DUAL EFFECT OF THE GHRL GENE VARIANT IN
THE MOLECULAR PATHOGENESIS OF OBESITY
Becer E1,2, Ergoren MC2,3,*
*Corresponding Author: Associate Professor Mahmut C. Ergoren, Ph.D., Department of Medical
Biology, Faculty of Medicine, Near East University, Near East Boulevard, 99138 Nicosia, Cyprus.
Tel.: +90-392-675-1000, Ext: 3035. Fax: +90-392-223-6461. Mobile: +90-0548-865-8889. E-mail:
mahmutcerkez.ergoren@ neu.edu.tr
page: 27
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INTRODUCTION
A worldwide public health problem, obesity shows
a complex etiology due to its association with type 2 diabetes
mellitus (T2DM), hypertension, cardiovascular disorders
as well as cancer. Human adiposity is the result of
the complex interaction of mainly social, psychological,
environmental and more importantly genetic factors [1].
Obesity is a result of excess weight due to storing of extra
calories as fat when a person consumes more calories than
they use as energy [2].
Epidemiological studies have shown that glucose
intolerance, hypertension and abdominal obesity lead to
coronary health diseases [3,4]. Genetic modifiers together
with environmental factors have an important role in the
susceptibility of obesity [5-7]. Thus, obesity phenotypes
that exhibit multifactorial genetic characteristics vary, depending
on lifestyle, dietary habits and genetic background
of the individual.
Therefore, phenotype-obesity relationship to show
which individual is at-risk for developing obesity and
which one is resistant to treatment interventions or diet,
should be well determined [4-9]. Nevertheless, to determine
the interaction between obesity and genetic markers,
genetic linkage and association studies were performed
to identify the candidate genes causing obesity. In 2005,
the Human Obesity Gene Map project conducted 1100
scientific studies on 500 genes, genetic determinants and
chromosomal regions that could possibly be associated
with human obesity phenotypes, and were reported in
particular cohorts [10]. Moreover, to date, approximately 100 genes have been associated with obesity and coronary
heart diseases [11]. Although the results vary according to
the evaluated population, genetic variants play a significant
role in the development of obesity.
Leptin and ghrelin are proteins that regulate appetite
and energy balance in the human body. Previous studies
have shown that genetic changes in those genes that encode
peptides or receptors are associated with body weight and
metabolic abnormalities [12]. Ghrelin, a potent growth
hormone stimulator (secretogogue), works in opposition
to leptin. It stimulates appetite and nutrition are called
orexigenic. Fasting increases the ghrelin level and it drops
after 60-120 min. after nutrient intake [13]. Previous studies
indicated that, the highest ghrelin level was found in
anorexia nervosa and Prader-Willi syndrome [14]. The
human ghrelin hormone is composed of 28 amino acid
peptides produced from 117 amino acid preproghrelin
[15]. The growth hormone secreting receptor (GHSR)’s
endogenous ligand, ghrelin, stimulates the appearance of
growth hormone (GH). Thus, it plays an important role
in apetitis control, body weight and insulin and glucose
metabolism [16,17]. Plasma ghrelin levels are inversely
proportional to obesity, T2DM as well as insulin resistance
[18-20]. Variations within the GHRL gene could possibly
raise ghrelin protein defects and affect its function.
The GHRL gene variants, Leu72Met and Arg51Gln,
resulting from nucleotide substitutions on the second
exon, have previously been associated with obesity in
many populations. The GHRL c.214G>T (p.Leu72Met)
(rs696217) polymorphism was localized in exon 2 within
the GHRL gene. The association between the Leu72Met
variant and obesity has been shown in obese Italian children
and in middle-aged overweight Japanese men [21,22].
On the other hand, no association was found in the Danish
population [23]. The GHRL Leu72Met variant and obesityrelated
phenotype and metabolic diseases vary according
to different populations. Surprisingly, there is no study to
show any association of the GHRL c.152C>T (p.Arg51
Gln) (rs34911341) variant and being obese in the literature
[24]. Detection of gene variants and modifiers that might
regulate the gene expression are crucial. Together with
determination of the allele frequencies within the population
are significant to precision medicine.
Recently, we have investigated the association between
the Adiponectin (ADIPOQ), the fat mass and obesity-
associated (FTO) and the angiotensin I-converting
(ACE) genes variants and obesity [25]. There is no investigative
study showing the relationship between the
GHRL gene polymorphisms and obesity in North Cyprus.
International databases such as the Human Genome
Variation and the American National Library of Medicine
have identified gene polymorphisms found in many societies
and explained their observed frequencies in the community.
Unfortunately, Cyprus and many middle eastern
countries such as Turkey do not exist in those databases. In
our study, we aimed to investigate the association between
the GHRL gene variations and obesity in the population
of North Cyprus.
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