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Study of Single Nucleotide Polymorphism rs13266634 in Zinc Transporter
Solute Carrier Family 30, Member 8 (SLC30A8) Gene in Type 2 Diabetes
Patients Resident in Ismailia City
Taher I. EL-Serafi, Samir M. Abdel-Moneium, Nagwan A. Sabek and Marwa
M. Hosny
Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University
Abstract
Background: Several genome-wide association studies identified a strong
association of SLC30A8 with type 2 diabetes in individuals of European ancestry.
The effect of the association of rs13266634 with type 2 diabetes or related
glycemic traits has not been fully extended to non-European populations, and a
comprehensive examination of common variants in the gene has not yet been
carried out in our population.
Objective:The aim of the present study was to investigate the association among
the polymorphisms of SLC30A8, and the risk of T2DM and to determine the
presence and frequency of single nucleotide polymorphism (SNP) rs13266634 in
SLC30A8 gene in T2D patients resident in Ismailia city.
Design: SLC30A8 SNP was genotyped using real time PCR allelic discrimination
TaqMan assay.A case control study was conducted in 68 casesof type 2 diabetes
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(51 women and 17 men) and 29 controlsubjects (13 women and 16 men) from out-
patients diabetic clinic of Suez Canal hospital and age and gender were matched.
The SNP rs13266634 was evaluated in SLC30A8 C > T genotype.
Results: The genotypes of control subjects were 27 (93%, C/T), 1 normal
homozygot (3.5% C/C) and 1 mutant homozygous (3.5%, T/T). In diabetic
subjects, there were 58 subjects carriers of heterozygous (C/T, 85%), 6 normal
homozygots (C/C, 9%) and 4 mutant homozygous (T/T, 6%). There was
significant difference in fasting blood glucose levels in control subjects compared
to diabetic subjects' P
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summary, the data in this study support substantial associations between the
common SLC30A8 polymorphisms in gene and the risk of type 2 diabetes.
Conclusions: Our results may provide evidence that SLC30A8 is a susceptible
locus for type 2 diabetes in our population, and its variant can influence insulin
secretion.
Keywords: SNP, Single Nucleotide Polymorphism, Solute Carrier Family 30,
Member 8 (SLC30A8).
Introduction
T2D represents 90-95% of the population with diabetes. According to the World
Health Organization(1), the number of patients with T2D in Egypt was 2,623,000
and in 2030, it is expected to increase to 6,726,000.It has reached epidemic
proportions and currently affects about 170 million people worldwide, with the
figure projected to be more than double by 2030(2).
Diabetes is a leading cause of both mortality and early disability, it is the leading
cause of blindness among working age adults, of end-stage renal disease, and of
nontraumatic limb amputations. Diabetes increases the risk of cardiac, cerebral and
peripheral vascular disease two to seven fold(3). T2D has a strong genetic
component. Major genes that predispose to this disorder have yet to be identified,
but it is clear that the disease is polygenic and multifactorial(4). T2D is due to
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variations within several genetic loci that confer increased susceptibility towards
the environmental challenges such as high-caloric fat and carbohydrate-enriched
diets and sedentary lifestyle with markedly reduced physical activity(5).
Linkage studies, candidate-gene approaches, and genome-wide association studies
identified single nucleotide polymorphisms (SNPs) within currently up to ten
genes which associate with an increased T2D risk. Most T2D risk loci are
supposed to contribute to -cell dysfunction(6). Zinc transporter 8, a member of the
zinc transporter family, is coded by solute carrier family 30 member 8 gene
(SLC30A8) on chromosome 8q24.11. The encoded protein has 369 amino acid
residues, with six transmembrane domains and a histidine-rich loop between
transmembrane domains IV and V, like other family members(7).
It has been reported that SLC30A8 is expressed predominantly in pancreatic cells
and transports zinc from cytoplasm into insulin secretary vesicles(8), in which
insulin is stored as a solid hexamer bound with two Zn2 ions before secretion(9).
Zinc plays an important role in all processes of insulin trafficking, i.e. synthesis,
storage, and secretion(8). The variations in SLC30A8 may affect zinc accumulation
in insulin granules and hence influence insulin stability and insulin trafficking.
Glucose stimulated insulin secretion is enhanced in insulinoma (INS-1) cells
transfected with SLC30A8 in a high glucose challenge(10).
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Researchers have identified SNP rs13266634, a nonsynonymous Arg (Arginine)325
Trp (Tryptophan)325 variant in the pancreatic beta-cell-specific zinc transporter
SLC30A8(8 ,11). Beneficial antioxidant effects of zinc supplementation have been
found in people with type 2 diabetes(12). Excessive apoptosis of pancreatic beta
cells has been associated with diabetes(13). Zinc depletion by itself is a well-known
inducer of apoptosis(14), thereby participating in decreased in beta cell mass. In
addition, some studies suggest that cells with deprived zinc stores are less able to
defend themselves against oxidative injuries, underlining the antioxidant properties
of zinc. Therefore, enhancing the capacity of beta cells to store zinc may help to
protect the pancreas against zinc depletion and/or oxidative stress frequently
observed in diabetes(10).
In the light of these novel findings, this study aimed to determine the presence and
the frequency of the SNP rs13266634, variant in the pancreatic beta-cell-specific
zinc transporter SLC30A8 and the association among the polymorphisms of
SLC30A8, and the risk of T2DM in our population resident in Ismailia city.
Subjects and Methods
Subjects: casecontrol study of 68 cases of type 2 diabetes (51 women and 17
men) aged 436 years and 29 controlsubjects (13 women and 16men) aged 42 6
years, attending out patient's diabetic clinic of Suez Canal hospital. Diagnosis of
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type 2 diabetes mellitus was based on clinical and laboratory criteria (1). Inclusion
criteria were as follows: 1) BMI (weight in kilograms divided by the square of
height in meters)
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NanoDrop (ND)-1000 Spectrophotometer V3.1.0 (NanoDrop Tech., Inc.
Wilmington, DE USA.) and stored at -20C.
Genotyping of SNP (rs13266634) SLC30A8: SLC30A8 SNP was genotyped using
real time PCR allelic discrimination TaqMan assay (Applied Biosystems,
California, USA). Each assay includes non-labeled forward and reverse primers
along with two fluorescent TaqMan oligonucleotide probes (allele 1-specific probe
labeled with VIC fluorophore, allele 2 specific probe labeled with FAM (6-
carboxy- fluoroescein fluorophore). The VIC and FAM reporter dyes are
covalently attached to 5' terminal base of the two probes and the non fluorescent
quencher dye is attached near the 3' ends. The probes are capable of differentially
binding to the amplicons generated during PCR reactions contained 20 ng of
sample DNA, 12.5l of TaqMan Universal PCR master mix, and 1.25 l of
TaqMan SNP genotyping assay mix. Appropriate negative controls were also run.
Real- time PCR was performed on an ABI Prism 7000 Sequence Detection System
(Applied Biosystems, Foster City, USA) using the following condition: 95C for
10 minutes, and then 40 cycles of amplification (92C denaturation for 15 seconds,
60C annealing/extension for 60 seconds) according to manufacture's protocol and
the discrepancy rate on duplicate genotyping was 0-1%.
Statistical analysis: Descriptive results of continuous variables are expressed as
mean SD. Before statistical analysis, normal distribution and homogeneity of the
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variables were tested. Comparison of variables between groups of subjects was
performed using the Students t test. We used Statistical Package for Social
Science SPSS for WINDOWS software (version 11.0; SPSS Inc, Chicago, IL) for
all statistical analyses. We evaluate the influence of selected SNPs on continuous
variables by using the Bonferroni test to adjust for covariates such as age, sex, and
BMI. Each variable was examined for normal distribution; mean values are
presented on untransformed and unadjusted variables. Statistical analysis was
performed with paired samples t-test. A 2-tailed value of P < 0.05 was considered
significant. All analyses were repeated after sequentially adding sex, current age,
and BMI as covariates.
Results
Genotyping and allelic frequencies among diabetic patients and controls subjects in
the association study were summarized in Table (I). To investigate the association
of SLC30A8 with risk of T2DM in our populations, real time PCR allelic
discrimination TaqMan assay was used to determine the distribution of allele and
genotype frequency of this variant. We conducted a casecontrol study of 68 cases
of type 2 diabetes (mean age, 426 years; 51 women and 17 men) and 29 control
subjects (mean age, 436 years; 13 women and 16 men) from out patient's diabetic
clinic of Suez Canal hospital. The genotypes were consistent with Hardy-Weinberg
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equilibrium, the frequencies of C and T alleles for control subjects were (50% and
50%) respectively, and for diabetic subjects were (51% and 49%) respectively.
The genotype distributions of SNP (rs13266634) SLC30A8 in control subjects
were (3.5%C/C, 93% C/T and 3.5%T/T) and (9% C/C, 85% C/T & 6% T/T) for
diabetic subjects (Table I).
Clinical and biochemical characteristics: The clinical and biochemical
characteristics of all subjects in the association study were summarized in Table 2.
There was no significant differences in age and sex, but there was statistical
significant differences in fasting blood glucose levels were observed between
diabetic subjects comparing to control subjects (215 87 mg/dl vs. 97 7 mg/dl,
p < 0.05), there was statistical significant differences in BMI were observed
between diabetic subjects comparing to control subjects (30 6 vs. 27 3.0 kg/m2
P
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(III), there were higher non statistical significant differences in lipid profile
(triglyceride, cholesterol and LDL-c levels between diabetic subjects carrier C/C
and C/T genotype. Also, there was statistically significantly a difference in
triglyceride levels between diabetic subject's carrier C/C and diabetic subject's
carrier C/T genotype (13735 mg/dl vs. 11034 mg/dl; P< 0.05); as shown in table
(IV).
Table (I): Genotyping and allelic frequency of SNP (rs13266634) SLC30A8 in T2D patients
and control subjects.Genotyping Allelic frequencyCC CT TT No. C T No.
Control 1(3.5%)
27(93%)
1(3.5%)
29100%
14.5(50%)
14.5(50%)
29100%
Diabetic 6(9%)
58(85%)
4(6%)
68100%
35(51%)
33(49%)
68100%
Table (II): Clinical characteristic and biochemical parameters of genotype of SNP(rs13266634) SLC30A8 between control and diabetic subjects.
Controls SubjectsNo.(29) MeanSD Diabetic patientsNo. (68) MeanSD P
Sex (male/female) 16/13 17/51 NsAge (years) 426 436 NsBMI(kg/m2) 273 306 0.04*FBG (mg/dl) 977 21587 0.001*Cholesterol (mg/dl) 21953 24239 0.211TG (mg/dl) 9027 11452 0.101HDL-C (mg/dl) 8718 5812 0.001*LDL-C (mg/dl) 13536 14246 0.351
Data presented as means SD, Abbreviations: Ns: Not significant, BMI: Body mass index,
FBG: Fasting blood glucose, TG: Triglyceride, HDL-c: High density lipoprotein cholesterol,LDL-C: Low density lipoprotein cholesterol.*P value 0.05 was significant *.
Table (III): Association of clinical characteristic and metabolic parameters with genotypeof SNP (rs13266634) SLC30A8 between control and diabetic subjects C/T genotype.
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Control C/T genotype Diabetic C/T genotype PMean SD Mean SD
No. 27 58Age (years) 42.66 42.96 NSBMI (kg/m2) 273.5 306 0.08
FBG (mg/dl) 987 20681 0.001*Cholesterol (mg/dl) 22150 24539 0.280TG (mg/dl) 8926 11034 0.108HDL-C (mg/dl) 8818.5 57.911 0.001*LDL-C (mg/dl) 13736.5 141.245.8 0.460
Table (IV): Association of clinical characteristic and metabolic parameters with genotypeof SNP SLC30A8 between C/T and C/C genotype diabetic subjects.
Diabetic C/C genotype Diabetic C/T genotype PMean SD Mean SD
No. 6 58Age (years) 472 42.96 NsBMI (kg/m2) 306 306 0.598FBG (mg/dl) 250102 20681 0.3372hrs PPBG (mg/dl) 25492 237113 0.421Cholesterol (mg/dl) 24548 22150 0.776TG (mg/dl) 13735 11034 0.001*HDL-C (mg/dl) 62.513.5 57.911 0.781LDL-C (mg/dl) 15648 141.245.8 0.790
G R O U P
H
D
L
Figure (1): Relation between the mean of HDL-C (mg/dl) between the control subjects anddiabetic patients. There was statistical significant difference between them P 0.05.
Discussion
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Control Diabetic
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Chimienti et al(10) demonstrated that the ZnT-8 protein is expressed only in
pancreatic beta cells in vivo. In cultured cells, overexpression of ZnT-8 augmented
total cellular zinc content, thus protecting cells from zinc depletion and enhanced
insulin secretion under hyperglycemic conditions, suggesting that ZnT-8 has a
major role in the insulin secretion pathway. Triggering ZnT-8 expression and/or
activity may be an interesting approach in the treatment of type 2 diabetes.
The identification of a new gene for polygenic T2DM was recently achieved by
genome-wide SNP assays. Among several SNPs associated with susceptibility to
T2DM, polymorphisms in SLC30A8, hematopoietically expressed homeobox
(HHEX), cyclin-dependent kinase (CDKN2A/B), insulin-like growth factor 2
mRNA-binding protein 2 (IGF2BP2), fat mass and obesity associated (FTO),were
first reported by several studies performed in European and Asian populations(19- 24).
These genetic variants have been repetitively confirmed by multiple studies in
various populations (25- 28). Nevertheless, the effects of genetic variants on the risk
of T2DM are somewhat inconsistent among different ethnic groups.
Our result showed that there were increase in prevalence of C/T genotype in
studied subjects, the frequencies of C and T alleles at SNP (rs13266634) SLC30A8
for control subjects were (50% and 50%) respectively, and for diabetic subjects
were (51% and 49%) respectively. The genotype distributions of SNP
(rs13266634) SLC30A8 C > T in control subjects were (3.5% C/C, 93% C/T &
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3.5% T/T) and (9% C/C, 85 % C/T & 6% T/T) for diabetic subjects. According to
our results, the risk allele frequencies of this SNP were significantly different
between our subjects and other ethnic groups. The frequency of risk allele C in
rs13266634 for diabetic subjects in our study (51%) was lower than those reported
in European or African populations (69.9 and 97.1%) respectively(20,26). These
significant differences in risk allele frequencies across ethnic groups indicate that
the genetic variations of T2DM susceptibility genes are diversely distributed
among different populations.
In our study, SNP in SLC30A8 gene showed a significant association with
T2DM.The present data demonstrate that the C/Tgenotype is associatedwith risk
of type 2 diabetes as we found that diabetic subjects carrying the C/Tgenotype
exhibited higher statistical significant of biochemical parameters; fasting blood
glucose, and HDL-c and higher non significant levels of triglyceride, cholesterol
and LDL-c than control subjects carryingthe C/Tallele. These results were similar
to the findings of another study(29) which reported a nominal association between
rs13266634, a nonsynonymous SNP in SLC30A8, and T2DM in a Japanese
population, while Horikoshi et al(25) reported that there was no significant
association in another Japanese population.
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Our results found that this SNP was associated with the risk of type 2 diabetes in
our population, showing similar effect sizes to those in Europeans, although the
risk allele frequencies of most of this SNP was different between populations(28).
The SLC30A8 C allele might not only cause a decrease in insulin release, but may
also lead to decreased beta cell mass via increased apoptosis. In addition,
overexpression of SLC30A8 in insulinoma cells has been shown to increase
glucose-stimulated insulin secretion Therefore, stimulating ZnT-8 production
and/or activity may potentially be a novel approach in the treatment of type 2
diabetes patients, in whom zinc depletion is likely to participate in both acute and
chronic beta cell dysfunction(10).
In 2007, four genome-wide association scans for T2D in European populations
have been published. The first was performed in a French population of lean T2D
patients with familial history of diabetes, and the three subsequent scans were
performed in the UK, Wellcome Trust Case Control Consortium (WTCCC),
showed P value=0.020(30); and two Finnish/Swedish populations, Diabetes Genetics
Initiative (DGI), showed P value=0.047 (20) and Finland-United States
Investigation of NIDDN Genetics (FUSION), showed P value=7.0 X 10-5(11). All
have found a strong evidence for linkage of T2D to SNP rs13266634, variant in the
pancreatic beta-cell-specific zinc transporter SLC30A8 (Solute Carrier family 30,
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member8), to a region on chromosome 8 at the position 118,253,964bp (base
pairs), with risk allele/non risk allele (C/T) cytosine/thymine.
Variant within a novel genetic locus SLC30A8 was reported with other three novel
genetic loci to be more frequent in subjects with T2D than in healthy controls. The
major allele of the SLC30A8 SNP rs13266634 is associated with reduced insulin
secretion stimulated by orally or intravenously administered glucose, but not with
insulin resistance by genotyping of 921 non-diabetic German subjects for the
reported candidate SNP, which is located in the final exon of SLC30A8 gene on
chromosome 8, and it encodes for protein that was shown to be required for insulin
maturation/storage. Therefore, the major allele of type 2 diabetes candidate SNP
within that genetic locus represents crucial allele for -cell dysfunction and, thus,
might confer increased susceptibility of -cells towards adverse environmental
factor(6).
The SLC30A8 gene encodes ZnT-8, a novel member of the cation diffusion
facilitator family, exclusively expressed in pancreatic beta cells(10). ZnT-8 is
thought to be a key protein for insulin secretion by regulating the homeostasis of
zinc, which is known as an essential metal ion for insulin storage and secretion into
intracellular vesicles(31). Because the rs13266634 SNP causes an amino acid change
(R325 W) in the intracellular C-terminus of the ZnT-8 protein, this single
nucleotide substitution might act as a gain-of-function mutation that increases
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protein translation efficiency or modifies the posttranslational structure, thereby
enhancing the beta cell secretory functions.
In conclusion, genetic variants of SLC30A8 loci may be associated with type 2
diabetes and altered glucose-stimulated insulin secretion. Therefore, the major
alleles of candidate SNPs within these loci represent crucial alleles for -cell
dysfunction. Further studies need to be conducted to examine whether these risk
variants predict the development of type 2 diabetes later in life.
References
1. World Health Organization. Fact sheets about diabetes mellitus, 2000.
2. Kasuga M. Insulin resistance and pancreatic beta cell failure. J Clin
Invest; 2006, 116:175660.
3. Lee Goldman, Dennis Ausiello (Goldman L, Ausiello D). Cecil
Textbook of Medicine, 22nd edition, Chapter 242, Diabetes Mellitus, 2004,
1424-33. Publishers??
4. Dennis L. Kasper, Anthony S. Fauci, Dan L. Longo, Eugene
Braunwald, Stephen L. Hauser, J. Larry Jameson. Harrison's Principles Of
Internal Medicine, 16th edition, Chapter 323, Diabetes Mellitus, 2005, 2157-
63. Publishers??
16
-
8/6/2019 Nagwan Biochem
17/22
5. Freeman H, Cox RD. Type-2 diabetes: A cocktail of genetic
discovery. Hum Mol Genet; 2006, 15:R202R209.
6. Harald Staiger, Fausto Machicao, Norbert Stefan et al.
Polymorphisms within Novel Risk Loci for Type 2 Diabetes Determine -
Cell Function.. PLoS ONE; 2007, 2(9): e832.
7. Chimienti F, Favier A, Seve M. ZnT-8, a pancreatic-cell-specific zinc
transporter. Bio Metals; 2005, 18:3137.
8. Chimienti F, Devergnas S, Favier A, Seve M. Identification and
cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin
secretory granules. Diabetes; 2004, 53:2330-7.
9- Gold G, and Grodsky GM:Kinetic aspects of compartmental storage and
secretion of insulin and zinc. Experiential (1984) 40:11051114
10-Chimienti F., Devergnas S., Franois Pattou, Frans Schuit, Rachel Garcia-
Cuenca, et al., : In vivo expression and functional characterization of the zinc
transporter ZnT8 in glucose-induced insulin secretion, Journal of Cell Science
2006), 119, 4199-4206
11-Laura J. Scott, Karen L. Mohlke, Lori L. Bonnycastle, Cristen J. Willer, Yun
Li, William L. Duren, et al, (2007). A Genome-Wide Association Study of Type 2
17
-
8/6/2019 Nagwan Biochem
18/22
Diabetes in Finns Detects Multiple Susceptibility Variants, Science316,
June 1, 2007; 1341 - 1345.
12-Anderson R. A., Roussel A. M., Zouari N., Mahjoub S., Matheau J. M. and
Kerkeni A., : Potential antioxidant effects of zinc and chromium supplementation
in people with type 2 diabetes mellitus. J. Am. Coll. Nutr. (2001). 20, 212-218.
13-Chandra J., Zhivotovsky B., Zaitsev S., Juntti-Berggren L., Berggren P. O. and
Orrenius S., : Role of apoptosis in pancreatic beta-cell death in diabetes. Diabetes
(2001). 50, S44-S47.
14-Chimienti F., Seve M., Richard S., Mathieu J. and Favier A.,: Role of cellular
zinc in programmed cell death: temporal relationship between zinc depletion,
activation of caspases and cleavage of Sp family transcription factors. Biochem.
Pharmacol. , 2001.62, 51-62.
15- Mei Z, Grummer-Strawn LM, Pietrobelli A, Goulding A, Goran MI, Dietz
WH.,: Validity of body mass index compared with other body-composition
screening indexes for the assessment of body fatness in children and adolescents.
AmericanJournal of Clinical Nutrition; 2002,7597985.
16-Trinder P.,: Enzymatic colorimetric test. Ann. Clin. Biochem., ., (1969). 6; 24.
17--Siedel J., Schlumberger h., Klose S., :Improved reagant for the enzymatic
determination of serum cholesterol. J. Clin. Biochem., (1981). 19; 838.
18
-
8/6/2019 Nagwan Biochem
19/22
18-Lopes-Virella MF., Stone p., Ellis s. and Colwell Ja., :Cholesterol
determination in high density lipoproteins reported by three different methods.
Clin. Chem., (1977). 23; 882.
19- Scott LJ, Mohlke KL, Bonnycastle LL et al., : A genome-wide association
study of type 2 diabetes in Finns detects multiple susceptibility variants. Science
(2007) 316:13411345
20- Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent
D, Belisle A, et al.,: A genome-wide association study identifies novel risk loci for
type 2 diabetes. Nature 2007, 445:881885
21-Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, et al. Genome-wide
association analysis identifies loci for type 2 diabetes and triglyceride levels.
Science (2007) , 316: 13311336.
22- Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H,
Timpson NJ, et al.,:Replication of genome-wide association signals in UK samples
reveals risk loci for type 2 diabetes. Science (2007) 316:13361341
23- Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A,
Lango H, et al.,: Common variants in WFS1 confer risk of type 2 diabetes. Nat
Genet. (2007) 39:951953
19
-
8/6/2019 Nagwan Biochem
20/22
24-Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H, Hirota Y,
Mori H, et al.,: Variants in KCNQ1 are associated with susceptibility to type 2
diabetes mellitus. Nat Genet (in press) PMID: (2008)18711367
25- Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, Froguel P,
Kadowaki T. : Variations in the HHEX gene are associated with increased risk of
type 2 diabetes in the Japanese population. Diabetologia (2007) ,50:24612466
26- Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir
T, Walters GB, et al., : A variant in CDKAL1 influences insulin response and risk
of type 2 diabetes. Nat Genet . (2007) 39:770775
27-Omori S, Tanaka Y, Takahashi A, Hirose H, Kashiwagi A, Kaku K, Kawamori
R, Nakamura Y, Maeda S. :Association of CDKAL1, IGF2BP2, CDKN2A/B,
HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a
Japanese population. Diabetes (2008) ,57:791795
28- Ng MC, Park KS, Oh B et al.,: Implication of genetic variants near TCF7L2,
SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2 and FTO in type 2 diabetes
and obesity in 6,719 Asians. Diabetes(2008)57:22262233
29- Furukawa Y, Shimada T, Furuta H, Matsuno S, Kusuyama A, Doi A, Nishi M,
Sasaki H, Sanke T, Nanjo K .: Polymorphisms in the IDE-KIF11-HHEX gene
20
-
8/6/2019 Nagwan Biochem
21/22
locus are reproducibly associated with type 2 diabetes in a Japanese population. J
Clin . Endocrinol, Metab, .:(2008 93:310314.
30-Eleftheria Zeggini, Michael N. Weedon, Cecilia M. Lindgren, Timothy M.
Frayling, Katherine S. Elliott, etal.,: Replication of Genome-Wide Association
Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes, Science316,
June 1, 2007;1336-1341.
31-Chausmer AB (1998) Zinc, insulin and diabetes. J Am Coll Nutr 17:109115.
Correspondence to:???????Department of Medical Biochemistry,Faculty of Medicine,Suez Canal UniversityE-mail:Author title: El-Serafi et al.Short cut Title: ?????
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