QJM: An International Journal of Medicine, 2016, 399–404
doi: 10.1093/qjmed/hcv149
Advance Access Publication Date: 3 September 2015
Original paper
ORIGINAL PAPER
Association of HaeIII single nucleotide polymorphisms
in the SLC2A1 gene with risk of diabetic nephropathy;
evidence from Kurdish patients with type 2 diabetes
mellitus
Sabrieh Amini1,*, Mitra Javanmardi2,*, Aram Mokarizadeh3,
Farzad Maroofi2, Chiya Jalali2, Namam-Ali Azadi4, Hamid Mohammadi5
and Mohammad Abdi3,6
From the 1Department of Biology, Sanandaj Branch and 2Department of Biochemistry, College of Science,
Kurdistan and Research Branch, Islamic Azad University, 3Cellular and Molecular Research Center and
4
Department of Epidemiology and Biostatistics, Faculty of Medicine, Kurdistan University of Medical Sciences,
5
Laboratory of Health Center, State Prisons and Security and Corrective Measures Organization and
6
Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences,
Sanandaj, Iran
Address correspondence to Dr Mohammad Abdi, Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences,
Pasdaran Boulevard, Sanandaj, Iran. email: [email protected]
*The first two authors contributed equally to this paper.
Summary
Aims: Given the growing rate of patients with type 2 diabetes mellitus, uncovering the effects of gene polymorphism
on diabetes pathogenesis has attracted a lot of attention. Because glucose transporter 1 is involved in glucose uptake,
the polymorphism of this gene may be an important risk factor in type 2 diabetes mellitus or in the progression of
diabetes complications such as diabetic nephropathy. As far as the authors are concerned, this study is the first one
aiming at evaluating the probable effects of solute carrier family 2 facilitated glucose transporter member 1 (SLC2A1)
HaeIII polymorphism on clinical and laboratory outcomes of Kurdish patients with type 2 diabetes mellitus.
Methods: This study was conducted involving 126 diabetic nephropathy patients and 150 diabetic patients without renal involvement. Serum levels of Cystatin C, fasting blood glucose, creatinine and urinary albumin; levels of glycated hemoglobin
and estimated glomerular filtration rate were measured. Moreover, the Hae III polymorphism of SLC2A1 gene was determined by PCR-restriction fragment length polymorphism (RFLP).
Results: The rate of CC genotype was higher (37%) in patients with diabetic nephropathy compared with controls.
There were a significant correlation between the CC genotype and risk of diabetic nephropathy. There were significant
correlations between genotypes, serum Cystatin C and estimated glomerular filtration rate in patients with diabetic
nephropathy.
C The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians.
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Conclusions: The results demonstrated the high frequency of C allele of SLC2A1 HaeIII in Kurdish patients with diabetic
nephropathy. It was also found that this polymorphism is a significant risk factor for diabetic nephropathy. The effect of
this polymorphism on clinical and laboratory characteristics of diabetic nephropathy patients was significant.
Introduction
Affecting millions of people worldwide, type 2 diabetes mellitus
(T2DM) is a highly increasing complex endocrine and metabolic
disorder that have led to high rates of morbidity and mortality.1
T2DM accounts for over 90% of diabetes and is recognized as a
global epidemic by the World Health Organization.2 Though the
etiology of T2DM is poorly understood, risk factors that may affect the development of this complex metabolic disease include
ethnicity, life style and genetic factors.3 T2DM is associated
with micro and macrovasacular complications, among which
diabetic nephropathy (DN) is the most serious microvascular
complication of diabetes mellitus and is one of the most important leading causes of the end stage renal failure in developing
countries. DN was found to be present in 12–23% of individuals
with T2DM. Besides, the prevalence of DN in Iranian patients
with T2DM is 14–26%.4 Higher levels of glucose uptake by glomerular mesangial cells have been introduced as the main cause
of nephron damage in DN.5 The main histological event associated with DN is Glomerular mesangial enlargement due to glumeruloesclerosis and accumulation of extracellular matrix
proteins.6 Besides, the glucose transporter 1 (Glut1), the main
glucose carrier in mesangial cells, is increased in renal cortex,7
and higher glucose concentrations over-express the Glut1 protein concentration.8 This positive feedback accelerates glucose
uptake in mesengial cells, activation of protein kinase C isoforms and polyol pathway, and accumulation of fibronectin.9
Furthermore, it has been shown that DN has a direct correlation
with ethnic and genetic background.10
Due to the high prevalence of T2DM, identifying the genes or
genetic loci associated with the risk or protection of T2DM is important for understanding the mechanisms underlying the disease and for providing patients with the potential benefits of
personalized prevention and treatment programs.11 As far as
the authors are concerned, to date, over 56 susceptibility loci
have been identified for T2DM. However, from this rapidly
growing list of candidate genes, only a few have consistently
been associated with the disease.12–15 In addition, these susceptibility loci have been identified predominantly in Caucasian
populations.11 Although several single-nucleotide polymorphisms (SNPs) have been studied as susceptibility loci for T2DM in
Iranian individuals,16–20 the genes that confer susceptibility to
this condition remain unknown.
Glut1, also known as solute carrier family 2 facilitated glucose transporter member 1 (SLC2A1), is located at 1p34.2; its
cDNA lengths is about 3.7 kb, with a core promoter region and
10 exons ranging in size from 97 to 1866 bp and the coding region accounts for <10% of the total.21,22 The SLC2A1 encodes the
membrane transport protein Glut1, a carrier protein that maintains the glucose concentration at about 5 mM and is responsible for the low-level of basal glucose uptake required to
sustain respiration in all cells, especially in erythrocytes.23
Previous investigations have examined SLC2A1 as a candidate
gene that might confer susceptibility to DN. Moreover, several
SLC2A1 gene SNPs including XbaI (rs841853), Enh2-1 (rs841847),
Enh2-2 (rs841848), HaeIII (rs1385129) and HpyCH4V (rs710218)
have been studied. The results obtained from those studies,
however, have generated considerable controversy.24 Many
studies have been conducted on the effects of SLC2A1 SNPs on
protein function among patients with different ethnicities;
however, they have yielded discrepant results.25 One possible
reason for the conflicting results may be genetic heterogeneity
in different populations or clinical heterogeneity in different
studies.24 In addition, to the best of the authors’ knowledge,
there is little, if any, information about the SLC2A1 gene obtained from Kurdish population. Therefore, this study attempted to assess the possible association of HaeIII SLC2A1
polymorphism with the development of nephropathy in
Kurdish patients with T2DM.
Materials and methods
Patients
A total of 380 patients (with disease duration 10 years) were
diagnosed with T2DM, according to the World Health
Organization diagnostic criteria for diabetes mellitus.26 All
studied subjects were admitted to the Diabetes outpatient center of Sanandaj Tohid Hospital (Kurdistan, Iran). Among these,
126 individuals (28 males and 98 females) having an average age
of 51.27 6 11.32 (within the age range of 38–78), with two 24 h
micro-albuminuria levels >30 mg/24 h, were considered to have
DN. The study also involved 254 T2DM patients without DN (130
males and 124 females) as control group with an average age of
47.2 6 9.7 (within the age range of 30–67), without a known history of DN at least for the past 10 years. In addition, patients
with a history of urinary tract infection, hematuria, nephritis
and other conditions of renal disease were excluded from the
study. All individuals were from Kurdistan, a province in western Iran with a population consisting of Kurds. Written informed consent was obtained from all patients and the study
was approved by the ethics committee of Kurdistan University
of Medical Sciences.
Collection of specimens
Fasting blood samples were collected and serums were separated. The whole blood was employed for measuring total glycosylated hemoglobin (HbA1c) and DNA analysis. Moreover,
serum samples were used for determining creatinine and
Cystatin C using commercial kits, according to the manufacturer’s instructions. Glomerular filtration rate (estimated glomerular filtration rate (eGFR)) was estimated according to
Modification of Diet in Renal Disease formula.27 In addition,
24-h urine specimen was used for urinary albumin assay based
on standard sandwich enzyme-linked immuno-sorbent assay
technology. All specimens were stored at 70 C, pending simultaneous analysis.
DNA extraction
Genomic DNA was extracted from the whole blood using DNA
Extraction Kit (DNP) (CinnaGen Inc, Tehran, Iran) according to
the manufacturer’s instructions. Blood samples were incubated
S. Amini et al.
with lysis buffer, then DNA was selectively precipitated. Next,
the insoluble DNA was washed and desalted by wash buffer and
was stored at 20 C, pending simultaneous analysis.
PCR-RFLP analysis
The HaeIII SLC2A1 SNP (g20882C>T) was identified using PCR
restriction fragment length polymorphism. The PCR reaction
was performed in a final volume of 25 ll using PCR Master Mix
kit (CinnaGen Inc, Tehran, Iran), and 10 pmol of each primer
with final concentration of 400 nM, and 100 ng DNA. Primer
pair was used to amplify a fragment of 177 bp of exon 2-SLC2A1
gene. SLC2A1-Exon 2 forward primer was 50 -CTCCCA
GACACGCCTATAACAGT-30 and SLC2A1-Exon 2 reverse primer
was 50 -GTTGGCTTATGGACACCAGCC-30 . The PCR condition
was: 5 min at 95 C (initial denaturation), followed by 45 cycles of
95 C for 45 s (denaturation), 60 C for 30 s (annealing) and 72 C
for 45 s using an Eppendorf Mastercycler (Eppendorf AG,
Hamburg, Germany). In each PCR run, samples with no DNA
template were used as negative controls. Amplified DNA fragments (177 bp) were cut by restriction enzyme BshFI (Jena
Bioscience, Germany) for 15 min at 37 C. The genotypes were
identified by electrophoresis of DNA fragments generated after
digestion (two bands: 109 and 68 bp for 20882 CC, one band:
177 bp for 20882 TT and three bands: 177, 109 and 68 bp for heterozygous 20882 CT genotype).
Statistical analysis
Chi-squared test was employed to evaluate whether the alleles
or genotype frequencies differ between cases and controls. For
2 2 contingency tables, the odds ratio (OR) and its confidence
interval were calculated to determine if the association was
statistically significant at nominal 5% level. Moreover, the
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potential correlations between cystatine C, eGFR, HbA1c, urinary micro-albumin, fasting blood glucose (FBG) and creatinine
were investigated using non-parametric Mann–Whitney test. In
all performed hypothesis tests, a P value < 0.05 was considered
as statistically significant. Wherever appropriate, results were
presented in tables as Mean 6 SD, if normality assumption was
met; otherwise Median 6 the interquartile range (IQR) was used.
Results
In the first part of the study, 126 DN patients and 254 patients
without DN at nucleotide 20882 of the SLC2A1 gene were genotyped to assess its potential association with DN. Genotype distribution in both T2DM patients with and without DN showed
significant deviation from a Hardy-Weinberg distribution
(P ¼ 0.000). The CC genotype was detected more frequently in
DN patients than in patients without DN, and the difference
was significant (37% vs. 8%, P ¼ 0.004). Interestingly, it was
found that the frequency of carriers of at least one T-allele at
position 20882 of the SLC2A1 gene (carriers of 20882 TT and
20882 CT genotypes) was significantly higher in patients without DN as compared with DN patients (92% vs. 62%, P ¼ 0.05).
The 20882 CC and 20882 CT genotypes were associated with DN
in T2DM patients (OR ¼ 6.3905, 95% CI ¼ 3.2595–12.5291, Z ¼ 5.4,
P ¼ 0.0001). A summary of the genotyping results is presented in
Figure 1. Furthermore, there were no statistically significant association between studied SNP and age and gender of
individuals.
Furthermore, DN patients had higher HbA1c, urinary microalbumin, serum creatinine, serum Cystatin C and eGFR when
compared with patients without DN (see Table 1). As shown in
Table 1, a noticeable increase in Cystatin C, serum creatinin,
urinary micro-albumin and eGFR was observed in patients with
Figure 1. Prevalence of SLC2A1 HaeIII genotypes in diabetic patients with and without DN. According to the plot, the prevalence of HaeIII SLC2A1 gene polymorphism
was statistically significant: *Between the CC genotypes in DN patients with no DN controls. **Between TT genotypes in DN patients with no DN controls. ***Between
CC and TT genotypes in DN patients with no DN controls. **** Between CC and TT genotypes in DN patients.
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Table 1. Laboratory characteristics of study groups
No DN (n ¼ 150)
DN (n ¼ 126)
FBG
(mg/dl)
HbA1c
(% of total hemoglobin)
microalbumin
(mg/24 h)
Cr
(mg/dl)
CysC
(ng/ml)
eGFR
(ml/min)
126.5 6 30.4
130.2 6 29.3
5.9 6 1.3
6.1 6 2.1
19.48 6 8.79a
184.04 6 60.56a
0.93 6 0.26b
1.54 6 0.24b
1060.4 6 435.97c
1657.79 6 243.9c
112 (33)d
85 (29)d
FBG, Fasting blood glucose; HbA1c, Glycated hemoglobin; Cr, Creatinine; CysC, Cystatin C, eGFR, estimated Glomerular filtration rate. Data are
presented as mean 6 SD, except for eGFR which is presented as median (IQR). Similar letters (i.e. a, b, c and d) in each column represent significant
difference (P < 0.05) between groups.
Table 2. Laboratory characteristics of patients with regard to genotypes
TT
CC
FBG
(mg/dl)
HbA1c
(% of total hemoglobin)
Microalbumin
(mg/24 h)
Cr
(mg/dl)
CysC
(ng/ml)
eGFR
(ml/min)
160 (82)
163 (78)
5.3 (1.5)
5.4 (0.8)
175.42 (23.5)
194.12 (35.04)
1.27 (0.2)
1.35 (0.8)
570 (670)a
640 (810)a
89 (24)b
58 (16)b
HbA1c, Glycated hemoglobin; Cr, Creatinine; CysC, Cystatin C. Since CT genotype had low values, it was removed from statistical analysis. Data are
presented as median (IQR). Similar letters (i.e. a and b) in each column represent significant difference (P < 0.05) between groups.
DN compared with other patients (P ¼ 0.05). On the other hand,
the difference between DN patients and patients without DN
with regard to HbA1c and FBG was not significant.
Table 2 illustrates the values of laboratory markers in different study genotype groups. As shown in this table, there were
significant differences regarding serum Cystatin C and eGFR between genotypes; in addition, the concentration of these
markers was significantly higher in CC genotype (median (IQR)
was 640 (810) for Cystatin C and 58 (16) mg/dl for eGFR) compared with TT genotype (median (IQR) was 570 (670) ng/ml for
Cystatin C and 89 (24) mg/dl for eGFR was). However, the median (IQR) concentration of FBG, HbA1c, creatinine and microalbumin was not significantly different between various
genotypes in patients’ group.
Discussion
In this study, we focused on SLC2A1 HaeIII polymorphism
which has been less studied in previous assessments. For the
first time in Iran and especially in Kurdistan region, our study
was carried on T2DM Kurdish patients. There are several studies concerning the role of genetic polymorphism in SLC2A1
gene in diabetic patients, especially patients with T2DM.10,24,28
Among all SNPs of this gene, less attention has been focused on
mutation at position 20882 in exon 2 (C20882T), which is identified as a silent polymorphism that might influence Glut1 protein expression and function in different human tissues and
different ethnicities. Some studies have shown that the polymorphism of this locus may result in higher risk of diabetes or
its complication. Other researches, however, did not confirm
these results.25,29 Therefore, the role of Glut1 HaeIII gene polymorphism in T2DM remains largely unclear. Given the little
(if any) information available in this area, this study that, to the
best knowledge of the researchers, is the first one conducted on
Kurdish population, investigated the relationship between
SLC2A1 T20882C (HaeIII) polymorphism and the clinical and laboratory features of T2DM with and without DN.
Ng et al.29 showed that the HaeIII (þ) allele has higher frequency in both control and diabetic patients. However, they did
not find a significant association between the incidence of
diabetes and this polymorphism. In contrary, another study reported a significantly higher susceptibility to DN for homozygote HaeIII SNP compared with CC þ CT genotypes while the OR
was 13.1.25 In a recent study, Marques et al.30 evaluated the impacts of Glut1 polymorphisms on susceptibility to DN in
Brazilian patients with type 1 diabetes. They analysed four common Glut1 gene polymorphisms (rs3820589, rs1385129, rs841847
and rs841848) in 452 patients. They showed that there is a negative significant correlation between rs3820589 and DN. They
could not find any association between rs1385129 (HaeIII) and
progression of renal disease in there population. The results obtained by this study are in line with the Ng study but reject the
results of the latters. The most frequent genotype observed for
SLC2A1 HaeIII polymorphism in the patients of this study was
CC. Moreover, it was found in this study that the C allele increases the risk of DN. In this study, the frequency of CC genotype
was higher in DN group, and this genotype had a great correlation
with risk of DN. The HaeIII polymorphism of SLC2A1 results in
affectless alanine substitution at location 15 with Ala. This polymorphism located on exon 2 of SLC2A1 gene which is a transmembrane domain with an alpha-helix structure. Higher rate of
C allele as it is shown in present study may result in higher uptake in glucose to mesangial cells and this mechanism may accelerate the development of DN. Furthermore, In line with previous
studies,10,29,30 we could not find any correlation between HaeIII
polymorphism with age and gender of studied subjects.
It has also been found that the distribution of SLC2A1 polymorphism is significantly influenced by ethnicity.10 A significant difference has been reported regarding the frequency of
the SLC2A1 rs841853 SNP between different ethnic groups.10 In
a recent meta-analysis carried out by Du et al.10 it has been
showed that the SLC2A1 rs841853 polymorphism may confer
increased susceptibility to T2DM in Asians. However, there is no
currently available strong evidence supporting the association
of this genetic variation with T2DM in Caucasians, Blacks or the
overall population.10 Given that there are a few studies, as far as
the authors are concerned, that have investigated the relationship between HaeIII polymorphism and risk of diabetes, there
cannot be a correct interpretation of the relation between ethnicity and HaeIII polymorphism.
S. Amini et al.
Glut1 has been widely studied both at molecular and functional levels. It is a membrane-embedded protein that mediates
the transfer of glucose from the surrounding medium into the
cells. Glut1 is translocated after insulin stimulation of adipocytes,31,32 which may contribute to the action of insulin on glucose uptake.33 Genetic changes in glucose transporter,
especially Glut1 in glomerular cells occur early in diabetes.
These changes play a pathogenic role in the development of
extracellular matrix (ECM) expansion and perhaps other features of DN. It appears that at least some diabetic patients may
be predisposed to nephropathy because of polymorphisms in
their SLC2A1 genes.34
On the other hand, the results of the current study clearly
showed that C allele of SLC2A1 HaeIII polymorphism associated
with higher Cystatin C and eGFR, two powerful markers of kidney damage. In line with previous studies, this study also indicated that HaeIII polymorphism of SLC2A1 might increase the
risk of DN.25 However, there was not any relationship between
HaeIII polymorphism and HbA1c, or between FBG and microalbuminuria.
In conclusion, the findings of this study revealed the high
frequency of CC genotype of SLC2A1 HaeIII polymorphism in
Kurdish patients with DN compared with diabetic patients without DN. Furthermore, a strong correlation was found between
this polymorphism and clinical and laboratory characteristics
in T2DM patients with DN compared with patients without DN.
Finally, it can be concluded from the findings of this piece of research that the C allele of HaeIII SNP of SLC2A1 gene is a powerful risk factor for the progression of DN in Kurdish patients with
T2DM.
Acknowledgements
The authors would like to thank all patients and healthy
stuffs who participated in this study. These informations
are true and the work has no financial supports.
Conflict of interest: None declared.
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