Cause and treatment
The metabolic syndrome:
genetics, lifestyle and ethnicity
y
Marju Orho-Melander
Over a few million years, human genes gradually evolved,
enabling us to survive frequent periods of famine. Our genes
are still essentially the same; but we are currently exposed
to lifestyles for which we are not programmed. We were
programmed for frequent physical activity and a relatively
low-energy diet. The collision between these ancestral genes
and the effects of urbanization is resulting in a global
epidemic of the metabolic syndrome. But it appears that
not all ethnic groups, or indeed people within the same
ethnic group, are affected in the same way. While the
metabolic syndrome epidemic can largely be explained by
environmental changes, Marju Orho-Melander describes the
importance of genetic factors in contributing to the large
variations in susceptibility to the different disorders of the
metabolic syndrome and the way these come together.
>>
Genetic factors
The causes of the metabolic syndrome
are complex and thought to involve
metabolic, hormonal, genetic, and
lifestyle interactions. Prospective
twin studies, familial segregation
and heredity studies clearly support
a genetic basis for the metabolic
syndrome and its components.1 Several
studies have provided estimates for
the degree to which the features
of the syndrome can be explained
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by genetic factors (heritability). Of
these components, HDL cholesterol
has shown the highest estimated
heritability (50% to 60%), while systolic
blood pressure has shown the lowest
(6% to 18%).1 Although the estimated
heritability of individual components
varies among populations, a significant
underlying genetic influence has been
indicated in all of the components
– and possibly also on their clustering.
Which genes matter?
Two approaches have been used
in the search for the genes behind
the metabolic syndrome. While the
‘candidate gene’ approach aims to
identify genes based on information
regarding their function, the ‘random
gene search’ approach assumes no
knowledge of the action of any gene
in relation to the underlying defects.
Several candidate genes have been
studied. Although a number of genes
and genetic variations have shown
an association with the metabolic
syndrome, most studies have been
difficult to replicate, and the progress
in identification of ‘true’ metabolic
syndrome genes has been slow.2
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Cause and treatment
A large number of genome-wide scans
for the components of the metabolic
syndrome have been performed in
different populations. Some of the
linked regions have been replicated
in several studies. In the last decade,
linkage analysis was the only alternative
to a random gene search. Recently,
it has become possible to perform
genome-wide association studies with
500 000 or more single nucleotide
polymorphisms (SNPs) covering
the whole human genome. These
studies may in the near future enable
us to estimate more accurately the
number of genes that matter.
( )
Susceptibility is often
mediated by the
common alleles, while
the derived alleles
provide protection.
The methods used to identify genes
causing rare hereditary diseases, such
as phenylketonuria, do not work
in the search for genes influencing
common complex diseases, such as
diabetes. Methods are needed for
detecting common DNA variations
(alleles) for susceptibility to a
disease. The susceptibility variants
often represent common inherited
alleles, while the derived (mutated)
alleles protect from the disease.
A good example of this is a
polymorphism in the PPARG
(PPARGamma) gene. In large metaanalyses combining a number of studies,
this gene has been shown to influence
susceptibility to type 2 diabetes. By
comparing the polymorphism Pro12Ala
in the PPARG gene to a chimpanzee
sequence, it was revealed that the risk
allele (Pro12) is ancestral; whereas
the protective and less common allele
(Ala12) is derived. The frequencies of
most of the susceptibility variants differ
greatly between different populations.
This probably reflects the wide range of
evolutionary scenarios underlying the
genetic risk to the metabolic syndrome.3
Environmental triggers
The importance of these genetic factors
does not mean that the metabolic
syndrome is caused by genetic defects
alone; in most cases, genetic factors
predispose a person to a disease, while
lifestyle factors determine whether (and
when) the disease will develop. Several
studies have demonstrated very clearly
the importance of dietary factors and
physical activity level in the development
of the metabolic syndrome.
Physical activity
For example, low levels of physical fitness
have been shown to predict the metabolic
syndrome as powerfully as conventional
A single nucleotide polymorphism (SNP – pronounced ‘snip’) is a DNA
sequence variation that occurs when a single nucleotide (A,T,C,or G) in
the genome sequence is altered. For a variation to be considered a SNP, it
must occur in at least 1% of the population. Scientists believe some SNPs
could predispose people to disease or influence their response to a drug.
Because SNPs do not change much from generation to generation, they
can be followed during population studies relatively easily. SNPs are thus of
great value for biomedical research and for developing medical therapies.
May 2006 Volume 51
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risk factors. Levels of physical activity
have been associated with features of
the metabolic syndrome, as well as with
the risk of coronary artery disease.
Additionally, there is compelling evidence
that exercise provides a protective
effect against the risk of early death in
people with the metabolic syndrome.4
( )
Lifestyle factors are
important determinants
of whether (and when)
a disease will develop.
Diet
Dietary interventions have been shown
to improve risk factors comprising
the syndrome.4 The type 2 diabetes
susceptibility gene PPARG belongs
to a family of nuclear hormone
receptors which control a multitude
of metabolic pathways. This gene
provides us with a nice example
of gene-diet interaction. PPARG
activators have been developed into a
major new type of anti-diabetes drug
– thiazolidinediones. Polyunsaturated
fatty acids are natural connectors
for PPARG. Several studies have
demonstrated that the genetic variation
in PPARG significantly influences our
physiological responses to dietary fat.5
Famine has been a constant threat
to human survival and has led to
the selection of ‘thrifty genes’ during
evolution. Additionally, the environment of
an early embryo can have a major impact
on its survival as well as on its immediate
and later physiology. Sadly, changes in the
environment of children and adolescents
in the USA during the last decade can
be measured in terms of the two-fold
increase in the number of children
affected by the metabolic syndrome.
Cause and treatment
© EC / R Canessa
Age and hormonal changes
The risk for the metabolic syndrome
and its component traits increases with
age. Much of the age-associated risk can
be explained by changes in the levels of
steroid hormones and their function.
Hormonal changes at the menopause,
for example, are associated with an
increase in total adiposity and central
fat distribution and thus increased
risk for the metabolic syndrome.
Over the last decade, a growing
number of other factors have been
described and linked with features
of the metabolic syndrome. These
include hormones such as leptin,
adiponectin and resistin. Along with
oestrogen, these hormones, which
are secreted by fatty tissue, act to
regulate energy metabolism. The
hormonal milieu and gene expression
differ between men and women. Thus,
the interactions between genetic and
environmental factors could lead to
different effects (and phenotypes)
in men and women. In line with
this, several chromosomal regions
were recently identified to be sexspecifically involved in susceptibility
to several of the traits associated
with the metabolic syndrome.6
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Regardless of
ethnicity, the most
important targets for
lifestyle intervention
are children.
Ethnicity-related factors
The prevalence of the metabolic
syndrome varies between ethnic
groups.7 According to the US National
Cholesterol Education Program
Adult Treatment Panel III definition,
adult prevalence of the metabolic
syndrome was 32% in Hispanic
Americans, 22% in African Americans
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Cause and treatment
and 24% in Caucasian Americans.
Similarly, a prevalence of 24% among
white people was reported in the
Framingham Offspring Study, and
a prevalence of 31% was reported
among people of Mexican origin
in the San Antonio Heart Study.
( )
The effects of
the metabolic
syndrome vary across
ethnic groups.
In addition to different frequencies,
the effects of the metabolic syndrome
vary across ethnic groups. Data
from the USA show that obesity
and obesity-related cardiovascular
diseases are more common in people
of African or Hispanic origin than
in Caucasians. Furthermore, the
relationship between obesity and
cardiovascular disease is different
between the different ethnic groups.
Recently, the higher susceptibility to
hypertension among people in the
USA of African origin was explained
by differential exposure to genetic
selection during the out-of-Africa
expansion. The higher susceptibility
of people of African origin when
exposed to lifestyle anomalies, such as
a high intake of salt, demonstrates the
collision between genes adapted to
hot climate and a ‘modern’ lifestyle.8
Conclusions
Fighting against the genes that
predispose to the metabolic syndrome
is a challenge. Regardless of ethnicity,
the most important targets for
lifestyle intervention are children.
Fortunately, a ‘vaccine’ is available:
proper nutrition, weight management
and adequate physical activity.
Special Issue
Marju Orho-Melander is an associate
professor in experimental endocrinology
at the Department of Clinical Sciences in
Malmö, Lund University, Sweden.
( )
A ‘vaccine’ is available:
proper nutrition,
weight management
and adequate
physical activity.
We know that it is not equally
effective on all genetic make-ups and
can, therefore, expect the growing
information on susceptibility genes
and gene-environment interactions
to lead us towards a more effective
assessment of individual risk and
better recommendations – a public
health approach that will potentially
facilitate savings in terms of health
spending, life years and quality of life.
References
1 Lin H-F, Boden-Albala B, Juo SH, et al. Heritabilities
of the metabolic syndrome and its components in the
Northern Manhattan Family Study. Diabetologia 2005;
48: 2006-12.
2 Groop L, Orho-Melander M. The dysmetabolic
syndrome. J Int Med 2001; 250: 105-20.
3 Di Rienzo FA, Hudson RR. An evolutionary framework
for common diseases: the ancestral –susceptibility
model. Trends Genet 2005; 21: 596-601.
4 Roberts CK, Barnard RJ. Effects of exercise and diet on
chronic disease. J Appl Physiol 2005; 98: 3-30.
5 Memisoglu A, Hu FB, Hankinson SE, et al. Interaction
between a peroxisome proliferator-activated receptor
gamma gene polymorphism and dietary fat intake in
relation to body mass. Hum Mol Genet 2003; 12: 2923-9.
Currently available definitions of the
metabolic syndrome are valuable
tools. However, with the exception
of the International Diabetes
Federation definition, which defines
a range of limits for central obesity
in different populations, these are
not adapted to ethnic variations.
May 2006 Volume 51
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6 Weiss LA, Pan L, Abney M, et al. The sex-specific genetic
architecture of quantitative traits in humans. Nat Genet
2006; 38: 218-22.
7 Cossrow N, Falkner B. Race/Ethnic issues in obesity and
obesity-related comorbidities. J Clin Endocrin Metab
2004; 89: 2590-4.
8 Young JH, Chang Y-PC, Chretien J-P, et al. Differential
susceptibility to hypertension is due to selection during
the out-of-Africa expansion. PloS Genetics 2005; 1: 730-8.
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