, we review the recent evidence of association of the genetic variants with hypercholesterolemia and the three lipid traits; total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C), their biological pathways and the associated pathogenetic mechanisms. Nearly 80 genes involved in lipid metabolism (encoding structural components of lipoproteins, lipoprotein receptors and related proteins, enzymes, lipid transporters, lipid transfer proteins, and activators or inhibitors of protein function and gene transcription) with single nucleotide variants (SNVs) that are recognized to be associated with hypercholesterolemia and serum lipid traits in genome-wide association studies and candidate gene studies were identified. In addition, genome-wide association studies in different populations have identified SNVs associated with TC, HDL-C and LDL-C in nearly 120 genes within or in the vicinity of the genes that are not known to be involved in lipid metabolism. Over 90% of the SNVs in both these groups are located outside the coding regions of the genes. These findings indicates that there might be a considerable number of unrecognized processes and mechanisms of lipid homeostasis, which when disrupted, would lead to hypercholesterolemia. Knowledge of these molecular pathways will enable the discovery of novel treatment and preventive methods as well as identify the biochemical and molecular markers for the risk prediction and early detection of this common, yet potentially debilitating condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-017-0488-4) contains supplementary material, which is available to authorized users.

Clinical and Biochemical Features of Different Molecular Etiologies of Familial Chylomicronemia

“…Some support for this may come from studies that have shown an association between mutations in APOA5 and APOC2 and hypercholesterolemia. 28 Environmental, or gene-environment interactions, may also be playing a role. Interestingly apo B levels were not significantly different between the 2 groups, although specific B-100 and B-48 assays were not performed.…”

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

“…Though our patients had negative gene panel testing for many of the genes known to be associated with Mendelian hypercholesterolemia syndromes, these panels do not account for all modifier genes within this pathway nor for noncoding variants, alleles of small effect size, or polymorphisms in known genes [5,25]. Importantly, common polymorphisms in all of these cholesterol metabolism genes are associated with population-based variation in lipoprotein profile and atherosclerotic cardiovascular disease risk, and individuals with LALD are not exempt from the effects of these variants [26][27][28]. Interestingly, ezetimibe, a pharmacological inhibitor of the NPC1L1 cholesterol transporter, has shown significant benefit in both animal models and patients with LALD, consistent with noncanonical LDL pathways modifying the LALD dyslipidemia phenotype [11,29,30].…”

Functional analysis and signaling pathway enrichment analysis of genes associated with Alzheimer’s disease and Parkinson’s disease

“…Влияние на кальций-опосредованный сигналинг обусловливает изменения уровня кальция в ýндоплазматической сети. Повышенное содержание Ca 2+ может вызывать синаптический дефицит и способствовать накоплению амилоидных бляшек при болезни Альцгеймера [16].…”