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.
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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)