Complex genetic determinants of hypertriglyceridemia

Hypertriglyceridemia (HTG) is a common dyslipidemia defined by elevated circulating blood triglyceride (TG) levels. Individuals with HTG are at risk for several health complications, which can include cardiovascular disease and in severe cases, acute pancreatitis. As the extreme manifestation of a physiological quantitative trait, HTG is influenced by genetic and non‐genetic factors. Genetic determinants include both rare single‐nucleotide variants (SNVs) and copy‐number variants (CNVs) in genes involved in TG metabolism, as well as common single‐nucleotide polymorphisms (SNPs) associated with TG levels. Despite understanding the complex genetic nature of HTG, the individual genetic influences on HTG have so far been examined only in a piecemeal manner. Here, we concurrently assessed rare SNVs and CNVs, and the accumulation of common SNPs in 104 Caucasian patients with mild‐to‐moderate HTG (defined as TG ≥3.3 and <10 mmol/L). As a reference “normolipidemic” group, we studied 503 healthy Caucasians from the open‐source 1000 Genomes Project. Patient DNA was subjected to next‐generation sequencing using our custom‐designed LipidSeq panel, which targets 73 genes and 185 SNPs associated with dyslipidemia and other metabolic disorders. We first screened for rare SNVs and CNVs in TG‐associated genes. For rare variants with likely large phenotypic effects, 1.0% of subjects had homozygous SNVs, and 12.5% had heterozygous SNVs or CNVs. In the normolipidemic controls, there were no homozygous SNVs, and 4.0% of subjects had heterozygous SNVs. We then assessed patients for an accumulation of common SNPs using a polygenic risk score. We identified an extreme score (defined as >90 th percentile of the normolipidemic population) in 27.9% of patients, compared to 9.5% of normolipidemic controls. Taken together, 41.3% of mild‐to‐moderate HTG patients had either a rare variant or high polygenic burden, compared to only 13.5% of controls. Compared to normolipidemic controls, mild‐to‐moderate HTG patients are 3.76‐fold (CI 95% 1.83–7.71; P<0.0001) more likely to carry a rare variant, 3.67‐fold (CI 95% 2.8–6.18; P<0.0001) more likely to have a high polygenic burden, and 4.51‐fold (CI 95% 2.83–7.19; P<0.0001) more likely to carry a TG‐related genetic factor, either a rare variant or polygenic burden of SNPs. We thus report the most in‐depth, systematic evaluation of genetic contributors of mild‐to‐moderate HTG to date. Next steps include: 1) identification of novel genetic determinants in patients negative for genetic determinants studied here; and 2) evaluations of genotype differences in clinical outcomes and intervention response. Support or Funding Information JSD is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Schulich School of Medicine and Dentistry (Cobban Student Award in Heart and Stroke Research, and Nellie L. Farthing Memorial Fellowship in the Medical Science). RAH is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics, and the Martha G. Blackburn Chair in Cardiovascular Research. RAH has received operating grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation, and Genome Canada. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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