Numerous
single nucleotide polymorphisms (
SNPs) have been found in recent genome wide
association studies (GWAS) to be associated with subtle plasma
triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of
lipoprotein metabolism--'hyperlipoproteinemia' (HLP)--it remains largely unresolved whether any of these
SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP
phenotypes. To address this question, we evaluated 28 TG-associated
SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson
phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several
SNPs associated with TG in normolipidemic samples, including
APOA5 p.S19W and -1131T>C,
TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094,
GALNT2 rs4846914 and
ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are
polygenic traits; (ii) these Fredrickson HLP types share numerous
genetic determinants among themselves; and (iii)
genetic determinants of modest TG variation in normolipidemic population samples also underlie--to an apparently even greater degree--susceptibility to these rare HLP
phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually
complex traits sharing among them several common
genetic determinants seen in GWAS of normolipidemic population samples.
