Genetics of Triglycerides and the Risk of Atherosclerosis
Curr Atheroscler Rep
Genetics of Triglycerides and the Risk of Atherosclerosis
Jacqueline S. Dron 0 1 2
Robert A. Hegele 0 1 2
0 Department of Medicine, Schulich School of Medicine and Dentistry, Western University , London, ON , Canada
1 Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University , 4288A-1151 Richmond Street North, London, ON N6A 5B7 , Canada
2 Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University , London, ON , Canada
Purpose of Review Plasma triglycerides are routinely measured with a lipid profile, and elevated plasma triglycerides are commonly encountered in the clinic. The confounded nature of this trait, which is correlated with numerous other metabolic perturbations, including depressed high-density lipoprotein cholesterol (HDL-C), has thwarted efforts to directly implicate triglycerides as causal in atherogenesis. Human genetic approaches involving large-scale populations and high-throughput genomic assessment under a Mendelian randomization framework have undertaken to sort out questions of causality. Recent Findings We review recent large-scale meta-analyses of cohorts and population-based sequencing studies designed to address whether common and rare variants in genes whose products are determinants of plasma triglycerides are also associated with clinical cardiovascular endpoints. The studied loci include genes encoding lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and angiopoietin-like proteins 3 and 4, and common polymorphisms identified in genome-wide association studies. Summary Triglyceride-raising variant alleles of these genes showed generally strong associations with clinical cardiovascular endpoints. However, in most cases, a second lipid disturbance-usually depressed HDL-C-was concurrently associated. While the findings collectively shift our understanding towards a potential causal role for triglycerides, we still cannot rule out the possibilities that triglycerides are a component of a joint phenotype with low HDL-C or that they are but markers of deeper causal metabolic disturbances that are not routinely measured in epidemiological-scale genetic studies.
Polygenic; Monogenic; Complex trait; DNA sequencing; Genetic association; Mendelian randomization
An enduring controversy in the lipoprotein field has centered
on the causal role of elevated plasma triglyceride (TG) levels
in atherosclerotic cardiovascular disease (CVD) . Are
TGrich lipoproteins the smoking gun or an innocent bystander in
atherogenesis? TG undoubtedly keeps bad company: Elevated
TG is a central feature of the atherogenic dyslipidemia
complex , which encompasses depressed high-density
lipoprotein (HDL) cholesterol (C) and elevated small dense
lowdensity lipoprotein (LDL) particles, both of which are
themselves plausibly causally related to CVD. High TG is further
correlated with such potentially causative non-lipoprotein
parameters as abdominal obesity, insulin resistance,
hypertension, hepatosteatosis, low-grade inflammation, a
procoagulant state, and perturbed endothelial function [3 ]. It
has been notoriously difficult to disentangle elevated TG
levels from this complex network of confounding variables
even in reductionist experimental systems based upon cellular
mechanisms, epidemiological data, or clinical trials . More
recently, human genetic researchers have offered their tools to
help clarify the controversy by attempting to isolate the effect
of TG-rich lipoproteins on CVD risk . But, while the
picture is somewhat less hazy in the era of Mendelian
randomization, we submit that definitive evidence for a direct causal
role of TG in CVD still eludes our grasp. Not ruled out are the
possibilities that TG forms a conjoint causal phenotype with
low HDL-C or is merely the tip of an iceberg of unmeasured
causal agents that are acting directly at the site of vascular
Hypertriglyceridemia is a commonly ascertained clinical
phenotype. A proposed simplified definition of
hypertriglyceridemia is based on somewhat arbitrary but clinically
useful consensus thresholds . A normal TG level is
<2 mmol/L (<175 mg/dL); mild-to-moderate elevation is
between 2 and 9.9 mmol/L (175 to 885 mg/dL), while a
severe elevation is >10 mmol/L (>885 mg/dL) . TG level
measured statically, either fasting or especially in the
nonfasting state, is an integrated marker for a large number of
associated lipoprotein disturbances . For example, TG is
ferried within TG-rich lipoproteins, which in the fasting
state are mainly very-low-density lipoproteins (VLDL) .
In the non-fasting state, chylomicrons are transiently
elevated and contribute in varying degrees to elevated TG levels
. Furthermore, the TG contained within remnants of
chylomicrons and VLDL, and also intermediate-density
lipoproteins (IDL), contributes to the integrated total TG level.
In addition, the cholesterol carried within non-HDL
particles, which comprise all the above atherogenic lipoproteins
plus Lp(a), and defined as total cholesterol minus HDL-C,
is correlated with TG levels . Apolipoprotein (apo) B
levels are also elevated when TG is elevated . In
particular, in the post-prandial state, the intestinal form of apo B
(B-48) is increased when chylomicrons and their remnants
are increased , while the hepatic form of apo B (B-100)
that characterizes VLDL particles fluctuates less in response
Prevalence of Hypertriglyceridemia
The distribution of fasting TG levels in North America
permits approximation of patient numbers with
hypertriglyceridemia according to the clinical cut-points proposed
above. From the Canadian Heart Health Surveys, the mean
overall TG level in adults was 1.55 mmol/L . A level of
2.0 mmol/L represents about the top 25th percentile, while
a level of 3.3 mmol/L represents the top 5th percentile, and
a level exceeding 10 mmol/L is seen in about one in 600
individuals [10, 11]. Assuming similar distributions of this
trait in contemporary westernized societies,
mild-tomoderate hypertriglyceridemia could be as prevalent as
one in four people at the low-end of the definition. The
traditional cut-point of the top 5th percentile that was used
to define “hyperlipoproteinemia type 4” is 3.3 mmol/L.
Severe hypertriglyceridemia >10 mmol/L has a population
frequency somewhat lower than heterozygous familial
Hypertriglyceridemia and Atherosclerosis
Using these definitions, the assimilated understanding of
biochemistry is that for individuals with mild-to-moderate
hypertriglyceridemia, the predominant lipoprotein disturbance
is VLDL, their remnants, and IDL . Chylomicrons can
also be present in this TG range, but the preponderance of
TG-rich lipoprotein species is of hepatic origin. These
particles are atherogenic, although it is not their TG content that
contributes to growth of the atherosclerotic plaque—the
cholesterol carried within these TG-rich lipoproteins finds itself at
the scene of the crime, within arterial wall foam cells and the
evolving plaque . This is a modernization of the seminal
Zilversmit hypothesis, an early and prescient articulation of
the atherogenic role of TG-rich lipoproteins . According
to this model, TG-rich lipoproteins are metabolically
independent of LDL-C in atherogenesis and, in fact, act additively to
further increase risk.
From the population distribution of TG levels, most
patients with “hypertriglyceridemia” fall within the
mild-tomoderate range, and thus any potential atherosclerosis risk is
tied to primarily smaller TG-rich particles such as VLDL and
IDL. At higher strata of TG levels, which become rarer as one
ascends the Gaussian extreme rightwards, larger particles such
as chylomicrons and their remnants begin to predominate. In
this important but much less commonly encountered
subgroup, it has been more or less axiomatic that chylomicrons
are too large to penetrate the arterial wall [4, 16]. However,
chylomicron remnants, especially on the smaller end of the
spectrum, may contribute to atherogenesis .
Thus, among the diverse range of patients with severe
hypertriglyceridemia, those with monogenic impairment of
l i p o l y s i s ( di s c us s e d b e l ow ) w ou l d h a v e pr i m a r i l y
chylomicronemia, with minimal to no increase in remnants,
mainly because the lipolytic deficiency prevents their
generation. Atherosclerosis risk is relatively low in this situation. In
contrast, among individuals with the same degree of TG
elevation due to varied polygenic plus secondary factors, the
spectrum of TG-rich particles is much more diffuse and
includes many remnant particles, since lipolysis is not
completel y i m p a i r e d [ 1 7 ] . H e r e , o n e c o u l d p o s t u l a t e t h a t
atherosclerosis risk is increased, due to the relative abundance
of atherosclerosis-related remnants.
Role of Genetics in Hypertriglyceridemia
Monogenic and polygenic factors contribute to both
mild-tomoderate and severe hypertriglyceridemia; the relative burden
of these factors together with secondary non-genetic factors
can determine the severity of the phenotype [6, 18]. Elevated
TG can result from either reduced catabolism or
overproduction of TG-rich lipoproteins, each of which arises in turn
depending on underlying genetic variation. The specific
combination of qualitatively and quantitatively abnormal TG-rich
lipoproteins distinguishes mild-to-moderate from severe
hypertriglyceridemia [6, 18].
As mentioned, elevated VLDL is the predominant
lipoprotein disturbance in individuals with TG levels between 2
and 9.9 mmol/L, while elevated chylomicrons start to
contribute to TG >10 mmol/L . Thus, factors related to
biosynthesis, secretion, and catabolism of VLDL would be
relatively more important in susceptibility to mild-to-moderate
hypertriglyceridemia. In contrast, factors related to
biosynthesis, secretion, and catabolism of chylomicrons are
relatively more important in susceptibility to severe
hypertriglyceridemia, although there is considerable overlap with
factors that modulate VLDL levels, particularly on the
catabolic side . A corollary of this model is that individuals
with polygenic severe hypertriglyceridemia have a greater
burden of genetic susceptibility components than
individuals with polygenic mild-to-moderate hypertriglyceridemia.
Furthermore, secondary factors may be quantitatively and
qualitatively more extreme in patients with severe compared
to mild-to-moderate hypertriglyceridemia. Finally, control
of secondary factors and medications might be relatively
more efficacious in normalizing TG levels in individuals
with polygenic mild-to-moderate hypertriglyceridemia than
in those with severe hypertriglyceridemia. Both
mild-tomoderate and severe hypertriglyceridemia are primarily
polygenic traits, with the exception of the small subgroup
with monogenic chylomicronemia due to deficiency of
lipoprotein lipase (LPL) and related factors .
Genetics of Severe Hypertriglyceridemia
As discussed above, severe hypertriglyceridemia is basically
synonymous with “chylomicronemia” [13, 19]. Given their
surface area-to-volume ratios, chylomicrons are essentially
the only particle physiologically able to produce such extreme
hypertriglyceridemia [13, 19]. If there is sufficient lipolytic
capacity to generate chylomicron remnant particles, VLDL
can be produced and VLDL remnants may also be elevated.
But, this is not the case in monogenic disorders that shut down
lipolysis. Thus, monogenic chylomicronemia is ultra-rare and
is associated with a narrowly defined increase in chylomicrons
and increased pancreatitis risk. In contrast, polygenic
chylomicronemia is much more common and is associated
with increased chylomicrons, VLDL, and remnants of both
in addition to IDL. HDL-C is depressed in both circumstances
[13, 19], although CVD risk is increased mainly in polygenic
Rare Variants in Monogenic Chylomicronemia
Monogenic chylomicronemia is extremely rare in the
population, appearing in one in 100,000–1,000,000 individuals [13,
19]. Clinical diagnosis can occur between infancy and early
adulthood [13, 19]. With excess accumulation of
chylomicrons, severe hypertriglyceridemia may be detected soon after
birth. Chylomicronemia, but not elevated VLDL, produces
plasma with a turbid, milk, or “lipemic” appearance. The main
risk to health of elevated chylomicrons per se is not vascular
disease, but rather acute pancreatitis, which can be
life-threatening. Monogenic chylomicronemia patients also show, from
a young age, failure to thrive and exhibit clinical
manifestations including eruptive xanthomas, lipemia retinalis,
hepatosplenomegaly, chronic abdominal pain, nausea, and
vomiting [13, 19].
Monogenic chylomicronemia follows autosomal recessive
inheritance of rare bi-allelic variants—either homozygous or
compound heterozygous—disrupting one of five canonical
genes involved in TG metabolism. These genes are as follows,
i n d e s c e n d i n g o r d e r o f p r e v a l e n c e i n m o n o g e n i c
chylomicronemia: LPL encoding LPL, GPIHBP1 encoding
glycosylphosphatidylinositol-anchored HDL-binding protein
1 (GPIHBP1), APOC2 encoding apo C-II, APOA5 encoding
apo A-V, and LMF1 encoding lipase maturation factor 1
(LMF1) . Large-effect loss-of-function disruptions
affecting these gene products cripple lipolysis, and in particular,
catabolism of chylomicron particles. In up to 90% of
monogenic chylomicronemia cases, LPL is the most commonly
disrupted gene, with bi-allelic loss-of-function variants .
Under normal physiological conditions, LPL is anchored to
the luminal surface of vascular networks traversing muscle
and adipose tissue, where it comes into contact with
circulating lipoproteins and helps to maintain TG levels . LPL
also interacts at various points in its life cycle with the
products of the other minor genes that cause monogenic
In addition to the direct loss of function of the LPL
gene, bi-allelic large-effect disruptions to the other four
canonical genes also prevent the hydrolyzing action of
LPL and result in the elevation of TG present in
monogenic chylomicronemia. LMF1 acts as a chaperone to
assist in the maturation of LPL, while GPIHBP1 is
responsible for transporting and anchoring mature LPL to the
vascular lumen surface, in which the lipase becomes fully
activated . Without the proper function of these two
proteins, through the mechanisms previously described,
reduced chylomicron catabolism results in severe
hypertriglyceridemia. Apo C-II and apo A-V are present
on chylomicrons and are necessary for the interaction
between these TG-rich lipoproteins and LPL. Apo C-II is
absolutely necessary for the particle’s interaction with
LPL and the initiation of hydrolysis, while apo A-V
interacts with GPIHBP1 to indirectly enhance the function of
LPL, although its exact mechanism of action is still not
fully understood. Similar to disruptions of LMF1 and
GPHIBP1, rare bi-allelic variants in APOC2 and APOA5
diminish the LPL-based catabolism of chylomicrons.
Interestingly, autoantibodies can arise against either LPL
 or GPIHBP1 [23 ], on the background of normal
gene structure, which also can lead to chylomicronemia.
To date, ~100 families worldwide have been reported with
monogenic chylomicronemia due to bi-allelic
loss-offunction variants in these four crucial genes; any
relationship with atherosclerosis is not definitive across these
very rare families.
Rare Variants in Polygenic Chylomicronemia
While monogenic chylomicronemia is extremely rare, it is
much more likely to observe rare heterozygous variants in
these genes in adult patients with severe hypertriglyceridemia.
Rare heterozygous loss-of-function variants are an important
genetic contributor to polygenic chylomicronemia. Most
healthcare providers seem to recall the monogenic basis of
severe hypertriglyceridemia but often retain the perception
that every patient encountered with severe
hypertriglyceridemia and pancreatitis must have one of these ultra-rare
deficiencies. This perception was perpetuated because of the
unavailability of testing for absent post-heparin lipase activity
or mutations in causative genes, both of which could
definitively rule out these monogenic disorders.
Although the degree of TG elevation is comparably severe
in monogenic and polygenic chylomicronemia, there are key
c l i n i c a l a n d b i o c h e m i c a l d i f f e r e n c e s . P o l y g e n i c
chylomicronemia is more often diagnosed in adulthood and
is associated with a broader range of deleterious lipoprotein
abnormalities (including elevated remnants and IDL), lower
pancreatitis risk, and likely increased CVD risk [13, 19].
These clinical differences may be due to only partially
disrupted lipolysis from heterozygosity for mutations in
LPL, GPIHBP1, APOC2, APOA5, and LMF1 [24, 25].
However, many heterozygotes for such dysfunctional
mutations have a normal lipid profile [24, 25]; a secondary factor is
required to force expression of the severe phenotype.
Not only are polygenic chylomicronemia patients more
likely to carry disruptive heterozygous variants in these
canonical genes, but they are also more likely to carry
rare variants in non-canonical genes involved in TG
metabolism [25–27]. For instance, CREB3L3 encoding the
transcription factor cyclic AMP-responsive
element-binding protein H is an example of a gene that harbors rare
large-effect determinants of human TG levels discovered
through the use of animal models . In addition, GCKR
encoding glucokinase regulatory protein is an example of
a gene that harbors rare large-effect determinants of
human TG levels that was initially identified as a common
locus for TG levels through large-scale genome-wide
association studies (GWAS) . Therefore, the list of rare
heterozygous large-effect variants underlying severe
hypertriglyceridemia is extensive.
Common Small-Effect Variants in Polygenic
In addition to the accumulation of rare heterozygous variants
within TG-related genes, another defining genetic feature of
polygenic chylomicronemia is the increased burden of
common single nucleotide polymorphisms (SNPs) associated with
TG levels [30, 31]. These variants are common in the general
population and have small phenotypic effects, with mild
influences on TG levels. GWAS have identified 185 SNP loci
associated with circulating levels of lipids and lipoproteins; of
these SNPs, >30 have a primary association with TG .
Essentially all reported SNPs also have associations with
multiple lipoprotein traits, typically a reciprocal relationship
between TG and HDL-C. This biological reality makes it
challenging to isolate genetic influences on TG only and to draw
conclusions when these markers are used as instruments in the
Mendelian randomization studies discussed below; it is
difficult to dissociate the effect of elevated TG from concurrently
depressed HDL-C in gauging causality in atherosclerosis.
Several GWAS-identified SNPs are within loci already
known from classical biochemistry and cell biology to be
involved in TG metabolism, including LPL and APOA5
. Others were found in close proximity to genes that at
the time were not relevant but were found to be in subsequent
studies (i.e. GCKR), and many SNPs identified are intergenic
and may be important in regulatory processes . When
c o n s i d e r i n g T G - a s s o c i a t e d S N P s i n p o l y g e n i c
chylomicronemia patients compared to normolipidemic
individuals, a distinct increase in SNP accumulation in these
patients has been observed and quantified using polygenic risk
scores [25, 26]. Individually, each SNP has a slight influence
on TG levels; however, when a substantial burden of multiple
small-effect variants is present in an individual, it can
synergistically contribute towards an overall large phenotypic
effect. There are some recent examples of patients with
chylomicronemia who also had a high polygenic risk score
for TG [34, 35].
The contributory effects coming from rare heterozygous
variants with larger phenotypic influences, and the excessive
accumulation of common variants scattered throughout the
genome, all work in concert to pro duce polygenic
chylomicronemia, including severe hypertriglyceridemia due
to perturbations of chylomicrons, as well as other TG-rich
Genetics of Mild-to-Moderate Hypertriglyceridemia
The same general architecture of genetic susceptibility is seen
in patients with mild-to-moderate hypertriglyceridemia as in
patients with severe hypertriglyceridemia . Specifically,
the pool of patients with the milder hypertriglyceridemia
phenotype formerly known as Fredrickson type 4 (here
considered equivalent to “mild-to-moderate hypertriglyceridemia”)
also shows enrichment of rare heterozygous large-effect
variants and common small-effect SNP loci bundled into a
polygenic risk score, although not as extreme as Fredrickson type 5
(here considered equivalent to “severe hypertriglyceridemia”)
. These findings need to be replicated but suggest that
hypertriglyceridemia along its spectrum of severity is a
polygenic trait with similar genetic susceptibility components,
both common and rare. Furthermore, final clinical expression
of the phenotype—i.e. mild-to-moderate or severe—is related
to qualitative and quantitative differences in the precise
mixture of susceptibility variants in an individual’s genome. A
higher burden of both rare and common TG-raising variants
would be associated with a more extreme phenotype, such as
polygenic chylomicronemia. Importantly, secondary
nongenetic factors, including diet, alcohol intake, obesity,
diabetes control, liver, and renal disease, are at least as important as
genetic susceptibility in determining the final quantitative TG
Genetics of Low Triglyceride Levels: Familial
F o r c o m p l e t e n e s s , w e b r i e f l y m e n t i o n f a m i l i a l
hypotriglyceridemia, defined as very low or absent TG levels
due to various genetic factors. The interested reader is referred to
a more thorough review of this topic . As with familial
hypertriglyceridemia, genetic determinants of hypotriglyceridemia
include ultra-rare monogenic syndromic disorders that are
associated with a range of other lipoprotein, biochemical and clinical
abnormalities, such as abetalipoproteinemia and homozygous
hypobetalipoproteinemia, which result, respectively, from
biallelic mutations in MTTP and APOB genes encoding,
respectively, microsomal TG transfer protein, and apo B . Other
informative conditions, mainly characterized by multiple biochemical
disturbances including very low TG levels, include deficiencies of
apo C-III and angiopoietin-like protein 3, which result from
biallelic mutations in APOC3 and ANGPTL3 genes, respectively
[37, 38]. Heterozygotes for MTTP loss-of-function variants have
no obvious clinical or biochemical phenotypes, while
heterozygotes for the other three deficiencies have depressed levels of
TG and other lipoprotein traits, including LDL-C. Observational
studies in these families suggest reduced risk of atherosclerosis,
although these findings are somewhat limited by incomplete
ascertainment and relatively small sample sizes.
Genetic Evidence for Association
Between Triglycerides and Atherosclerosis
The genetic evidence linking TG levels and atherosclerosis
risk has been reviewed recently, from the perspective of
LPL biology [39 ]. Both common and rare genetic variants
that are associated with plasma TG levels in populations
can be tested for their association with atherosclerosis
endpoints, such as coronary heart disease (CHD) using
metaanalyses of several cohorts within the Mendelian
randomization framework . Under this construct, if a genetic
variant associated with TG is also associated with the
clinical endpoint, the conventional interpretation is that TG
itself is directly associated with the outcome. However, in
the case of TG levels, almost all significantly associated
genetic variants—both common and rare, both large-effect
and small-effect—are concurrently associated with at least
one other lipid trait, usually reduced HDL-C (see Table 1).
In the recent reporting of these studies, investigators tend
to emphasize the directionally consistent genetic
association between elevated TG and elevated clinical endpoints.
However, virtually, none of these variants individually or
in combination is associated with TG in a completely
So, even with this mountain of evidence purporting to
show a causal relationship of TG with atherosclerosis, the
possible involvement of correlated trait, usually low HDL-C,
cannot be ruled out. While not explicitly stated, emphasis on
TG may be due to a systematic unconscious bias that has
arisen against HDL over the past decade for various reasons
[51, 52]. HDL has fallen upon hard times in terms of
consideration of its direct role in atherosclerosis risk; recent studies
of variants that jointly influence TG and HDL-C tend to focus
on the TG component.
Common Variants Associated with Triglycerides
and Atherosclerosis Risk
For instance, common APOA5 variants were associated with
both higher TG and increased CHD risk but were concurrently
associated with lower HDL-C levels . Furthermore, the
common LPL p.S474X (also known as p.S447X)
gain-ofRare inactivating variants
Any of 10 rare variants
Any of four rare variants
Any of seven rare variants
Selected genetic factors and their association between lipid and lipoprotein levels, and coronary artery disease
effect on CAD?
CAD (TG predictor)
CAD (HDL-C predictor)
CAD (LDL-C predictor)
0.36β (0.057 SEM) 1 × 10−9
−0.04β (0.037 SEM) 0.35
0.38β (0.034 SEM) 2 × 10−22
5 × 10−7
Table 1 (continued)
G215E (also known as G188E;
N318S (also known as N291S; rs268)
S474X (also known as S447X; rs328)
Four alleles (S447X, N291S, D9N, G188E)
Five alleles (S447X, N291S, D9N, G188E)
Six alleles (S447X, N291S, D9N, G188E)
effect on CAD?
CAD coronary artery disease, CVD cardiovascular disease, GWAS genome-wide association study, HDL-C high-density lipoprotein cholesterol, HR
hazard ratio, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction, NA not applicable (for CAD endpoint, this indicates that the full lipid
profile was not available), NS not significant, OR odds ratio, SD standard deviation, SEM standard error, SNP single nucleotide polymorphism, TC total
cholesterol, TG triglycerides
*P values for these metrics were not available in text by Thomsen et al. 
**Percent change calculations based on the median lipid levels for non-carrier and carrier groups, provided by Do et al. .
function variant has long been associated with reduced TG,
increased HDL-C, and reduced CHD risk in small cohorts
, while the relatively common LPL p.D36N
loss-offunction variant has been associated not only with increased
TG and increased CHD risk but also with reduced HDL-C
. Associations of these two LPL variants with the joint
high TG/low HDL-C atherogenic dyslipidemia complex and
with CHD risk were recently confirmed in a large case-control
sample [43 ]. Another recent study that combined
epidemiological samples and electronic health records analyzed
common LPL variants and reported an odds ratio for CHD of 1.51
per one standard deviation of genetically determined increased
TG, although these well-known variants—including LPL
p.S474X, p.D36N and p.N318S—also have reciprocal effects
on HDL-C levels, which were not reported in that paper .
Another study used multivariate regression to isolate the
genetic effect on HDL-C and CHD risk; rather complicated
statistical models showed that combinations of genetic
determinants with predominantly TG-related effects were correlated
with increased CHD risk, while combinations of genetic
determinants with predominantly HDL-C-related effects were
not . However, almost all other studies of common
variants and CHD risk have not been able to dissociate TG from
Rare Variants Associated with Triglycerides
and Atherosclerosis Risk
Similar inability to unscramble joint inverse effects on TG and
HDL-C is seen in studies of rare genetic variants. For instance,
massive high-throughput sequencing efforts showed that rare
heterozygous loss-of-function APOC3 mutations are
primarily associated with reduced plasma TG levels: Mutation
carriers had significantly reduced CHD risk, again supporting the
idea that TG might contribute directly to atherosclerosis [46,
47]. However, these rare variants were almost always
associated with reduced LDL-C and increased HDL-C [46, 47]. In
addition, carriers of rare heterozygous loss-of-function
mutations in APOA5 that increased plasma TG levels had a twofold
increased risk of early CHD , but these variants were also
associated with increased LDL-C and decreased HDL-C.
Furthermore, three recent studies of common and rare
ANGPTL4 loss-of-function variants associated with lower
TG and higher HDL-C showed associations with reduced
cardiovascular risk [42 , 43 , 44 ]. Again, risk modulation was
attributed to TG effects, despite the significant impact on
HDL-C. The apparent protective effect of high HDL-C in
the context of low TG cannot seem to be disentangled in these
genetic experiments [42 , 43 , 44 ].
There are more examples. Among 46,891 individuals with
LPL gene sequencing data available, one in ~250 had a
damaging rare mutation in LPL . The authors found ~15%
higher corrected TG levels in these individuals, although
HDL-C was concurrently reduced by ~10%, and calculated
remnant cholesterol was also increased by ~10%. Compared
with non-carriers, heterozygous carriers had more CHD (odds
ratio = 1.84 P < 0.001) . Again, the authors focused almost
entirely on levels of TG and remnant cholesterol, even though
the latter was mathematically derived from TG and was thus
highly correlated with it. In another study using a Mendelian
randomization design, heterozygous carriers of rare
ANGPTL3 loss-of-function mutations, seen in one in ~300
people, had 17% and 12% reductions in plasma TG and
LDL-C levels, compared with non-carrier controls; in this
instance, HDL-C was not increased . Carrier status was
associated with a 34% reduction in odds of CHD (P = 0.04),
although admittedly, this was a rather borderline association
for such a gargantuan sample size. Again, although TG
showed the greatest perturbation as a result of the genetic
variation, a possible additive or potentiating effect of
concurrent reduced LDL-C could not be excluded . Another
example of the confounding and interrelationship between
lipoprotein and lipid traits was seen in a study of Icelanders,
in which a rare loss-of-function variant of ASGR1, encoding
an asialoglycoprotein receptor, had reduced TG and
nonHDL-C, and increased HDL-C, together with 34% reduced
CAD risk [48 ]. Of course, non-HDL-C is a derived variable
that does not represent an exclusive biological entity; by
analogy, perhaps total plasma TG is a non-specific integrated trait
that is either the composite of or an indirect marker for other
bioactive components, some of which may directly act on the
vascular wall in atherogenesis.
Thus, plasma TG is a confounded metabolic variable or
biomarker. The integrated overview is that atherosclerosis risk is
elevated in individuals with mild-to-moderate
hypertriglyceridemia, a largely polygenic trait. In mild-to-moderate
hypertriglyceridemia, cholesterol for arterial plaque formation
is contributed from VLDL, their remnants, and IDL. Among
rarer individuals with severe hypertriglyceridemia,
atherosclerosis risk would be increased among individuals with a diffuse
spectrum of large TG-rich chylomicron remnants (i.e. in
polygenic chylomicronemia) but probably not among those with
c h y l o m i c r o n s p r e d o m i n a n t l y ( i . e . i n m o n o g e n i c
chylomicronemia). The association of elevated TG levels with
atherosclerosis is consistent from epidemiologic, mechanistic,
and clinical trials, and the more recent genetic findings seem
to be compelling. However, it continues to be challenging to
disentangle the effects of TG from HDL-C. TG-raising variant
alleles of several genes have shown generally strong
associations with clinical CVD endpoints; however, in almost every
case, a second lipid disturbance—usually depressed
HDLC—was concurrently associated, as outlined in Table 1.
While the findings collectively shift our understanding to
implicate TG towards causality, we still cannot rule out the
possibilities that TG are a component of a joint phenotype with
low HDL-C or that they are markers of deeper metabolic
disturbances that are not routinely measured in
epidemiologicalscale genetic studies. Finally, the presence of unmeasured
secondary factors, both lipid-related and non-lipid-related, would
further contribute to—or perhaps primarily
explain—increased atherosclerosis risk in genetically predisposed
individuals with higher TG levels.
Acknowledgments RAH has received operating grants from the
Canadian Institutes of Health Research (Foundation Grant), the Heart
and Stroke Foundation of Ontario (T-000353), and Genome Canada
through Genome Quebec (award 4530).
Compliance with Ethical Standards
Conflict of Interest Jacqueline S. Dron declares no conflicts of interest.
Robert A. Hegele declares honoraria for membership on advisory
boards and speakers’ bureaus for Aegerion, Amgen, Gemphire, Ionis/
Akcea, Lilly, Merck, Pfizer, Regeneron, Sanofi, and Valeant.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Open Access This article is distributed under the terms of the Creative
C o m m o n s A t t r i b u t i o n 4 . 0 I n t e r n a t i o n a l L i c e n s e ( h t t p : / /
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
Papers of particular interest, published recently, have been
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