This study investigated whether a single nucleotide polymorphism (SNP) in the leptin receptor gene (LEPR), rs1137101, is associated with obesity and type 2 diabetes in Saudi women. The researchers genotyped 425 Saudi women, including 150 obese diabetic women, 130 obese non-diabetic women, and 145 normal weight women. They found that the rs1137101 polymorphism was mainly present in the obese diabetic and obese non-diabetic groups. Additionally, there was no significant difference in genotype between the obese diabetic and obese non-diabetic groups. Therefore, this LEPR polymorphism may be a genetic risk factor for both obesity and type 2 diabetes in Saudi women.
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Leptin receptor rs1137101 variant is risk factor for obesity and type II diabetes in
Saudi adult women
Rowyda .N. Al-Harithy, Noura .S. Al-Zahrani-
Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
Address all correspondence to:Dr. Rowyda .N. Al-Harithy-Biochemistry Department,King Abdul Aziz University P. O. Box
40288 Jeddah 21499,Kingdom of Saudi Arabia.
Abstract:
Genetic variations at the leptin receptor gene locus have been linked to diseases accompanying obesity and/or
obesity-related diseases in different populations. However, the results from Previous studies have reported conflicting
results. The aim of this study was to investigate whether LEPR gene SNP Gln223Arg (rs1137101) is associated with
obesity and type II diabetes in Saudi adult women. Therefore, SNP rs1137101 in LEPR gene in a total of 425 women
(150 obese diabetic, 130 obese non-diabetic, and 145 normal weight) was investigated using PCR and sequencing
techniques.
The genotype analysis of obese diabetic, obese non-diabetic, and normal weight revealed that the polymorphism
seemed mainly confined to the first two groups of the cohort. In both obese non-diabetic and diabetic subjects,
genotype distribution differ significantly from those expected under Hardy-Weinberg equilibrium conditions (obese
non-diabetic, x2=132.6, P=0.0001; obese diabetic, x2=248.6, P=0.0001). In addition, there was no significant
difference in the genetic distribution for rs1137101 polymorphism between obese non-diabetic and diabetic women
(x2=0.01, P=0.92). The allele frequency for the polymorphism rs1137101 had a frequency of 0.09 in obese non-
diabetic and 0.05 in obese diabetic females. As a conclusion, rs1137101 polymorphism of the LEPR gene is associated
with susceptibility to obesity and type II diabetes. This polymorphism may represent genetic marker for the risk of
obesity and type II diabetes.
Running title: rs1137101polymorphism of the leptin receptor
Key words: rs1137101 polymorphism, leptin receptor, obesity, type II diabetes.
Introduction:
Obesity is a very serious problem that has been a
global epidemic since it has progressively increased
over the past several decades. It is considered as a
public health challenge because of its association with
a numerous diseases and clinical disorders, including
type II diabetes [1,2,3,4,5]. In the Kingdom of Saudi
Arabia (KSA), few epidemiologic studies have been
done to assess the prevalence of obesity and type II
diabetes. The studies showed that the percentage of
prevalence of obesity increased between 1997 and
2012 from 22.1 to 33.8% [6,7]. In 2011, among the
Saudi population, the prevalence of diabetes was
34.1% in males and 27.6% in females [8]. The
etiologies of obesity and diabetes in humans are
complex and often involve an interaction of genetic
and environmental factors. Work on obesity-related
gene–environment interactions is still in its
infancy. Having a better understanding of the genetic
contributions to obesity and gene–environment
interactions will generate a better understanding of the
causal pathways that lead to obesity. Such knowledge
could someday yield promising strategies for obesity
prevention and treatment.
Leptin receptor (LEPR) gene is a single-
transmembrane-domain receptor of the cytokine-
receptor family with widespread tissue distribution and
several alternatively spliced isoforms [9,10]. Its
product has defined a new biological pathway for the
regulation of food intake and energy expenditure. The
LEPR gene has been cloned [9] and mapped to 1p31 in
humans [11]. Polymorphisms (SNPs) in the 20 exons
and introns of LEPR gene have been identified
[11,12,12,14,15,16,17,18]. A Common variant in exon
6 of LEPR is SNP rs1137101 that causes a change of
glutamine to arginine at codon 223 [12]. The
rs1137101 polymorphism is within the region
encoding the extracellular domain of the leptin
receptor and, therefore, the amino acid change affects
all forms of the receptor. It has been shown that the
LEPR rs1137101 polymorphism is associated with the
variation in ligand binding; higher levels of ligand
binding activity have been demonstrated in individuals
homozygous for the G (LEPR Arg223Arg) allele than
in carriers of the A (LEPR 223Gln) allele [19]). The
frequency of this polymorphism was reported in many
articles and was distinct in different ethnic groups.
Some of these studies were conducted in the United
States [11,14, 20, 21,22], Asia [17,23,24], Europe
3. International Journal of Medical Sciences and Health Care Vol-1 Issue-7 (Ijmshc-703)
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[16,19,25,26,27], and Oceania [28,29]. In the search of
variants that could be important in the pathophysiology
of human obesity, SNP rs1137101 has been
investigated as possible factor [21,30,31,32,33,34,35].
Given the inconclusive nature of most studies
published to date, it is necessary to perform further
studies concerning this gene in other populations. So
far, the Saudi populations have not been included in
these studies. Motivated by the potential importance of
rs1137101 polymorphism in obesity, this study aims to
determine the relationship of rs1137101 polymorphism
with obesity and type II diabetes.
Methods
Subjects
Total of 425 women (150 obese diabetic, 130 obese
non-diabetic, and 145normal weight) were selected for
polymorphism screening. Diabetic obese women
(BMI>30kg/m2
) were recruited from diabetic patients
attending a diabetic clinic at National Guard Hospital,
Jeddah (KSA). Obese non-diabetic (BMI >30kg/m2
)
and positive controls (BMI<25kg/m2
) were randomly
chosen from individuals who volunteered for physical
check-ups in the diabetic clinic at National Guard
Hospital. All subjects signed a consent form after
being informed of the purpose and procedures of the
study. Females of ages 45-65 years were retained for
the present study and younger age were excluded from
the study. This cross-sectional study was conducted in
the Department of Biochemistry Science College, King
Abdul Aziz University, Jeddah, Saudi Arabia. The
sequencing assay was done in King Faisal Specialist
hospital and Research center, Riyadh, Saudi Arabia.
Measurements
For all the subjects, weight and height were measured
by the same observer to the nearest 0.5kg and 0.5cm;
respectively. Body mass index (BMI) was calculated
as weight (kg) divided by height (m) squared. Subjects
in this study were classified as normal weight (BMI<
25kg/m2
), or obese (BMI> 30kg/m2
).
DNA extraction and genotyping
DNA was extracted from whole blood using the
procedure described in Ultraclean DNA isolation kit
(USA), and used for subsequent analysis. The region
containing the polymorphism was amplified by
polymerase chain reaction (PCR) using primer pair
previously described (Thompson et al., 1997). The
reaction profiles consisted of an initial denaturation at
95o
C for 15min, followed by 40 cycles at 95o
C for
45sec, annealing at 60o
C for 45sec, and extension at
72o
C for 1min, with a final extention at 72o
C for
10min. All PCR products were analyzed by agarose
gel (2%) electrophoresis, purified, and sequenced by
automated sequence analysis using Mega Bace/1000
DNA analysis system (Molecular Dynamics American
Life Science, USA).
Statistical analysis
The allele frequencies of LEPR were tested for the
Hardy-Weinberg equilibrium using the Chi-Square
test. The same test was used in comparing genotype
distributions of the rs1137101 polymorphism between
obese non-diabetic, obese diabetic, and normal weight
subjects. The level of significant was defined at P≤
0.05.
Results
The amplification and the sequencing for exon 6
fragments were done for all the volunteers to screen
for nucleotide variation in the second position of codon
223. The PCR products were electrophoreised on 2%
agarose gel along with the DNA Molecular Weight
Marker XIV (size range from100-1500 b), and showed
sizes of 400bp (Figure 1). Upon sequencing of exon 6
of the LEPR gene, an A to G transition was found in
obese non-diabetic women (17.3% variant frequency)
and obese diabetic (9.7% variant frequency) at
nucleotide 668 (codon 223). The transition caused an
amino acid substitution; Glutamine was changed to
Arginine (Gln223Arg). No sequence variants were
found in the 145 normal weight individuals. Figure 2
shows the Sequence analysis of the rs1137101 variants
of the amplified exon 6 of LEPR gene.
The genotype distribution and allele frequencies for
the rs1137101 polymorphism of the LEPR gene are
presented in Table 1. In obese non-diabetic subjects,
frequency of Gln223 and Arg223 alleles were 0.91 and
0.09 respectively. The genotype distributions deviate
significantly from Hardy-Weinberg equilibrium
(X2
=132.6; df =2; P=0.0001). In obese diabetic
women, Gln223 and Arg223 allele frequencies were
0.95 and 0.05 respectively. The genotype distributions
deviate significantly from Hardy-Weinberg
equilibrium (X2
=249.6; df =2; P=0.0001).
In comparing genotype distributions of the rs1137101
polymorphism between obese non-diabetic and obese
diabetic subjects, Chi-Square test was used and
showed no significant difference in the genetic
distribution for rs1137101 polymorphism between
obese non-diabetic and diabetic women (x2
=0.01,
P=0.92). The genotype distribution of the rs1137101
4. International Journal of Medical Sciences and Health Care Vol-1 Issue-7 (Ijmshc-703)
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polymorphism was significantly different between the
two groups and the normal weight subjects (X2
=9.3; df
=1; P=0.002). These results imply a linkage of
rs1137101 polymorphism with obesity and type II
diabetes in Saudi women.
Discussion
Our results provide further support for the reported
LEPR rs1137101polymorphism effect on the risk of
obesity and type II diabetes, strengthening the notion
that this interaction effect may possibly influence type
II diabetes development. Genotype analysis of obese
diabetic, obese non-diabetic, and normal weight
revealed that the polymorphism seemed mainly
confined to the first two groups of the cohort.
Differences in genotype frequencies were observed
between obese diabetic and obese non-diabetic
women, but were not significant. The insignificant
result does not rule out the possibility that the
rs1137101 polymorphism may play a role in the
progression toward the diabetic state. Type II diabetes,
like obesity, is a polygenic disease and susceptibility to
type II diabetes is influenced by a number of genes,
each believed to have a small effect on disease
development.
We suggest that LEPR rs1137101polymorphism may
exert a small effect on the disease. This result
highlights the importance of examining rs1137101
polymorphism when assessing susceptibility to obesity
and type II diabetes and supports the idea that obesity
and type II diabetes can develop through key genes
exerting minor effects. The striking finding was the
extremely high occurrence of heterozygous genotype
C/T at rs1137101 in exon 6 of the of the LEPR gene.
The heterozygous and homozygous variant genotype
showed that Gln/Arg percentage is higher than
Arg/Arg percentage in both groups. This result does
not rule out the possibility that variation in one allele
may cause obesity and type II diabetes in combination
with an as yet unidentified and/or not studied variation
in other alleles.
Our data is consistent with earlier studies that showed
an association with obesity [11,19,21,36]. Thompson
and co-workers were the first to report an association
between Gln223Arg genotype and BMI in Pima
Indians [11]. Similar results have been reported in
postmenopausal Caucasian women [19], in the
Brazilian populations [21] and in Mexican adolescents
[36]. All studies indicated that carriers of the Arg allele
have higher BMI, fat mass, and leptin levels than Gln
homozygotes. In contrast to our results, other
researchers have demonstrated a lack of association of
this SNP with adiposity [20,22,37,38,39,].
There have been conflicting reports of association of
rs1137101 polymorphism with obesity and type II
diabetes. Investigators have pointed out reason for
hiding the effect of rs1137101 polymorphism, and they
relate that to the differences in the background
variation in other genes among studied populations
(11,12,21]. We suggest that the inconsistency in the
results may be due to the type of obesity in the
population studied, ethnicity, and/or the possibility that
other SNPs within the leptin receptor may affect this
data. Potential limitations of this study include its
moderate size. However, the inclusion of only women
of ages between 45 to 65 years provide a distinct
advantage when performing genetic studies and
evaluating the corresponding associations.
In comparing allele frequency of the polymorphism
investigated to the frequencies observed in several
other ethnic populations, it showed that, obese non-
diabetic women had a variant allele frequency (Arg
0.09) much lower than the rest of the other groups. In
British, Quebec, American, French, Australian, Greek,
and Danish showed homogenous frequencies (0.44,
0.45, 0.46, 0.44, 0.42, 0.32, and 0.43, respectively). On
the other hand, Japanese, Pima, and Pacific Island of
Nauruan were found to exhibit higher frequencies for
Arg allele of the rs1137101 polymorphism. It has been
suggested that the frequencies differ with ethnicity
[40]. In that regard, we suggest that the cause of
obesity in Saudi women may be uniquely different to
the causes of these diseases in other populations. Also,
persons with the Arg allele are more prone to obesity
and type II diabetes.
In conclusion, the results support the hypothesis of an
effect of rs1137101 polymorphism on obesity and type
II diabetes in humans. However, this effect does not
seem to have a major impact on adiposity and type II
diabetes in Saudi women. Additional functional studies
to clarify the role of the rs1137101 polymorphism on
leptin action in human metabolism are needed.
Competing interests: The author declares that they
have no competing interests.
Acknowledgments: I thank all the participants for
their generous cooperation.
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Figure 1 :Amplification of theexon 6 of LEPR gene by PCR. Lane M: molecular weight marker (100bpladder). Lanes
1-16: the amplified exon 6 fragments (size of 400bp(
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Figure 2: Sequence analysis of the rs1137101 variants of the amplified exon 6 of the LEPR gene.
Table 1: Genotype and Allele frequencies of rs1137101 polymorphism in obese non-diabetic and diabetic Saudi
women.
Group Gln/Gln Gln/Arg Arg/Arg Gln223 Arg223
Obese non-
diabetic
(n=130)
0.600 (60.0%) 0.308 (30.8%) 0.092 (9.2%) 0.91 0.09
Obese
diabetic
(n=150)
0.613 (61.3%) 0.333 (33.3%) 0.053 (5.3%) 0.95 0.05