Human Molecular Genetics Advance Access originally published online on August 5, 2009
Human Molecular Genetics 2009 18(21):4189-4194; doi:10.1093/hmg/ddp361
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A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia
1 Vascular Biology Research Group 2 Robarts Clinical Trials, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A 5K8 3 Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, ON, Canada L8L 2X2
* To whom correspondence should be addressed at: Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, #4288A-100 Perth Drive, London, ON, Canada N6A 5K8. Tel: +1 5199315271; Fax: +1 5199315218; Email: hegele{at}robarts.ca
Received April 18, 2009; Revised July 19, 2009; Accepted July 27, 2009
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.