Journal
FRONTIERS IN ENDOCRINOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2020.00455
Keywords
autosomal recessive; complex trait; familial chylomicronemia syndrome (FCS); multifactoriel chylomicronemia (MCM); polygenic score; triglyceride
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Funding
- Canadian Institutes of Health Research
- Jacob J. Wolfe Distinguished Medical Research Chair
- Edith Schulich Vinet Research Chair in Human Genetics
- Martha G. Blackburn Chair in Cardiovascular Research
- Heart and Stroke Foundation of Canada [G-18-0022147]
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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 inLPL, APOC2, APOA5, LMF1, andGPIHBP1genes. In contrast, susceptibility to multifactorial chylomicronemia (MCM), which has an estimated prevalence of similar to 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.
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