APOC3 Mutation, Serum Triglyceride Concentrations, and
Coronary Heart Disease
Michael Y. Tsai1*and Jose ´ M. Ordovas2
of the importance of lowering triglyceride concentra-
tions in conjunction with lowering LDL cholesterol
(LDL-C)3to achieve optimal reduction of the risk for
coronary heart disease (CHD). Historically, LDL-C
was the only target of pharmacologic therapy in CHD
lished in 1988 used only LDL-C cutoffs as guidelines.
Since then, there have been incremental changes with
regard to the importance of lowering triglyceride con-
centrations in addition to LDL-C. In ATP II, triglycer-
ide was still not recognized as an independent risk
factor, but the upper limit considered healthy for tri-
glycerides was lowered from 250 to 200 mg/dL. ATP II
ment of patients with increased triglycerides with ei-
ther nonpharmacologic or pharmacologic therapies.
maintains that lowering of LDL-C should be the pri-
mary target of therapy, it also recommended that
non-HDL cholesterol (LDL ? VLDL) be used as the
secondary target of therapy.
In part, the increased recognition of the impor-
tance of lowering triglycerides has been a result of in-
creased recognition of the metabolic syndrome (MS).
Although the diagnosis of MS is based on meeting at
least 3 of the 5 criteria (increased triglycerides, low
HDL-C, abdominal obesity, high blood pressure, and
increased fasting glucose concentrations), by far the
management of MS, by treating the underlying cause
through diet and exercise, through specific pharmaco-
logical therapies which lower triglycerides and hyper-
tension, or both.
The fact that increased serum triglyceride concen-
long been recognized. The debate has always focused
on whether it is an independent risk factor. Increased
has long been demonstrated that increased serum tri-
trations and decreased HDL and LDL particle sizes.
Moreover, treatment of patients with triglyceride-
lowering therapies such as fibric acid derivatives not
only lowers serum triglycerides but also increases
HDL-C concentrations. In particular, reducing serum
triglycerides is known to be associated with increased
HDL2, the larger HDL particles thought to be more
protective than the smaller HDL3particles. Similarly,
although increased triglycerides may not be the only
mechanism for decreased average particle size of LDL,
small, dense LDL particles, thereby further rendering
an individual’s lipid profile to be less atherogenic (1).
Early publications argued that the risk associated
on the HDL-C concentration and/or the qualitative
have demonstrated that increased triglycerides are an
independent risk factor. In particular, postprandial
studies have now demonstrated that increases in
cles are associated with increased atherogenicity, and
this effect is independent of the atherogenic effect of
triglycerides on LDL and HDL particles (2).
The recent study of Pollin et al. (3) has now fur-
ther confirmed the importance of triglycerides as an
independent risk factor for CHD. In an attempt to dis-
cover human mutations that are responsible for varia-
performed a high-fat feeding intervention and a
genome-wide association study (GWAS) in 809 Old
Order Amish individuals as part of the Heredity and
1Department of Laboratory Medicine & Pathology, University of Minnesota,
Center on Aging at Tufts University, Boston, MA.
* Address correspondence to this author at: 420 Delaware St. SE, Mayo Mail
Code 609, Minneapolis, MN 55455-0392. Fax 612-625-1121; e-mail
Received March 20, 2009; accepted April 30, 2009.
Previously published online at DOI: 10.1373/clinchem.2009.124669
3Nonstandard abbreviations: LDL-C, LDL cholesterol; CHD, coronary heart dis-
ease; ATP, Adult Treatment Panel; MS, metabolic syndrome; GWAS, genome-
wide association study; HAPI, Heredity and Phenotype Intervention Heart Study;
NHLBI, National Heart, Lung, and Blood Institute; GOLDN, Genetics of Lipid
Lowering Drugs and Diet Network; SNP, single nucleotide polymorphism;
VCAM-1, vascular cell adhesion molecule 1; ICAM-1, intercellular adhesion
molecule 1; CAC, coronary artery calcium; MESA, Multi-Ethnic Study of Athero-
sclerosis; CARDIA, Coronary Artery Risk Development In Young Adults; OR, odds
ratio; PPAR?, peroxisome proliferator-activated receptor ?; PROVE-IT, Prava-
statin or Atorvastatin Evaluation and Infection Therapy.
2Department of Agriculture, Human Nutrition Research
Clinical Chemistry 55:7
http://www.clinchem.org/cgi/doi/10.1373/clinchem.2009.124669The latest version is at
Papers in Press. Published May 14, 2009 as doi:10.1373/clinchem.2009.124669
Copyright (C) 2009 by The American Association for Clinical Chemistry
Phenotype Intervention Heart Study (HAPI) (4).
Along with the National Heart, Lung, and Blood Insti-
tute (NHLBI)-sponsored Genetics of Lipid Lowering
Drugs and Diet Network (GOLDN), in which 1200 in-
dividuals were subjected to a fat challenge meal, the
HAPI study is 1 of the 2 largest studies focusing on the
understanding of genetics of fasting and postprandial
triglyceride concentrations. The HAPI GWAS study
eventually led to the discovery of a single nucleotide
polymorphism (SNP), rs10892151, which is in linkage
disequilibrium with a loss-of-function mutation in
to the discovery of a C-to-T substitution on the 55th
nucleotide of the APOC3 gene that results in a prema-
ture stop-codon substituting for an arginine residue at
the 19th position of the protein. The premature stop
codon, when present in the APOC3 gene, results in the
carriers of this loss-of-function mutation have half the
apoC-III protein concentrations, and they have re-
duced fasting and postprandial triglyceride concentra-
tions. The finding that a loss-of-function mutation in
tration is in agreement with the well-known function
over, apoC-III may activate vascular endothelial cells
through increased expression of vascular cell adhesion
molecule 1 (VCAM-1) and intercellular adhesion
molecule 1 (ICAM-1).
Electron-beam computed tomography has in the
past decade been used to quantify coronary artery cal-
cium (CAC) in many multicenter studies, such as
and Coronary Artery Risk Development In Young
Adults (CARDIA). It is thought to be a very good
CAC score on the study participants, Pollin et al. (3)
showed that individuals who were carriers of the R19X
mutation in the APOC3 gene were significantly less
likely to have any CAC [odds ratio (OR) 0.35, P ?
lower CAC scores compared to the reference ranges
established in the MESA cohort (OR 0.40,P ? 0.01 for
carriers to have CAC ?100 Agatston units).
the fasting and postprandial triglyceride concentra-
tions and is associated with lowered risk of CHD, im-
plies that a lifelong reduction in triglycerides reduces
an individual’s risk of CHD. The study is interesting in
tion of 57 mg/dL in participants who do not carry the
R19X mutation is already very low. For carriers of the
mutation, the mean triglyceride concentration was
only 31 mg/dL; in contrast, the healthy triglyceride
concentration in ATPIII is defined as ?150 mg/dL.
but also with increased HDL-C and lowered LDL-C.
Whereas lowering triglycerides from relatively high
concentrations (?150 mg/dL) is known to be associ-
ated with increased concentrations of HDL-C, not
much is known about whether lowering of triglyceride
to ?100 mg/dL is always associated with increased
erides, such as niacin, fish oil, and fibrates, are also
known to bind to peroxisome proliferator-activated
receptor ? (PPAR?) receptors, leading to the down-
regulation of APOC3. In GOLDN, SNPs in APOC3
lowering of triglycerides by fenofibrate (4). Further
studies are needed to elucidate whether downregula-
tion of APOC3 expression is linked to upregulation of
genes involved in HDL metabolism.
The results from the study Pravastatin or Atorva-
statin Evaluation and Infection Therapy (PROVE-IT)
demonstrated that aggressive lowering of LDL to 62
mg/dL, compared with lowering LDL to 95 mg/dL, re-
sulted in reduction of a recurring event or death from
relatively high percentage of a recurring event at an
LDL concentration of 62 mg/dL could mean other
therapeutic targets used in combination with LDL-C
reduction may be of further benefit in secondary
If the results from the Lancaster Amish can be ex-
trapolated to the general population, the question
arises, could secondary prevention of CHD benefit
from an aggressive reduction of LDL-C (to 60 mg/dL)
and reduction of triglycerides to below that of the cur-
rent target of 150 mg/dL? In view of the interesting
finding from the HAPI study, more research on the
reduction of triglycerides, either singly or in combina-
tion with reduction of LDL-C, may contribute to im-
proved clinical outcome in both primary and second-
ary prevention of CHD in the future (3).
the intellectual content of this paper and have met the following 3 re-
quirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures of Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the
of data, or preparation or approval of manuscript.
Clinical Chemistry 55:7 (2009)
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