TY - JOUR
T1 - An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia
AU - Johansen, Christopher T.
AU - Wang, Jian
AU - Lanktree, Matthew B.
AU - McIntyre, Adam D.
AU - Ban, Matthew R.
AU - Martins, Rebecca A.
AU - Kennedy, Brooke A.
AU - Hassell, Reina G.
AU - Visser, Maartje E.
AU - Schwartz, Stephen M.
AU - Voight, Benjamin F.
AU - Elosua, Roberto
AU - Salomaa, Veikko
AU - O'Donnell, Christopher J.
AU - Dallinga-Thie, Geesje M.
AU - Anand, Sonia S.
AU - Yusuf, Salim
AU - Huff, Murray W.
AU - Kathiresan, Sekar
AU - Cao, Henian
AU - Hegele, Robert A.
PY - 2011
Y1 - 2011
N2 - 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. 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. HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants
AB - 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. 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. HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants
U2 - https://doi.org/10.1161/ATVBAHA.111.226365
DO - https://doi.org/10.1161/ATVBAHA.111.226365
M3 - Article
C2 - 21597005
SN - 1079-5642
VL - 31
SP - 1916
EP - 1926
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 8
ER -