Published Online on 22 December 2016

Proc Indian Natn Sci Acad 82 No. 5 December 2016 pp. 1425-1436
 Printed in India. DOI: 10.16943/ptinsa/2006/48877

Review Article
Nutri (Epi) Genomics and Metabolic Syndrome
NAGA MURALIDHAR MERUGU 1 , RAGHUNATH MANCHALA 2 and RAJENDER RAO
KALASHIKAM1,2*
1Laboratory of Molecular Genetics, National Centre for Laboratory Animal Sciences, National Institute

of Nutrition, Indian Council of Medical Research, Hyderabad, India

2Endocrinology and Metabolism Division, National Institute of Nutrition, Indian Council of Medical

Research, Hyderabad, India

1,2Laboratory of Molecular Genetics, National Centre for Laboratory Animal Sciences, National Institute

of Nutrition, Indian Council of Medical Research, Hyderabad, India

(Received on 07 June 2016; Accepted on 16 August 2016)

The metabolic syndrome is a cluster of risk factors such as obesity, insulin-resistance, hypertension, dyslipidemia,
inflammation associated with an increased risk of type 2 diabetes mellitus (T2DM) and cardio vascular diseases (CVD).
Rapid globalization, urbanization and industrialization have spawned epidemics of metabolic syndrome and it has become
one of the major threats among adolescents and children. It is influenced by the interaction of genes, nutrition, environment,
and lifestyle. The technological advances in life sciences have led to the realization that certain nutrients are not only
essential, but also specific quantity of each nutrient is necessary for optimal health. Therefore, it is important to understand
the biological impact of gene–nutrient-disease interactions, which will provide an insight into the pathogenesis and progression
of metabolic syndrome. The present review is focused on the role of gene-nutrient interactions (Nature vs Nurture) towards
the development of metabolic syndrome and associated co-morbidities and its epigenetic regulation.

Keywords: Epigenenomics; Nutrigenomics; Gene-nutrient Interactions; Metabolic Syndrome; Obesity; Type 2

Diabetes Mellitus; Cardio Vascular Diseases; Hypertension

Introduction diet could positively or negatively influence an

Nutrition clearly had a predominant and recognizable
role in health and disease since the times of the
renowned Greek physician Hippocrates. However,
our understanding of diet and its effects on health has
evolved with time from crude associations to
conclusive facts (Mutch et al., 2005). The
technological developments in life sciences and the
advent of modern science, have led to the realization
that certain nutrients are not only essential, but also
specific quantity of each nutrient is necessary for
optimal health. Further, it is now realized that the
nutrient/diet can directly contribute to diseases.
Advances in genome sequencing and complete
elucidation of the Human Genome Project (HGP) has
led to questions, whether the interaction between
genes/genotypes and bioactive compounds of nutrient/
*Author for Correspondence: E-mail: rkrajender@yahoo.com
individual’s health (Sales et al., 2014). Bioactive
compounds in the diet and genetics are two major
factors which determine the development of metabolic
syndrome that comprises cardiovascular diseases,
diabetes, hypertension and obesity (Mutch et al.,
2005; Gaboon, 2011). Adequate amount of nutrients
indeed prevent/delay the development of metabolic
syndrome. To understand these interactions between
genes and nutrients, the term “Nutrigenomics” was
coined. Nutrigenomics implies the use of biochemistry,
physiology, nutrition, genomics, proteomics,
metabolomics, transcriptomics and epigenomics to seek
and explain the existing reciprocal interactions between
genes and nutrients at a molecular level.
Nutrigenomics and nutrigenetics are two sides of the
same coin. While the former describes how nutrients
1426
affect metabolic pathways and homeostatic control
epigenetically, the latter tries to understand how the
genetic make-up of an individual influences their
response to diet. The discovery of these gene-nutrient
interactions would aid in personalized diets according
to individual’s genotype (Sales et al., 2014). Further,
understanding of gene–nutrient interactions would help
in mitigating the symptoms of existing diseases and/
or to prevent future illnesses, especially in the area of
non-transmissible chronic diseases (NTCDs), which
are currently considered as an important global public
health problem.
Nutrition, Genomics and Epigenomics
Nutrigenomics is the science of the effect of nutrients
and bioactive components on gene expression and
helps one understand how diet regulates gene function
(transcription and translation), DNA methylation,
proteome and metabolome (i.e. in the simplest terms:
diet → gene interactions) which can be studied
independently or in an integrated manner, to diagnose
health status and/or to understand disease trajectory
(Elliott and Johnson, 2007; Gaboon, 2011). Recent
developments in nutrigenomics has established the
effects of ingested nutrients and other food
components on gene expression and its regulation in
order to delineate the dietary components having
beneficial or detrimental effects on health. It would
also determine the individual nutritional requirements
(personalized diet), association between diet and
metabolic syndrome which is essential to understand
the aetiology of type-2 diabetes, obesity and
cardiovascular disease (CVD). Although humans have
99.9% identical gene sequences; 0.1% genetic
variation makes an individual unique from others with
respect to their phenotype, susceptibility to disease or
health and their differential responses to nutrients
(Elliott and Johnson, 2007). Nutritional factors strongly
affect the association of common gene variants with
multi-factorial chronic conditions. Evidently, major
metabolic diseases are closely inter-related, often
through obesity, caused mainly by dysregulation of
energy homeostasis. Under certain circumstances, diet
can be a risk factor for some individuals, while in
others it may be beneficial (Rajoka et al., 2012). On
the other hand, nutrigenetics is to elucidate the effect
of genetic variation on the interaction between diet &
disease, for example; phenylketonuria (PKU) and
describes how the genetic make-up of a particular
Naga Muralidhar Merugu et al.
individual co-ordinates their response to various dietary
nutrients (i.e. in the simplest terms: gene → diet
interactions) (Mutch et al., 2005; Berna et al., 2014).
Further, it also shows why and how people respond
differently to the same type of nutrient. It has the
potential to provide scientific evidence for personalized
dietary recommendations concerning health
management based on the individual’s genetic makeup.
Generally dietary bioactive compounds act on the
genome directly or indirectly and alter gene expression.
Some diet-regulated genes are likely to play a role in
the onset, progression, and/or severity of metabolic
syndrome. Further, dietary interventions based on
knowledge of nutritional requirement, nutritional status
and genotype could be used to prevent, mitigate or
cure metabolic syndrome.
Epigenetics is defined as the study of changes
in organisms caused by the modification of gene
expression, rather than the alteration of the genetic
information itself. Epigenetic regulation is an essential
process in normal development that occurs all through
life. Further, it has been explained as the study of
external or environmental factors that turn genes on
and off and affect how cells read genes. The
excitement about epigenetics is how the gene
expression stably reprogrammed in response to
transient external stimuli. It is required to achieve
stable expression or repression of genes in specific
cell types or at specific time-points and constitutes
the link between genotype and phenotype. Most
importantly, it could be inherited between generations
steadily by mitosis and meiosis through cell
differentiation. Epigenetic conditions can illustrate the
reason why an organism produces many different cell
types during its development, despite the fact that most
of the cells in a multi-cellular organism share the same
genetic information. Epigenetic change is a regular
and natural occurrence but can also be influenced by
several factors including diet, environment/lifestyle,
age and disease state. Studies have shown that the
effects of nutrition/diet could be passed on
epigenetically to the offspring add weight to the idea
that histones act as metabolic sensors, converting
changes in metabolism into stable patterns of gene
expression. Three important mechanisms involved in
epigenetic regulations include DNA methylation,
histone modifications and non-coding RNA (siRNA/
miRNAs) associated gene silencing. The interplay
and progressive combination of these regulatory
Nutri (EPI) Genomics and Metabolic Syndrome
mechanisms may ‘‘lock’’ the epigenome in specific
states, thereby determining the fate and physiology
of a given cell (Katada et al., 2012). Thus, intake of
dietary methyl-groups (choline, methionine, genistein
and folate) during critical periods of development can
alter promoter DNA and histone (de) methylation/
(de) acetylation, resulting in life-long changes in gene
expression and thereby altering the epigenome
towards obesity in adulthood. Further, exposures to
nutritional status (under-nutrition/over-nutrition) that
occur at different developmental stages such as pre-
conception, in utero and early life may result in
epigenetic dysregulation, which put the individuals at
a higher risk to develop chronic diseases later in life.
The methylome is the genomic distribution of
methylated DNA sequence present in a cell and is
capable of undergoing modification with respect to
the environment/diet or the developmental stage
(Kanherkar et al., 2014). DNA methylation occurs
at the cytosine residues of DNA, especially in CpG
dinucleotides present in regions called CpG islands.
DNA methylation is generally associated with reduced
transcriptional activity through decreased binding of
transcription factors and also by attracting methyl CpG
binding proteins that act as transcriptional repressors.
Over 85% of CpG dinucleotides are spread out in the
genome and located in repetitive sequences that are
heavily hypermethylated/transcription - silenced in the
normal cells, a state crucial to the integrity of the
chromatin structure of the genome (Zhu and Yao,
2007). Further, genetic variation could have an effect
on promoter DNA methylation percentages and
subsequently on the regulation of gene expression
(Kalashikam et al., 2014). On the other hand, histones
are globular proteins around which DNA is packaged
to make chromatin. Enzyme modifications, such as
methylation and acetylation of lysine residues in their
amino termini, lead to the conformational change in
histones. Acetylation leads to increased DNA
accessibility, and methylation can either increase or
decrease DNA accessibility depending upon the
specific type of methylation and histone modification
(Yasui et al., 2003). DNA methylation and histone
modification often work in tandem, as MBPs (methyl
– CpG - binding proteins) recruited by DNA
methylation that may exert their effects through
recruitment of histone deacetylases, resulting in
chromatin condensation and transcriptional
inactivation.
1427
Interplay of various regulatory mechanisms are
expected to have regulatory roles in the inheritance
and vulnerability to metabolic diseases i.e., obesity,
type 2 diabetes, hypertension and CVD by affecting
the expression(s) of the associated gene(s). Also,
during specific developmental phases, intrauterine
atmosphere can vary the epigenetics of an individual
and may work as a foundation for the metabolic
disease like obesity and other phenotypes during later
stage of life. For example, variations in birth weight
are affected by several factors like in utero and
placental factors, maternal genes and BMI, paternal
genes, smoking, alcohol consumption, drug use, and
exercise during pregnancy etc. In a similar manner,
poor/malnutrition during early and post-natal period
also affects the mother’s metabolism to acclimatize
and favour storage of nutrients in mother’s body. A
study on Pima Indians showed that paternally imprinted
gene located on chromosome 11 position 80 cM
influences birth weight (Lindsy et al., 2002). Similarly,
in a study on Mexican Americans, quantitative trait
loci (QTL) on chromosome 6q, was found to be
associated with birth weight regulation (Arya et al.,
2006). Hence, gene-environment (GXE) interactions
play a significant role in the aetiology of obesity,
perhaps via modifications in DNA methylation patterns
(Kalashikam et al., 2014). Apart from the well
established fact that variations at DNA sequence level,
the epigenetic incidents also seem to contribute to the
development of metabolic diseases and its
epidemiology, which is evident from modern day
sedentary living style.
Research studies have shown that during the
early years of life, monozygotic (MZ) twins are
epigenetically indistinguishable from each other.
Interestingly, with increasing age, remarkable
differences become noticeable in their overall content
and genomic distributions of 5-methylcytosine in DNA
and histone acetylations. Similarly, diet/environment
could have an influence on individual’s BMI and health.
A comparative study of epigenetic metastability of
6,000 unique genomic regions between matched
monozygotic (MZ) and dizygotic (DZ) twins
demarcated epigenetic differences in both the MZ
and DZ twins (Kaminsky et al., 2009). Molecular
mechanisms of heritability may not be limited to
differences in DNA sequence only. Indeed, epigenetic
modifications also act as one of the very important
governing factors in unravelling the secrets behind
1428
the blue prints of DNA sequence. Latest developments
indicate that epigenetic research would add a new
dimension by explaining inter-individual variations in
body weight. With the use of advanced technologies,
epigenetic profile of the metabolic diseases like obesity,
CVD etc associated genes can be discerned and could
be applied in a genome-wide approach. Latest
technological developments and ongoing research on
epigenetics aspects are continuously uncovering the
role of epigenetics in a variety of human disorders
and fatal diseases. The renewed interest in epigenetics
has led to new findings about the relationship between
epigenetic changes and a host of disorders including
various cancers, mental retardation, immunity,
neuropsychiatry and paediatrics. Specifically, it is very
important to explore more about diet and epigenetic
changes and its relation with development of metabolic
diseases.
To understand the development and or
progression of metabolic disease, the present day
predictors are circumscribed by heritability,
environmental factors such as diet, lifestyle, and gut
microbiome. It is very clear that advances in
nutrigenomics and epigenomics would further the
understanding of the complex interplay between
genotype, phenotype and environment, which are
required for development of personalised nutrition in
the future. Improving diet and other lifestyle
behaviours’ has considerable potential for reducing
the global burden of non-communicable diseases,
especially metabolic diseases and promoting better
health.
Gene-nutrient Interaction
Gene-nutrient interactions are complex and hard to
predict, thus demonstrating the need for highly
controlled genotypes and environmental conditions that
allow identification of different regulatory patterns
(Doo and Kim, 2015). Differences in genetic make-
up or genotype are the factors that determine the
phenotype; on the other hand nutrient imbalances could
also play a key role (Nature Vs Nurture). Whether
dietary intervention affect the outcome of phenotype
(GXE=P) is determined by the diseased condition
known to have genetic and/or environmental
components (nutritional) (Perusse and Bouchard,
2000). A large number of studies have shown that
nutrients alter gene expression at the level of gene
Naga Muralidhar Merugu et al.
regulation, signal transduction and through alterations
in chromatin structure and protein function. All
organisms in the universe, simple or complex, have
the ability to respond to nutrient or nutrient/ hormonal
signals, which regulate gene expression i.e., synthesis
of mRNA, encoding the enzymes involved in their
metabolism (Qi and Cho, 2008). Nutrients such as
macronutrients (fatty acids, proteins and
carbohydrates) and micronutrients (minerals and
vitamins) along with phytochemicals in food regulate/
alter gene expression. Nutrients act as signalling
molecules that activate cellular sensing mechanisms,
which in turn degrade them (nutrients) into metabolites.
Hence, the modifications in gene expression may
affect muscle, liver, pancreatic β cells, hypothalamus,
adipose tissue etc. The effects of these gene-nutrient
interactions can be deleterious or protective thereby
regulating energy homeostasis and metabolic
pathways. Use of high throughput technologies has
facilitated the collection of important information by
studying the interaction of bioactive food components
with genome at cellular and molecular level.
Development of metabolic syndrome is practically
linked with unbalanced nutrient intakes and generation
of reactive oxygen (ROS) and nitrogen species
(RNS). The nutrients keep the desired balance
between total oxidation status and total antioxidant
response of the organism to maintain a balance
between these two variables (Rajoka et al., 2012).
Metabolic Syndrome (Mets)
The metabolic syndrome (MetS) is a clinical entity of
substantial heterogeneity, represented by a cluster of
biochemical and physiological abnormalities
(Goyenechea et al., 2008; Phillips, 2013). The major
risk factors for developing MetS are physical
inactivity, diets rich in fats (particularly saturated fatty
acids) and carbohydrates, contributing to the clinical
features such as central obesity, insulin resistance,
inflammation, hypertension and dyslipidaemia.
Clustering of these risk factors leads to an increased
risk for the development of type 2 diabetes and
cardiovascular disease (Roche et al., 2005; Qing Song
et al., 2006; Taylor et al., 2013; Han et al., 2016).
Therefore, it is important to understand the biological
impact of gene–nutrient-disease interactions that
provide an insight into the pathogenesis and
progression of metabolic syndrome.
Nutri (EPI) Genomics and Metabolic Syndrome
Obesity
Obesity is an important clinical and public health
challenge, characterized by excess adipose tissue
accumulation resulting from an imbalance in energy
intake and expenditure. It has become one of the major
threats in the industrialized world not only among
adults, but also among adolescents and children. It is
influenced by the interaction of genes, nutrition,
environment and lifestyle. Apart from environmental
and social factors, genetic differences play an
important role in the development of obesity (Rao et
al., 2014). Central adiposity is the primary causal
factor in developing insulin resistance, the hallmark
of metabolic syndrome (MetS) (Roberts et al., 2013).
Several studies have reported that mutations in a
number of genes including leptin (LEP), leptin receptor
(LEPR), pro-opiomelanocortin (POMC), fat mass and
obesity- associated gene (FTO) and melanocortin-4
receptor (MC4R) are associated with fat accumulation
and obesity development (Martínez et al., 2007;
Fawcett et al., 2010; Deliard et al., 2013; Muller et
al., 2014). Youssef et al. (2013) have reported that
high energy intake is associated with the Trp 64 Arg
polymorphism of ADRB3 gene, leading to significant
increase in the risk of obesity. A promoter variant
rs11872992 in MC4R has shown that increased food
intake and decreased energy expenditure leads to
increased risk for obesity. A mis-sense variant in the
IL6R (interleukin 6 receptor) gene, Asp 358 Ala (T >
G substitution) interacts significantly with dietary
energy intake and the risk of abdominal obesity.
Intake of total fat and saturated fatty acid (SFA) was
significantly associated with waist circumference in
individuals carrying the peroxisome proliferator-
activated receptor alpha (PPARa) Leu 162/Leu 162
genotype, but not in those with the Val 162 allele
(Youssef et al., 2013). A population-based study
showed Gly 482 Ser of the PPARGC1A gene was
associated with increased risk of obesity only in elderly
men (age > 50) with low physical activity (Ridderstrale
et al., 2006). Recently, a significant interaction
between the FTO gene variant rs9939609 and physical
activity in relation to obesity risk has been reported in
a Danish population (Phillips, 2013). FTO gene was
one of the first genes to be associated with BMI,
with increased intake of nutrients and decreased
satiety found to be more prevalent in subjects with
MetS. Another study reported that a G>A transition
at position -2549 in the promoter region of the LEP
1429
gene was shown to be associated with obesity and
also the carriers of -2549A allele have higher leptin
levels and lower weight loss despite they were
subjected to low calorie intake (Basic et al., 2012). A
clear understanding of potential gene-nutrient
interactions, would give possible insights to manipulate
diet in such a way to minimize the metabolic risk for
obesity.
Insulin resistance (IR) and impaired glucose
tolerance (IGT)
Impaired glucose tolerance (IGT) is a pre-
diabetic state of hyperglycaemia that is associated
with insulin resistance and increased risk of
cardiovascular pathology (Nathan et al., 2007). Insulin
is a pancreatic hormone that helps the body use
glucose, the main source of energy which travels in
bloodstream to cells throughout the body. As blood
glucose level increases after a meal, the pancreas
release insulin to clear excess glucose from circulation.
Insulin resistance is a condition in which the body
produces insulin but it is not used properly by
metabolically active tissues such as muscle, adipose,
and liver cells. As a result, their bodies need more
insulin to help glucose enter the cells and over time
this results in a condition called “hyperinsulinemia”.
Subsequently, excess glucose builds up in the
bloodstream, setting the stage for diabetes.
Intervention studies have shown that high fat diets
exacerbate insulin resistance and low-fat diets, have
a beneficial effect (Zivkovic et al., 2007).
Polymorphisms in adiponectin gene (APM1, ADIPOQ,
ACRP30), and its receptors (ADIPOR1 and
ADIPOR2) are strongly associated with obesity, type
2 diabetes and insulin resistance (Tschritter et al.,
2003; Kitamoto et al., 2015). Further, studies reported
that homozygosity of G allele rs3790433 for the leptin
receptor (LEPR) was also associated with increased
risk of insulin resistance and metabolic syndrome
(Ferguson et al., 2010). Haplotype of the adiponectin
gene is associated with several features of insulin
resistance in non-diabetic individuals, including low
serum adiponectin levels. In addition, associations of
two single nucleotide polymorphisms (SNPs); the
+276G>T (rs1501299), the +45T>G, (rs2241766)
polymorphism in the adiponectin gene is associated
with higher insulin levels and insulin resistance
(Melistas et al., 2009). The presence of the risk allele
for KCNQ1(Potassium Voltage-Gated Channel
1430
Subfamily Q Member 1) variants rs2237897,
rs2237892, and rs2283228 were found to be associated
with increased fasting glucose level and decreased
β-cell function (Tan et al., 2009). A non-synonymous
variant of N-acetyltransferase 2 (NAT2) [rs1208
(803A>G, K268R)] is strongly associated with
decreased insulin sensitivity that is independent of
BMI (Knowles et al., 2015). One of the most studied
polymorphism (rs1801253) in the ADRB1 gene codes
for arginine or glycine at amino acid 389 (Arg389Gly)
found to be associated with high levels of insulin and
insulin resistance (Lima et al., 2007), and this allele is
more prevalent in subjects with high body mass index
(BMI). The intestinal fatty acid-binding protein
(IFBP), coded by the FABP2 gene, is one of the most
abundant proteins in enterocytes and its genetic
variation was associated with insulin resistance in Pima
Indians. Acetyl-CoA carboxylase β (ACC2) plays a
key role in fatty acid synthesis and oxidation pathways,
and studies showed that polymorphisms in ACC2 gene
(rs2075263, rs2268387, rs2284685, rs2284689) were
associated with impaired insulin sensitivity and
metabolic syndrome (MetS) (Phillips et al., 2010).
Dyslipidemia
Dyslipidemia is one of the very early features of MetS
and frequently precedes IGT. The pathological
condition of dyslipidemia are associated with abnormal
amount of lipids in circulation, particularly elevated
levels of low density lipoprotein (LDLs) and
decreased levels of high density lipoprotein (HDLs)
(Bitzur et al., 2009). Dyslipidemia result in high levels
of low-density lipoprotein (LDL), with more than 700
distinct mutations in LDL receptor genes. Increased
triglycerides and decreased HDL cholesterol levels
are mainly associated with mutations in the lipoprotein
lipase (LPL) and apolipoprotein E (APOE) genes,
which are important for lipoprotein metabolism.
Several variants of the APOA1/C3/A4/A5 and
APOE/C1/C2 gene clusters have been consistently
associated with the characteristic dyslipidemia of the
MetS. Apo E4, an iso-form of APOE, is very strongly
associated with vascular inflammation and
cardiovascular disease or increased risk for
myocardial infarction (Phillips et al, 2008). Long-chain
acyl CoA synthetase 1 (ACSL1) involved in
mitochondrial beta-oxidation of long chain fatty acids
and play an important role in fatty acid metabolism.
Studies showed that polymorphisms in ACSL1 gene
Naga Muralidhar Merugu et al.
(rs4862417, rs6552828, rs13120078, rs9997745, and
rs12503643) have been associated with insulin
resistance and dyslipidemia (Phillips et al., 2010). A
number of lipid sensitive transcription factors, including
FXR, LXR, RXR, PPAR, PGC1alpha, PGC1 beta,
SREBP-1a and SREBP-1c, have been implicated in
the development of the MetS. PPAR is a good
candidate gene for the MetS because of its multiple
roles in adipocyte differentiation, fatty acid metabolism,
insulin sensitivity and glucose homeostasis. The
Pro12Ala polymorphism of PPAR has been identified
as the most widely reproduced genetic variation for
the risk of T2DM and an excellent example of the
relevance of gene–nutrient interactions in the
development of T2DM and MetS (Altshuler et al.,
2000).
Hypertension
Hypertension or high blood pressure is a common
disease worldwide. Arterial hypertension constitutes
an important pathogenic element in obesity-associated
metabolic syndrome, and CVD. Major risk factors
for pathogenesis of hypertension include genetics,
nutrients (sodium, chloride, low potassium and low
calcium, low omega-3 fatty acid), obesity and other
environmental factors (Rajoka et al., 2012). The genes
responsible for renal water and electrolyte balance
act directly by impacting the function of renal sodium
transporters and indirectly by altering the expression
of adrenal/mineralocorticoid hormones. Polymorphic
genes implicated in blood pressure regulation include
renin-angiotensin; including those encoding
angiotensinogen (AGT), angiotensin converting
enzyme (ACE) and aldosterone synthetase
(CYP11B2). Angiotensin has two genotypes -AA
and GG. On the same type of diet, individuals with
AA genotype were found to have reduced blood
pressure, but not individuals with GG genotype.
Heterozygote AG genotype had intermediate level of
blood pressure (Gard, 2010). Sodium transport/
metabolism-related genes, such as those encoding for
epithelial sodium channel (ENaC) subunits, 11B-
hydroxysteroid dehydrogenase and adducin are of
interest, given the well-proven association between
dietary salt intake and hypertension. Recent genome-
wide association studies (GWAS) have identified an
association between blood pressure and the gene
encoding for folate-metabolising enzyme, methylene
tetrahydrofolate reductase (MTHFR) and showed an
Nutri (EPI) Genomics and Metabolic Syndrome
increased risk of hypertension in people homozygous
for the 677C→T polymorphism. Riboflavin in the
form of FAD acts as a cofactor for MTHFR. CVD
patients with the relevant MTHFR 677 TT genotype
had significantly higher blood pressure as compared
to CC or CT genotypes (McNulty et al., 2014). These
patients were highly responsive to riboflavin
intervention. Gene-based association scan found IGF1,
SLC4A4, WWOX, and SFMBT1 associated with
hypertension (Yang et al., 2012). IGF encodes insulin-
like growth factor 1, which is associated with
cardiovascular disorders, metabolic syndrome,
decreased body weight/size and changes in insulin
levels in mice. SLC4A4 (Solute Carrier Family 4
Member 4) encodes the electrogenic sodium
bicarbonate co-transporter 1 and is associated with
decreased body weight/size and abnormal ion
homeostasis in mice. Similarly, WWOX encodes the
WW domain-containing protein, which is related to
hypoglycaemia and hyperphosphataemia. SFMBT1,
which encodes the Scm-like with four MBT domains
protein 1, is a novel hypertension gene.
Inflammation
Diet is an important regulatory factor in immune
response; while malnutrition leads to susceptibility to
infections due to immuno-suppression, over-nutrition
leads to immuno-activation due to susceptibility to
inflammatory condition. Therefore, optimal nutrition
is required for a healthy immune balance.
Observational and interventional studies suggest that
diets rich in trans fats and/or saturated FAs are highly
related to the immune response by increasing the
circulating pro-inflammatory cytokines; interleukin-6
(IL-6), C-reactive protein (CRP), tumour necrosis
factor- alpha (TNF-α) (Hansongyi et al., 2013).
Therefore, high fat and/or carbohydrate diet causes
excessive body fat accumulation, impairs immune
system and affects the inflammatory status. Obesity
(a crude index of adiposity/BMI) is associated with
alterations in immunity (a chronic low-grade
inflammation) in which there is an elevation of a
variety of circulating adipokines, including leptin,
adiponectin, resistin, and visfatin, as well as pro-
inflammatory cytokines such as IL-6, CRP, interferon
gamma (IFN-γ), and TNF-α etc (Shoelson et al.,
2007; Hansongyi et al., 2013). These elevated pro-
inflammatory molecules produced by the adipose
tissue are implicated as active participants in the
1431
development of metabolic syndrome (Nino-Fong et
al., 2007). Adipose tissue not only acts as major energy
storage tissue but is also a metabolically dynamic
endocrine organ and an important source of several
bioactive compounds such as hormones, cytokines,
chemokines, growth factors and complement proteins.
These substances play a central role in the whole
body homeostasis by influencing a variety of biological
and physiological processes such as food intake,
energy balance, insulin action, glucose/lipid
metabolism, angiogenesis /vascular remodelling, blood
pressure, and coagulation. Excessive fat storage in
adipose tissue due to positive energy balance (excess
nutrient intake) leads to hypoxia and hypoxia-induced
fibrosis, adipose tissue cell death, and adipocyte stress,
which in turn trigger the chronic systemic low grade
inflammation. Studies have shown that TNF-α-
308G>A polymorphism in the promoter region is
associated with increased plasma TNF-a
concentrations and is associated with insulin
resistance, obesity, type 2 diabetes, and metabolic
syndrome (Hoffstedt et al., 2000; Vendrell et al.,
2003; Gupta et al., 2012). The association between -
174G>C polymorphism (rs1800795) in the promoter
region of the IL-6 gene and insulin resistance is
modified by body mass index (BMI) (Underwood et
al., 2012). A study showed that the concomitant
presence of promoter polymorphisms of TNF-a (G-
308A) and IL-6 (C-124G) in obese subjects with
impaired glucose tolerance carry twice the risk of
conversion to type 2 diabetes, when compared with
other genotypes (Kubaszek et al., 2003).
Consequential Risks Associated With Metabolic
Syndrome
Type 2 Diabetes (T2DM)
Type 2 Diabetes Mellitus characterized by
hyperglycaemia, results from defects in insulin
secretion and activity or both. It is associated with
dysfunction and failure of different organs, such as
blood vessels, heart and kidneys. T2DM is clinically
defined as having an overnight fasting serum glucose
> 126 mg/dL or a haemoglobin A1c (HbA1c) > 6.5%.
Diabetes is more prevalent among specific ethnic/
racial groups, providing evidence for genetic
predisposition. Genetic and functional data indicate
that CAPN10 (which encodes cysteine protease
calpain 10) plays an important role in insulin resistance
1432
and intermediate phenotypes. Calpain 10 (CAPN10)
was the first T2DM susceptibility gene identified
through a genome-wide scan followed by positional
cloning (Dedoussis et al., 2007). CAPN10 variants
have been linked with several MetS phenotypes,
including hyper triglyceridemia, BMI and
hypertension. Studies have reported that six genes
account for majority of the monogenic forms of
diabetes. These are hepatic nuclear factors (HNF-
1α, 4α and 1β), glucokinase (GCK), insulin promoter
factor-1 (IPF-1), and neuro D1 transcription factor
(NEUROD1) (Gloyn, 2003). Further, Transcription
factor 7–like 2 (TCF7L2) gene variants (rs7903146
SNP ) are specially associated with an increased risk
both for T2DM and MetS by causing excess fat and
glycogen deposition in the liver, glucose intolerance
and hyperlipidaemia (Phillips, 2013). A study reported
that the gene, Two pore segment channel 2(TPCN2)
plays a role in metabolic regulation, and the single
nucleotide polymorphism rs1551305 in TPCN2 is
associated with type 2 diabetes risk (Fan et al., 2016).
The KCNJ11 gene, a member of the potassium
channel gene and the common polymorphisms (SNPs)
in KCNJ11 gene, such as rs5219, rs5215, rs5210,
rs5218, rs886288, and rs2285676 were shown to be
involved in diabetes (Haghvirdizadeh, 2015). A study
reported that KCNJ11 SNPs 74 (3p+215), 76 (A190)
and 77 (E23K) showed significant association with
T2DM (Dedoussis et al., 2007). FABP (FABP1) is
an abundant cytosolic lipid-binding protein that
regulates lipid transport and metabolism. The c.334-
135G>A polymorphism (rs2197076) located in the 3
prime un-translated region (UTR) of the FABP1 gene
was associated with the risk of type 2 diabetes and
the homeostatic model assessment index (HOMA
index) (Mansego et al., 2012).
Several studies in humans and animal models
have shown anti-diabetic effects of dietary flavonoids
on glucose homeostasis by regulating expression of
different genes in pancreas, liver, skeletal muscle and
white adipose that are involved in various cellular
pathways. Consumption of anthocyanins, particularly
from blueberries, apples and pears, was consistently
associated with a lower risk of T2DM (Berna et al.,
2014). These compounds were shown to regulate
carbohydrate digestion, insulin secretion, insulin
signalling and glucose uptake in insulin-sensitive
tissues by modulating intracellular pathways. Naringin
and hesperidin, the two major flavanones present in
Naga Muralidhar Merugu et al.
citrus fruits have also been shown to protect against
T2DM by activating peroxisome proliferator activated
receptors (PPARs) in liver and adipose tissue. Studies
in mice showed that bilberry anthocyanin
supplementation improved insulin sensitivity in T2DM
by down regulating the expression of gluconeogenic
enzymes and up regulation of peroxisome proliferator
activated receptor alpha(PPARα), long chain carnitine
palmitoyltransferse I (L-Cpt-1), Glucose transporter
type 4 (Glut4) and aconitase (Aco) expression in the
liver (Takikawa et al., 2010). The dietary flavones,
apigenin and luteolin found in celery, parsley were
shown to protect the cells from cytokine-induced
apoptosis by inhibiting inducible nitric oxide synthase
(iNos) expression. The major dietary isoflavones;
daidzein and genistein, primarily present in soy foods
have been shown to improve glucose tolerance and
circulating insulin concentration by increasing islet â
cell proliferation, β cell mass and survival (Kim et al.,
2007). The genotype and diet interaction studies
showed that peroxisome proliferator-activated
receptor gamma (PPARG) Pro12Ala genotype
modified the association between total dietary fat
intake and risk for obesity. The Pro/Pro homozygotes
of PPARG have been reported to be at increased
risk for obesity and insulin resistance (Roche et al.,
2005). Scavenger Receptor Class B Member
1(SCARB1) genetic variability plays a significant role
in lipoprotein metabolism. Research findings show that
subjects carrying the A allele in exon 1 at the SCARB1
gene locus (SCARB1 exon 1, rs4238001) were
associated with significant increase in insulin
sensitivity after the consumption of a MUFA-rich diet
compared to the effect on G/G individuals (Dedoussis
et al., 2007). The fatty acid (FA)-binding protein 2
(FABP2) gene that codes for intestinal FABP
(IFABP), is crucial for fat absorption and transport.
Subjects with the Thr54 allele had higher FFA
concentrations than did those who were homozygous
for the Ala54 allele when consuming a saturated fatty
acid (SFA)-rich diet. This suggests a plausible
mechanism for the FABP2 Ala54/Thr54
polymorphism-diet interaction for the determination
of insulin sensitivity and T2D (Dedoussis et al., 2007).
Cardiovascular Disease (CVD)
CVD can be characterized as a group of multi-
factorial conditions that include cerebro vascular
diseases (stroke with transitory ischemic attack),
Nutri (EPI) Genomics and Metabolic Syndrome
peripheral vasculopathy and cardiac ischemic disease
(CHD), which includes acute myocardial infarction
(AMI), angina pectoris and sudden death (Jannes et
al., 2004). The major risk factors associated with
cardiovascular diseases are age, family history,
sedentary lifestyle, physical inactivity, hypertension,
obesity, diabetes and high blood cholesterol. All these
pathological entities are closely related to both genetic
factors and environmental influences (Rajoka et al.,
2012). CVD may also result from a variety of genetic
causes, including single-gene mutations, interaction
of multiple genes and environmental factors.
Obesity per se is a major cardiovascular risk
factor and polymorphic genes involved in controlling
energy balance provide ‘‘favourable’’ or
‘‘unfavourable’’ background for the development of
CVD. Elevated plasma levels of total cholesterol, LDL
cholesterol and triglycerides predispose to the
development of atherosclerotic plaques.
Apolipoprotein (apo) A-1 is a key component of HDL
and both apo A-1 and HDL cholesterol have been
identified as protective factors for CVD. Genetic
variation in genes encoding apolipoproteins, some
enzymes and hormones can alter individual’s sensitivity
to develop the CVD (Ordovas, 2006). Individuals
with the E4 allele in the apolipoprotein E gene show
higher low-density lipoprotein (LDL)-cholesterol (bad
cholesterol) levels with increased dietary fat intake
compared with those with the other (E1, E2 and E3)
alleles receiving equivalent amounts of dietary fat.
Polymorphism in genes encoding lipid transport
proteins, their receptors, and lipid-processing enzymes
and inflammation- related proteins are associated with
the characteristic changes in blood lipid concentrations.
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Conclusion
Since ancient times, humans have known that
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