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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DISCUSSION
The current investigation aimed to evaluate the association
between putative obesity-associated GHRL
rs34911341 (C>T) (Arg51Gln) and rs696217 (G>T) (Leu
72Met) gene markers and their likely effect on obesity
pathogenesis in the society of Turkish-Cypriots. To the best of our knowledge, this is the first study to evaluate
the GHRL gene variations in this population and other ethnic
populations in the Middle Eastern geographic region.
Recent studies have indicated that association studies vary
among populations. Since 1974, Turkish-Cypriots have
been located in Northern Cyprus having a de jure population
of only 256,644 [30]. Obesity is a world health problem,
and the number of individuals who suffer from obesity
also rise day by day in Cyprus. Previously, many gene loci
were associated with obesity in different studies [9,10,31].
However, the predisposition effect of these gene loci show
differences according to the interaction with environment
as well as ethnic origin. Recently, we investigated the
relationship between FTO rs9939609 (A>T), ADIPOQ
rs2241766 (G>T), and ACE rs4340288 polymorphism
and obesity in the current population [25] and our results
indicated that the FTO gene rs9939609 A allele was found
to have a strong association with pathogenesis obesity in
Turkish-Cypriots. Additionally, Becer et al. [32] did not
find direct association between obesity and the LEPR gene
Q223R polymorphism in Turkish-Cypriots]. Nevertheless,
the association between the GHRL gene variants and obesity
has been a matter of interest in recent years, especially
after bariatric surgery becoming a lifesaving trend.
Ghrelin, an orexigenic hormone in humans, is secreted
mainly by the stomach stimulating growth hormone release,
appetite and food intake, and plays a key role in regulating
the energy homeostasis of the organism [32]. Previously,
ghrelin polymorphisms were linked to BMI-related obesity
and metabolic syndrome with variable results [30,33,34].
As expected, in our study the GHRL rs696217 T allele
showed a statistically significant association with waist
circumference and hip circumference level in all subjects.
The GHRL Arg51Gln [rs34911341 (C>T)] was associated
with hypertension in Caucasian subjects [35], on the other
hand, the 51Gln marker has been found to have a protective
factor against the development of T2DM [24,36]. The
Arg51 residue is a site for proteolytic cleavage to synthesis
ghrelin, and its substitution to the 51Gln variant leads to
lower ghrelin plasma levels, resulting in less abundant
synthesizing of the preproghrelin peptide [37]. In the current
study, MAF of the GHRL 51Gln allele was less than
0.1% in both obese and non obese groups (0.94 and 0.00%,
respectively), which is closely comparable to that reported
among the global population (0.003) [29]. Our results failed
to show a significant over- or under-representation of any
of the GHRL Arg51Gln polymorphism in the obese group.
On the other hand, the GHRL gene Leu72Met
[rs696217 (G>T)] missense variant has been associated
with alcohol use disorder, alcohol consumption [38] and
bulimina nervosa [39]. Moreover, Steinle et al. [40] reported
that Met72 allele was associated with metabolic
syndrome as well as higher fasting glucose, LDL-C and
higher triglyceride levels in the Old Order Amish population.
Recent meta-analysis study by Huang et al. [41]
reported that the GHRL gene Leu72Met variation was
possibly protective against T2DM in Caucasians and
predisposing in Asians. The consequence of c.214G>T polymorphism is the amino acid substitution Leu72Met.
This amino acid residue is outside of the mature ghrelin
and the functional results of the nucleotide change is not
known [39]. In our study, the frequency of the minor allele
rs696217 T (Met72) was found to be significantly higher
in obese subjects (p = 0.0005). Thus, the GHRL rs696217
T single nucleotide polymorphism may be associated with
obesity in the population of Turkish-Cypriots.
Subjects with the rs696217 GT genotype (heterozygous)
had significantly lower serum HDL-C than GG
(wild type) subjects. Su et al. [42] showed that carriers
of the Met72 allele had significantly lower TG/HDL-C
than Leu72 genotype carriers after a high-carbohydrate
diet. Thus, these results may suggest that it is not the
preproghrelin Leu72Met polymorphism alone that is involved;
other potential intervening factors, such as nutritional
factors, may also affect plasma lipids profiles.
As well as other genetic epidemiology studies, the
limitation of this study investigation was that the number
of subjects included in the current study was relatively
small, and this might lower the sensitivity. Secondly, due
to financial issues we were unable to include serum ghrelin
level in the biochemical parameters. Therefore, this study
lacked comparisons of the GHRL gene markers (Arg51Gln
and Leu72Met) and ghrelin hormone.
Conclusions. Overall, the results from this study determine
the very good evidence of the homozygous Met72
Met genotype at the in exonic locus on the GHRL gene
may be an inherited risk factor for developing the obesity
pathology in the Turkish-Cypriot population. Along with
additional, the GHRL gene Leu72Met variant may be offered
as a screening option to the patients who come in for
obesity clinic as well as medical check-up. Depending on
the results, the individuals may be guided to change their
lifestyle such as engaging in more physical activities and
designing new diet plans.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
Funding. This study was supported by the Near East
University Scientific Project Unit (BAP) with registration
number SAG-2016-2-036.
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