Jacqueline S Dron1, Jian Wang2, Henian Cao2, Adam D McIntyre2, Michael A Iacocca1, Jyler R Menard3, Irina Movsesyan4, Mary J Malloy4, Clive R Pullinger4, John P Kane4, Robert A Hegele5. 1. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. 2. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. 3. Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario, Canada. 4. Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA. 5. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: hegele@robarts.ca.
Abstract
BACKGROUND: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete. OBJECTIVE: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and 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 polygenic risk score was used to assess the accumulation of common variants. RESULTS: As there were no significant differences in the prevalence of genetic determinants between 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 polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P < .0001) more likely to carry one of these types of genetic susceptibility compared with controls. CONCLUSIONS: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenic HTG, whereas only 1.1% had biallelic or homozygous monogenic HTG.
BACKGROUND:Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete. OBJECTIVE: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and 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 polygenic risk score was used to assess the accumulation of common variants. RESULTS: As there were no significant differences in the prevalence of genetic determinants between 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 polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P < .0001) more likely to carry one of these types of genetic susceptibility compared with controls. CONCLUSIONS: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenic HTG, whereas only 1.1% had biallelic or homozygous monogenic HTG.
Authors: Jaroslav A Hubacek; Dana Dlouha; Vera Adamkova; Lucie Schwarzova; Vera Lanska; Richard Ceska; Martin Satny; Michal Vrablik Journal: Mol Diagn Ther Date: 2019-08 Impact factor: 4.074
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Authors: Jacqueline S Dron; Jian Wang; Adam D McIntyre; Henian Cao; John F Robinson; P Barton Duell; Priya Manjoo; James Feng; Irina Movsesyan; Mary J Malloy; Clive R Pullinger; John P Kane; Robert A Hegele Journal: J Lipid Res Date: 2019-09-13 Impact factor: 5.922
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