Severe hypertriglyceridemia is primarily polygenic

Background Hypertriglyceridemia(HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinantsof HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenicand polygenic, is thus incomplete. Objective The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinantsand molecular contributors. Methods We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL , APOC2 , GPIHBP1, APOA5 , and LMF1 genes were screened for rare variants, and a polygenicrisk score was used to assess the accumulation of common variants. Results As there were no significant differences in the prevalence of genetic determinantsbetween cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenicrisk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26–7.82]; P Conclusions We report the most in-depth, systematic evaluation of genetic determinantsof severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenicrisk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenicHTG, whereas only 1.1% had biallelic or homozygous monogenicHTG.