Genetic determinants of the metabolic syndrome

Abstract

The metabolic syndrome is a commonly encountered clinical phenotype presenting as concurrent metabolic abnormalities, including central obesity, dysglycemia, dyslipidemia, and hypertension. Several definitions exist, and it is debated whether or not the clustered risk factors impart a higher cardiovascular risk than the simple sum of the individual components. Nevertheless, the concept of a metabolic syndrome has proven helpful in emphasizing the importance of obesity, insulin resistance and related traits in relation to cardiovascular disease risk. Furthermore, the metabolic syndrome as defined by the National Cholesterol Education Program appears to have a component of heritability, which suggests a genetic basis. Indeed, patients with certain rare single-gene disorders express clusters of abnormalities commonly seen in the metabolic syndrome. Moreover, studies indicate that common genetic variants are associated with the development of this syndrome, although the associations are quite weak and replication of findings has been poor. As with most complex traits, it is premature to propose molecular genetic testing for diagnosis, treatment or both. Unresolved issues include the roles of gene-environment interactions, ethnicity, and sex. In this review, we look at the currently available evidence for common genes that predispose to the development of the metabolic syndrome.

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Genetic determinants of the metabolic syndrome
Rebecca L Pollex and Robert A Hegele*
INTRODUCTION
Over the past 5 years the metabolic syndrome
has attracted considerable interest and been
the subject of much debate as researchers and
clinicians have weighed its validity and poten-
tial to identify individuals at risk of diabetes,
cardio vascular disease (CVD), or both.
1,2
The
metabolic syndrome is defined as the clustering
of multiple metabolic abnormalities, including
abdominal obesity, dyslipidemia (elevated
serum triglyceride and depressed serum HDL-
cholesterol levels), dysglycemia (elevated blood
glucose levels), and hypertension. Overall,
the etiology of the metabolic syndrome is
complex, and is determined by the interplay
between genetic and environmental factors
and their influence on the development of
obesity, insulin resistance and various inflam-
matory processes.
1
Although often overlooked
and poorly understood, genetic susceptibility
is starting to be investigated, albeit by using
the current imperfect phenotypic definitions
of the metabolic syndrome. We review here
the existing evidence for common genes that
predispose individuals to the development of
the metabolic syndrome.
DEFINITION OF THE METABOLIC
SYNDROME PHENOTYPE
At least five different phenotypic definitions have
been put forward for the metabolic syndrome,
including those proposed by the WHO, the US
National Cholesterol Education Program Adult
Treatment Panel III (NCEP ATP III), and, most
recently, the International Diabetes Federation
(Table 1).
3–7
Each definition attempts to
provide a list of simple clinical markers that
can be used to identify individuals with the
metabolic, pro inflammatory and prothrom-
botic disturbances that are not routinely
measured but which are possibly pathogenic
in CVD.
1
The current International Diabetes
Federation definition prioritizes abdominal
obesity as the most important factor in the
metabolic syndrome,
5
making only individuals
The metabolic syndrome is a commonly encountered clinical phenotype
presenting as concurrent metabolic abnormalities, including central
obesity, dysglycemia, dyslipidemia, and hypertension. Several definitions
exist, and it is debated whether or not the clustered risk factors impart
a higher cardiovascular risk than the simple sum of the individual
components. Nevertheless, the concept of a metabolic syndrome has
proven helpful in emphasizing the importance of obesity, insulin resistance
and related traits in relation to cardiovascular disease risk. Furthermore,
the metabolic syndrome as defined by the National Cholesterol Education
Program appears to have a component of heritability, which suggests
a genetic basis. Indeed, patients with certain rare single-gene disorders
express clusters of abnormalities commonly seen in the metabolic
syndrome. Moreover, studies indicate that common genetic variants
are associated with the development of this syndrome, although the
associations are quite weak and replication of findings has been poor. As
with most complex traits, it is premature to propose molecular genetic
testing for diagnosis, treatment or both. Unresolved issues include the roles
of gene–environment interactions, ethnicity, and sex. In this review, we
look at the currently available evidence for common genes that predispose
to the development of the metabolic syndrome.
KEYWORDS association studies, genetics, metabolic syndrome,
single-nucleotide polymorphisms
RL Pollex is a research assistant in the Vascular Biology Group and
RA Hegele is Director of the Blackburn Cardiovascular Genetics Laboratory,
Robarts Research Institute, London, ON, Canada.
Correspondence
*Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 100 Perth Drive,
Room 406, London, ON N6A 5K8, Canada
hegele@robarts.ca
Received 25 December 2005 Accepted 22 May 2006
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doi:10.1038/ncpcardio0638
REVIEW CRITERIA
We searched PubMed for all available publications between 2002 and January
2006, using the following terms: “metabolic syndrome”, “insulin resistance
syndrome”, “polymorphism”, and “genetic association”. All relevant identified
articles were English-language papers.
SUMMARY
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with increased waist girth eligible for subse-
quent assessment of the additional criteria. As
increased waist circumference is frequently a
predominant feature of the syndrome in most
populations, similar subgroups will be identi-
fied as being at risk with this definition as with
the other methods.
Regardless of the definition used, the meta-
bolic syndrome is widespread, affecting approx-
imately 25% of people in North America and
many other subpopulations worldwide.
1
Furthermore, in the NCEP ATP III defini-
tion, the metabolic syndrome has empirical
value clinically as a prospective determinant of
disease risk, since it has been associated with a
moderate increase in the development of CVD
and also more strongly associates with diabetes
incidence.
2
PATHOPHYSIOLOGY OF THE METABOLIC
SYNDROME
The predominant underlying risk factors for the
metabolic syndrome are abdominal obesity and
insulin resistance. Associated conditions that
have an important role include chronic inflam-
mation and physical inactivity.
1
The initial under-
standing of the metabolic syndrome stemmed
from the observation that insulin resistance and
hyperinsulinemia were closely associated with
the clustering of disturbed metabolic symp-
toms.
8
This aggregation was often referred to
as the insulin-resistance syndrome. Visceral fat
accumulation, often caused by overnutrition and
physical inactivity, results in an unusually high
release of free fatty acids, causing lipotoxic effects
and insulin resistance and leading eventually to a
state of hyperglycemia.
1
In addition, visceral fat
Table 1 Comparison of metabolic syndrome definitions.
Guide-
line
Glucose/insulin abnormality Obesity/central
adiposity
Dyslipidemia Hypertension
(with or without
medication)
Other Minimum
criteria for
diagnosis
WHO
(1999)
3
Type 2 diabetes, impaired
fasting glucose (FBG
≥6.1 mmol/l), impaired
glucose tolerance (2 h PPG
≥7.8 mmol/l), or lowest 25% for
hyperinsulinemic euglycemic
clamp-glucose uptake
Waist-to-hip ratio
>0.9 (M) or >0.85 (F)
and/or BMI >30 kg/m
2
Triglycerides
≥1.7 mmol/l
and/or HDL-C
<0.9 mmol/l (M)
or <1.0 mmol/l (F)
BP
≥140/90 mmHg
(and/or
medication)
Microalbuminuria
(≥20 μg/min
albumin excretion
rate or albumin:
creatinine ratio
≥30 mg/g)
Glucose
intolerance/
insulin
resistance,
plus two
other
features
EGIR
a
(1999)
6
Insulin resistance:
hyperinsulinemia (nondiabetic
fasting insulin in top 25%)
and impaired fasting glucose
(FBG ≥6.1 mmol/l)
Waist circumference
≥94 cm (M) or
≥80 cm (F)
Triglycerides
>2 mmol/l and/or
HDL-C <1.0 mmol/l
BP
≥140/90 mmHg
(and/or
medication)
— Insulin
resistance,
plus two
other
features
NCEP
ATP III
(2001)
4
Impaired fasting glucose (FBG
≥6.1 mmol/l)
Waist circumference
>102 cm (M) or
>88 cm (F)
Triglycerides
≥1.69 mmol/l, HDL-C
<1.04 mmol/l (M) or
<1.29 mmol/l (F)
BP
≥130/≥85 mmHg
(and/or
medication)
— Any three
features
AACE
(2003)
7
Glucose intolerance (FBG
≥6.1 mmol/l or 2 h PPG
>7.8 mmol/l)
BMI ≥25 kg/m
2
Triglycerides
≥1.69 mmol/l, HDL-C
<1.04 mmol/l (M) or
<1.29 mmol/l (F)
BP
≥130/≥85 mmHg
b
Family history
of or high-risk
ethnic group for
type 2 diabetes,
hypertension or
CVD; polycystic
ovarian syndrome;
sedentary lifestyle;
advancing age
Clinical
judgment
based on
all features
IDF
(2005)
5
Glucose intolerance (FBG
≥5.6 mmol/l) or pre-existing
diabetes
Waist circumference:
European ≥94 cm (M)
or ≥80 cm (F); South
Asian and Chinese
≥90 cm (M) or ≥80 cm
(F); Japanese ≥85 cm
(M) or ≥90 cm (F)
Triglycerides
≥1.7 mmol/l, HDL-C
<1.0 mmol/l (M) or
<1.3 mmol/l (F)
BP
≥130/≥85 mmHg
(and/or
medication)
—
Central
adiposity
plus two
other
features
a
Individuals without diabetes only.
b
Without medication only. Abbreviations: AACE, the American College of Endocrinology; BP, blood pressure;
CVD, cardiovascular disease; EGIR, European Group for the Study of Insulin Resistance; F, female; FBG, fasting blood glucose; HDL-C, HDL cholesterol;
IDF, International Diabetes Federation; M, male; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; PPG, postprandial glucose.
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accumulation results in dysregulation of adipo-
cytokine secretion, including hyposecretion of
adiponectin and hypersecretion of leptin, tumor
necrosis factor and interleukin 6, each of which
might also mediate many of the changes in the
metabolic syndrome.
1
Thus, from environmental
factors to obesity, inflammation and insulin resis-
tance, the unraveling of the metabolic syndrome
so far indicates the dynamic interplay between a
number of contributing factors.
THE METABOLIC SYNDROME PHENOTYPE
Debate over the meaning of the metabolic
syndrome phenotype
Arguments have been put forward that the
risk-factor cluster represented by the metabolic
syndrome label does not necessarily impart a
higher CVD liability than the simple sum of the
individual risk-factor components.
9
This position
has support from studies in which, after adjust-
ment for the individual component risks, the
metabolic syndrome as a whole was no longer
a significant predictor, or its impact was greatly
attenuated.
9
In addition, the practical utility of
the metabolic syndrome as a predictor of CVD
risk has been questioned, as its evaluation, in
comparison with the traditional Framingham risk
prediction model for CVD, has demonstrated no
convincingly increased predictive ability for such
risk.
9
For example, in the San Antonio Heart
Study,
10
which followed 2,570 individuals over
approximately 8 years, the Framingham risk
score seemed to be a better predictor of CVD
than the presence of the metabolic syndrome: the
hazard ratios were 7.9 (95% CI 5.3–11.7) and 1.5
(95% CI 1.0–2.2), respectively.
10
The definition
of the metabolic syndrome in that study did not,
however, include such potent risk factors as age,
smoking and total cholesterol, which contribute
largely to the predictive value of the Framingham
score. In this context, the metabolic syndrome
phenotype could be seen as complementary to
the Framingham score. Furthermore, neither
approach to risk stratification currently includes
novel biomarkers, such as C-reactive protein or
adiponectin, which could further improve predic-
tion,
9
although the evidence for their clinical
utility remains questionable.
11,12
Despite these
shortcomings, however, the dissemination of the
concept of the metabolic syndrome phenotype
has proven to be critical in directing the atten-
tion of both clinicians and researchers towards
the importance of obesity, insulin resistance and
related traits as contributors to CVD risk.
Genetic mechanisms
Genes could influence the development of the
metabolic syndrome in multiple ways.
13
Each
of the syndrome’s key components—obesity,
dyslipidemia, dysglycemia and high blood pres-
sure—has a genetic basis, for which candidate
genes have been identified. Such associations
might facilitate or enable the development of
the syndrome. For example, visceral obesity
has been associated with variation in ADIPOQ,
which encodes adiponectin.
14
In addition, blood
pressure has been associated with variations in
AGT, which encodes angiotensinogen,
15
and
plasma lipid concentrations have been associ-
ated with variations in the APOE and APOC3
genes encoding apolipoproteins E and C-III,
respectively.
16,17
Thus, variants associated with
the individual components of the metabolic
syndrome phenotype could underlie association
with the entire syndrome.
Furthermore, some candidate gene prod-
ucts might act within a common pathway that
affects more than one syndrome component,
and possible single-gene associations have
been identified. For example, NR3C1, which
encodes the glucocorticoid receptor, has been
associated with obesity, hypertension, and
insulin resistance.
18
ADIPOQ has been associ-
ated with diabetes, hypertension, and dyslipid-
emia.
19,20
GNB3, which encodes the β3 subunit
of G protein, has been associated with hyper-
tension and obesity.
21,22
Variations in genes
encoding certain transcription factors such as
FOXC2 and SREBP1 have been associated with
insulin sensitivity and plasma concentrations of
triglycerides.
23,24
These genes might, therefore,
be candidates for association studies with the
whole metabolic syndrome phenotype.
HERITABILITY OF THE METABOLIC
SYNDROME
Findings from twin and family studies suggest a
heritable contribution in the clustering of meta-
bolic syndrome factors.
25–30
For instance, among
2,508 male twin pairs in the US, clustering of
hypertension, diabetes, and obesity was reported
in 31.6% of monozygotic pairs but only 6.3% of
dizygotic pairs.
25
Similar evidence for heritable
factors was found in a twin study of female pairs.
26
In a study of 432 individuals from 68 Japanese
American families, significant genetic influences
were noted on all metabolic syndrome compo-
nents, especially dyslipidemia, of which around
50% of the variance was attributable to genetic
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influences.
27
The evidence suggesting causative
genes underlying the metabolic syndrome has
encouraged investigators to study both the rare
monogenic forms of the syndrome and also the
common trait by various approaches, including
genetic linkage and association analysis.
Single-gene human models
Study of monogenic forms of the metabolic
syndrome, which are seen in a few patients with
certain single-gene disorders,
13
might help us
to understand the common form. For instance,
individuals with familial partial lipodystrophy
due to mutations in either LMNA, which encodes
lamin A/C, a nuclear envelope protein, or PPARG,
which encodes peroxisome proliferative acti-
vated receptor γ, display the defining features
of the metabolic syndrome, including insulin
resistance, dyslipidemia, and hypertension.
13,31
Furthermore, these individuals, especially
women, have markedly increased CVD risk.
32
Close phenotypic evaluation of these
patients has revealed distinct stages of disease
evolution.
13
For instance, in familial partial lipo-
dystrophy, the initial metabolic disturbance is
insulin resistance, followed closely by the develop-
ment of dyslipidemia, with hypertension and
diabetes occurring later in disease evolution,
and CVD occurring later still.
13
The clarified
progression of abnormal phenotypes in familial
partial lipodystrophy has suggested a rational,
staged treatment regimen that might modulate
the natural history and development of the CVD
endpoints. Furthermore, understanding these
stages of disease progression might have value
not only for patients with this rare condition,
but perhaps also for patients with the common
metabolic syndrome phenotype.
Genome-wide linkage scanning
The strategy of interrogating the entire human
genome to detect chromosomal segments that
are linked with complex phenotypes has been
applied to the metabolic syndrome. At least four
genome-wide linkage scans have attempted to lay
the foundation for finding genes. For instance, a
study of 2,209 individuals from 507 US families
showed links between the metabolic syndrome
and chromosome loci 3q27 and 17p12. The
quantitative trait locus 3q27 was strongly linked
to six relevant traits: weight, waist circumference,
leptin, insulin, insulin-to-glucose ratio, and hip
circumference.
33
The 17p12 locus was linked
primarily with plasma leptin. A second study of
261 individuals without diabetes from 27 Mexican
American families showed significant linkage for
the metabolic syndrome with two unique regions
on chromosome 6 (D6S403 and D6S264) and a
region on chromosome 7 (D7S479–D7S471).
34
A third study of US families found evidence for
linkage on several chromosomal regions (1p34.1,
1q41, 2p22.3, 7q31.3, 9p13.1, 9q21.1, 10p11.2,
and 19q13.4).
35
A key finding of this study
was the observation of ethnic-group-specific
linkages. Finally, a study of Hispanic families
reported that the q23–q31 region of chromo-
some 1 harbored at least one gene related to the
metabolic syndrome.
36
Importantly, no specific
gene or mutation has been found as a result of
any of these studies. Some of these chromosomal
regions have been previously linked with CVD
and diabetes risk factors, and, therefore, they
could harbor potential candidate genes for the
metabolic syndrome. The results must, however,
be interpreted in light of the caveats for all gene
linkage studies involving complex traits.
37
Genetic association studies
Despite suggestions of a genetic component
underlying the metabolic syndrome, the iden-
tification of associated genes has been chal-
lenging and few associations have been reported
so far. Since 2002, at least 20 genetic association
studies with the metabolic syndrome have been
reported,
38–57
including 13 positive associations
(Tables 2 and 3). These studies typically involve
single-nucleotide polymorphism (SNP) variants
in candidate genes. In general, the reported associ-
ations are weak and lack supportive evidence
across multiple study samples. Conflicting associ-
ations have been reported between the metabolic
syndrome and polymorphisms in genes encoding
angiotensinogen-I-converting enzyme (ACE),
41,50
fatty-acid-binding protein 2 (FABP2),
43,47
and G
protein β3 subunit (GNB3).
39,54
By contrast, posi-
tive associations of the metabolic syndrome with
common SNPs in APOC3
47,54
and PPARG
45,52
were replicated in more than one study sample.
Rare dysfunctional mutations in LMNA are
causative in familial partial lipodystrophy.
13,31
In a study of Amish participants, the common
LMNA 1908C
>T polymorphism (trivial name
p.H566H), located near the lamin A and lamin C
transcript splice site, had a significant association
with the metabolic syndrome defined according
to the NCEP ATP III guidelines (odds ratio 1.4,
P = 0.017).
57
In Canadian aboriginal people, this
same variant was associated with high BMI, the
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ratio of waist-to-hip circumference, leptin, and
percentage of body fat.
58,59
Another genetic association with the meta-
bolic syndrome according to NCEP ATP III was
reported for the gene encoding the β2-adrenergic
receptor (ADRB2) in a study of 1,195 French
men and women.
42
Two common SNPs change
the amino acid sequence at codons 16 and 27
(trivial names p.G16R and p.D27E). Both SNPs
were associated with the metabolic syndrome
in men (P = 0.005 and P = 0.040, respectively)
but not in women. This difference suggests that
genetic susceptibility in this instance is influ-
enced by sex. Similarly, a large-scale association
study examining 110 candidate genes for the
metabolic syndrome among patients with coro-
nary artery disease, found several associations
that were significantly sex-dependent.
51
Apolipoprotein C-III is a protein constit-
uent of triglyceride-rich lipoprotein particles
that inhibits the action of lipoprotein lipase.
Historically, APOC3 has been one of the most
studied genes in lipoprotein metabolism.
SNPs within the APOC3 promoter have been
previously associated with elevated plasma
tri glycerides. APOC3 promoter SNPs have
now also been associated with the metabolic
syndrome in South Asian men and women
47
and aboriginal Canadian women.
54
Another candidate gene for the metabolic
syndrome is PPARG, which encodes a ligand-
activated transcription factor that is involved in
many biological processes ranging from lipid
and glucose metabolism to fatty-acid trans-
port to adipocyte differentiation. Two studies,
each involving more than 1,000 participants,
have reported positive associations for SNPs in
PPARG. Frederiksen et al.
45
showed a decreased
risk of developing the metabolic syndrome as
defined by the European Group for the Study
of Insulin Resistance in homozygotes for the
A12 allele of the common PPARG p.P12A poly-
morphism. While Meirhaeghe et al.
52
found no
association between the metabolic syndrome
and the same SNP genotype in a French sample,
haplotypes that were constructed using three
Table 2 Genetic studies showing associations with the metabolic syndrome.
Gene Polymorphism name P value Comments Definition of
metabolic
syndrome
Number in sample
(nationality)
ACE
50
I/D (intron 16) 0.003 — WHO 1,461 (Chinese)
ADRB2
42
G16R
Q27E
<0.005
<0.04
Association found in
men only
NCEP ATP III 1,195 (French)
AGT
54
T174M 0.018 Women only NCEP ATP III 515 (Oji-Cree)
APOC3
54
–455T>C 0.029 Women only NCEP ATP III 515 (Oji-Cree)
APOC3
47
–455T>C, –482C>T NS — NCEP ATP III 180 (Indian)
FABP2
47
A54T
APOC3/FABP2 combined
haplotype
0.031
0.003
— NCEP ATP III 180 (Indian)
GNB3
54
825C>T 0.0056 Women only NCEP ATP III 515 (Oji-Cree)
IL6
48
Promoter haplotype <0.01 — WHO 2,828 (Danish)
LDLR
51
Silent SNP, exon 13 0.008 — NCEP ATP III 762 (US [white], with
coronary artery disease)
LMNA
57
H566H 0.017 — NCEP ATPIII 971 (US [Amish])
LRPAP
51
Silent SNP, exon 5 0.0003 Women only NCEP ATP III 762 (US [white], with
coronary artery disease)
NOS3
44
1132T>C 0.0022 Hypertensive only NCEP ATP III 199 (Spanish)
PPARG
52
Haplotype (–681C>G,
–689C>T, P12A, 1431C>T)
P12A
0.045
NS
— NCEP ATP III
EGIR
1,155 (French)
PPARG
45
P12A 0.02 — EGIR 2,245 (Danish)
Abbreviations: EGIR, European Group for the Study of Insulin Resistance; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III;
NS, not significant; SNP single-nucleotide polymorphism.
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other PPARG SNPs showed an association with
NCEP-defined metabolic syndrome.
52
Difficulties in translating genetic
associations into practice
As with any experimental approach, genetic asso-
ciation studies between the metabolic syndrome
and SNPs in human samples have strengths and
limitations.
60
The potential strengths of this
type of study include the simplicity of the study
design, reliability and cost-effectiveness of geno-
typing, uncomplicated statistical analysis, and the
potential for both clear interpretation and rele-
vance to human health and disease. Experience
has shown, however, that many factors conspire
to undermine the validity of association studies.
The initial publication of a positive association is
frequently followed by reports of non replication
or refutation, as is already the case with studies
in the metabolic syndrome. While there might
be some good reasons for nonreplication, this
pattern is frequent, familiar and disconcerting.
An index of the tenuous nature of genetic asso-
ciations in CVD is provided by the fact that
few, if any, DNA markers—typically SNPs—
are currently used routinely in the clinic, for
instance, as part of risk stratification proto-
cols; this feature is also true for the metabolic
syndrome. This reality is a reflection of the
current technologies, which are limited in their
ability to investigate the great amount of varia-
tion in the human genome. Newer technologies,
such as the use of high-density SNP genotyping
microarrays, that allow the interrogation of
thousands of such polymorphisms might allow
for the identification of DNA markers that will
be truly useful diagnostically.
CONCLUSION
The concept of the metabolic syndrome pheno-
type has represented a fundamental advance by
focusing clinical attention on the importance
of abdominal obesity as a CVD risk factor.
Somewhat paradoxically, however, the meta-
bolic syndrome does not yet have one clini-
cally operative definition, and its existence as
a distinct clinical entity has even been called
into question. Although the latter viewpoint is
somewhat extreme, the metabolic syndrome is
clearly a complex trait with numerous features.
Furthermore, the disorder probably results
from the interaction of environmental factors,
such as caloric excess and physical inactivity,
with underlying genetic susceptibility factors.
Table 3 Genetic studies showing no association with the metabolic syndrome.
Gene Polymorphism name P value Definition of
metabolic syndrome
Number in sample
(nationality)
ACE
41
I/D (intron16) N/A WHO 643 (Brazilian)
a
ADRB3
46
W64A 0.50 EGIR 2,117 (Danish)
FABP2
43
A54T 0.095 NCEP ATPIII 414 (European)
b
GHRL
40
L72M 0.50 NCEP ATPIII 2,413 (Danish)
GNB3
39
825C>T N/A WHO 7,518 (Danish)
GNB3
53
825C>T 0.36 NCEP ATPIII 1,134 (French)
LEP
53
5' UTR +19G>A 0.84 NCEP ATPIII 1,134 (French)
LTA
49
T60N 0.37
c
WHO 3,036 (Danish)
PPARA
56
L162V 0.84 NCEP ATPIII 632 (French Canadian)
d
PPARG
55
161C>T
P12A
0.51
0.27
NCEP ATPIII modified 253 (Korean)
e
PPARGC1A
38
G482S 0.74 NCEP ATPIII 2,349 (Danish)
SLC27A1
53
intron 8 +48G>A 0.81 NCEP ATPIII 1,134 (French)
TNF
53
–308G>A 0.12 NCEP ATPIII 1,134 (French)
UCP3
53
–55C>T 0.95 NCEP ATPIII 1,134 (French)
a
All participants had type 2 diabetes mellitus.
b
All participants had coronary heart disease.
c
P = 0.03 for one or more
components of the metabolic syndrome.
d
Men only.
e
Women only. Abbreviations: EGIR, European Group for the Study of
Insulin Resistance; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; N/A, not available.
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488 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE POLLEX AND HEGELE SEPTEMBER 2006 VOL 3 NO 9
www.nature.com/clinicalpractice/cardio
While evidence for genetic determinants exists
from observations in twins and families, genetic
linkage and association studies have not yet
identified genomic DNA markers that have
even remote potential for clinical use. Context-
dependent factors, such as ethnicity, diet and
sex,
61
also strongly influence the pathogenesis of
the metabolic syndrome. This complexity makes
extremely difficult the identification of replicable
genetic associations that might one day form
the basis of clinical predictive tests of suscep-
tibility to, development of complications from,
and response to interventions for the metabolic
syndrome, or a combination of these.
KEY POINTS
■ The metabolic syndrome is a common
phenotype that imparts increased risk
of cardiovascular disease and diabetes
■ A single clinically operative definition of the
metabolic syndrome is not yet available, but
is evolving
■ The metabolic syndrome is defined by cut-
off points applied to abdominal obesity,
blood pressure, blood glucose, and
plasma triglyceride and HDL-cholesterol
concentrations
■ Genetic studies on the metabolic syndrome
have been attempted and a genetic
contribution appears to exist
■ No consistent or replicated genetic test is
currently available that can be used clinically
in the diagnosis, treatment, or both of the
metabolic syndrome
■ Environmental factors and complex gene–
environment interactions also play an important
part in metabolic syndrome expression
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Acknowledgments
Support has been provided
by the Jacob J Wolfe
Distinguished Medical
Research Chair, the Edith
Schulich Vinet Canada
Research Chair (Tier I) in
Human Genetics, a Career
Investigator award from
the Heart and Stroke
Foundation of Ontario,
and operating grants from
the Canadian Institutes for
Health Research, the Heart
and Stroke Foundation
of Ontario, the Ontario
Research and Development
Challenge Fund (Project
#0507) and by Genome
Canada.
Competing interests
The authors declared
they have no competing
interests.
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