%A Dron,Jacqueline S. %A Hegele,Robert A. %D 2020 %J Frontiers in Endocrinology %C %F %G English %K Autosomal recessive (AR),Complex trait,familial chylomcronaemia syndrome,Multifactorial chylomicronemia,Polygenic score,triglyceride %Q %R 10.3389/fendo.2020.00455 %W %L %M %P %7 %8 2020-July-24 %9 Review %# %! Genetics of Hypertriglyceridemia %* %< %T Genetics of Hypertriglyceridemia %U https://www.frontiersin.org/articles/10.3389/fendo.2020.00455 %V 11 %0 JOURNAL ARTICLE %@ 1664-2392 %X Hypertriglyceridemia, a commonly encountered phenotype in cardiovascular and metabolic clinics, is surprisingly complex. A range of genetic variants, from single-nucleotide variants to large-scale copy number variants, can lead to either the severe or mild-to-moderate forms of the disease. At the genetic level, severely elevated triglyceride levels resulting from familial chylomicronemia syndrome (FCS) are caused by homozygous or biallelic loss-of-function variants in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. In contrast, susceptibility to multifactorial chylomicronemia (MCM), which has an estimated prevalence of ~1 in 600 and is at least 50–100-times more common than FCS, results from two different types of genetic variants: (1) rare heterozygous variants (minor allele frequency <1%) with variable penetrance in the five causal genes for FCS; and (2) common variants (minor allele frequency >5%) whose individually small phenotypic effects are quantified using a polygenic score. There is indirect evidence of similar complex genetic predisposition in other clinical phenotypes that have a component of hypertriglyceridemia, such as combined hyperlipidemia and dysbetalipoproteinemia. Future considerations include: (1) evaluation of whether the specific type of genetic predisposition to hypertriglyceridemia affects medical decisions or long-term outcomes; and (2) searching for other genetic contributors, including the role of genome-wide polygenic scores, novel genes, non-linear gene-gene or gene-environment interactions, and non-genomic mechanisms including epigenetics and mitochondrial DNA.