title: An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.
abstract: OBJECTIVE
  Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.
  
  
  RESULTS
  First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.
  
  
  CONCLUSIONS
  HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
authors: Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, Canada.
authors: Christopher T
authors: CT
authors: Johansen
authors: Jian
authors: J
authors: Wang
authors: Matthew B
authors: MB
authors: Lanktree
authors: Adam D
authors: AD
authors: McIntyre
authors: Matthew R
authors: MR
authors: Ban
authors: Rebecca A
authors: RA
authors: Martins
authors: Brooke A
authors: BA
authors: Kennedy
authors: Reina G
authors: RG
authors: Hassell
authors: Maartje E
authors: ME
authors: Visser
authors: Stephen M
authors: SM
authors: Schwartz
authors: Benjamin F
authors: BF
authors: Voight
authors: Roberto
authors: R
authors: Elosua
authors: Veikko
authors: V
authors: Salomaa
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Geesje M
authors: GM
authors: Dallinga-Thie
authors: Sonia S
authors: SS
authors: Anand
authors: Salim
authors: S
authors: Yusuf
authors: Murray W
authors: MW
authors: Huff
authors: Sekar
authors: S
authors: Kathiresan
authors: Henian
authors: H
authors: Cao
authors: Robert A
authors: RA
authors: Hegele
references: JAMA. 2007 Jul 18;298(3):299-308
references: 17635890
references: J Clin Invest. 1987 Dec;80(6):1597-606
references: 3680515
references: JAMA. 2008 Nov 12;300(18):2142-52
references: 19001625
references: J Lipid Res. 2011 Feb;52(2):189-206
references: 21041806
references: J Biol Chem. 1990 Apr 5;265(10):5910-6
references: 1969408
references: Hum Mol Genet. 2008 Sep 15;17(18):2894-9
references: 18596051
references: J Cardiovasc Risk. 1996 Apr;3(2):213-9
references: 8836866
references: Nature. 2010 Aug 5;466(7307):707-13
references: 20686565
references: CMAJ. 2007 Apr 10;176(8):1113-20
references: 17420495
references: PLoS Genet. 2006 Dec;2(12):e190
references: 17194218
references: Nat Genet. 2010 Aug;42(8):684-7
references: 20657596
references: Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2450-5
references: 17717288
references: Lancet. 2000 Jul 22;356(9226):279-84
references: 11071182
references: Lipids Health Dis. 2007 Sep 20;6:23
references: 17883852
references: Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):956-62
references: 19304573
references: Nat Genet. 2009 Mar;41(3):334-41
references: 19198609
references: Lancet. 2010 May 8;375(9726):1634-9
references: 20452521
references: Mol Cell Biochem. 2009 Jun;326(1-2):35-43
references: 19130180
references: JAMA. 2007 Jul 18;298(3):309-16
references: 17635891
references: Nat Genet. 2007 Dec;39(12):1483-7
references: 17994020
references: Nat Clin Pract Cardiovasc Med. 2008 Nov;5(11):730-7
references: 18779834
references: Am J Cardiol. 2000 Nov 1;86(9):943-9
references: 11053704
references: J Clin Invest. 1960 Dec;39:1777-90
references: 13712364
references: Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):411-7
references: 15591215
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Nat Rev Genet. 2009 Feb;10(2):109-21
references: 19139765
references: Hum Mol Genet. 2009 Nov 1;18(21):4189-94
references: 19656773
references: Nat Genet. 2006 Aug;38(8):904-9
references: 16862161