A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia

Human Molecular Genetics, Nov 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.

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A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia

Robert A. Hegele 2 Matthew R. Ban 2 Neil Hsueh 2 Brooke A. Kennedy 2 Henian Cao 2 Guang Yong Zou 1 Sonia Anand 0 Salim Yusuf 0 Murray W. Huff 2 Jian Wang 2 0 Population Health Research Institute, McMaster University, Hamilton Health Sciences , Hamilton, ON , Canada L8L 2X2 1 Robarts Clinical Trials, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON, Canada , N6A 5K8 2 Vascular Biology Research Group 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 underlieto an apparently even greater degreesusceptibility 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. - INTRODUCTION Genome-wide association studies (GWAS) have generated excitement due to the new possibilities of better understanding the genetic architecture of complex diseases (1 4), such as hyperlipidemia (5). One concern raised about GWAS in general is that the magnitude of genetic associations is relatively modest in scale, and thus possibly of limited interest or importance biologically or medically (1). For the quantitative trait of plasma lipoproteins, many familiar and new loci have emerged from recent GWAS (6 14), however, the magnitude of the genetic effects in normolipidemic samples were very modestto an extent that many medical practitioners might question their relevance (5). One piece of evidence that would enhance the perception of the potential clinical value of these single nucleotide polymorphisms (SNPs) would be demonstration of their association with disorders that clinicians routinely diagnosis and manage. The Fredrickson or World Health Organization International Classification of Diseases ontology of primary hyper lipoproteinemia (HLP) types have been used as clinical and biochemical shorthand by generations of physicians (15). Most Fredrickson types (Supplementary Material, Table S1), specifically HLP types 1, 2B, 3, 4 and 5 (MIM 238600, 144250, 107741, 144600 and 144650, respectively) feature elevated plasma triglyceride (TG) concentration as part of their definition (5,15 17). The exception is familial hypercholesterolemia [FH; HLP type 2A (MIM 143890)], which is often due to heterozygous mutations in LDLR encoding the low-density lipoprotein (LDL) receptor (18). In rare instances, single gene mutations have been found in hyperchylomicronemic patients with HLP type 1, particularly homozygous mutations either in LPL, which encodes lipoprotein lipase (LPL), or in APOC2, which encodes its cofactor apolipoprotein (apo) C-II (19). Thus, the genetic bases of HLP types 1 and 2A have largely been elucidated. Furthermore, 10% of adults with HLP type 5 have a heterozygous loss-of-function mutation in one of several genes encoding proteins involved in TG metabolism (20). However, most cases of HLP types 2B, 3, 4 and 5 are incompletely characterized at the molecular genetic level, although HLP type 3 requires homozygosity for the APOE E2 isoform as a necessary, but not sufficient, genetic condition for expression of the phenotype (5). We previously found that: (1) APOA5 variants -1131T.C and p.S19W are frequently present in and strongly associated with Fredrickson types 2B, 3, 4 and 5 and also with hypertriglyceridemia (HTG) in general lipid clinic patients (21); and (2) several common SNPs, found to be contributors to subtle variation in TG concentration in normolipidemic controls, including SNPs in APOA5, APOE, TRIB1, TBL2, GCKR and GALNT2 were significant determinants of HLP type 5 (22). On the basis of these results, we hypothesized that c (...truncated)


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Robert A. Hegele, Matthew R. Ban, Neil Hsueh, Brooke A. Kennedy, Henian Cao, Guang Yong Zou, Sonia Anand, Salim Yusuf, Murray W. Huff, Jian Wang. A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia, Human Molecular Genetics, 2009, pp. 4189-4194, 18/21, DOI: 10.1093/hmg/ddp361