Introduction
Type 2 diabetes mellitus (DM) is a major public
health issue that affects over one billion people worldwide
(1). Type 2 DM is a complex disease
that involves genetic and environmental factors and their
interactions (2). Due to the high
prevalence of type 2 DM, identifying the genes or genetic loci
associated with the risk or protection of type 2 DM is important
for understanding the mechanisms underlying the disease and for
benefiting the patients with personalized prevention and treatment
programs.
Genome-wide association studies (GWASs) and
subsequent meta-analyses have identified >56 susceptibility loci
for type 2 DM (3–11). However, these susceptibility loci
have been identified predominantly in Caucasian populations.
Differences in allele frequencies and the effect of size among
different ethnicity groups yielded the discovery of new loci in
different populations (12).
Although several single-nucleotide polymorphisms (SNPs) have been
identified as susceptibility loci for type 2 DM in Japanese
individuals (10,11), the genes that confer susceptibility
to this condition remain to be identified definitively.
Previous GWASs have identified various loci and
genes that confer susceptibility to coronary heart disease (CHD)
for Caucasian populations (13,14).
As type 2 DM is an important risk factor for CHD, we hypothesized
that certain polymorphisms may contribute to the genetic
susceptibility to CHD through affecting the susceptibility to type
2 DM. The purpose of the present study was to examine a possible
association of type 2 DM in Japanese individuals with 29 SNPs
identified as susceptibility loci for CHD by meta-analyses of the
GWASs.
Subjects and methods
Study population
The study population comprised of 3,757 Japanese
individuals (1,444 subjects with type 2 DM and 2,313 controls) who
either visited outpatient clinics or were admitted to the
participating hospitals (Gifu Prefectural General Medical Center,
Gifu; Gifu Prefectural Tajimi Hospital, Tajimi; Japanese Red Cross
Nagoya First Hospital, Nagoya; Inabe General Hospital, Inabe;
Hirosaki University Hospital, Reimeikyo Rehabilitation Hospital and
Hirosaki Stroke Center, Hirosaki, Japan) between 2002 and 2012 due
to various symptoms or for an annual health checkup. Written
informed consent was obtained from all the participants and the
Institutional Review Board of each participating hospital approved
the study.
Type 2 DM is defined according to the criteria of
the World Health Organization, as described previously (15,16).
Subjects with type 2 DM had a fasting plasma glucose level of ≥6.93
mmol/l (126 mg/dl), a blood glycosylated hemoglobin (hemoglobin
A1c) content of ≥6.5%, or were taking anti-diabetic medication.
Individuals with type 1 DM, maturity onset diabetes of the young,
DM associated with mitochondrial diseases or single-gene disorders,
pancreatic diseases or other metabolic or endocrinological diseases
were excluded from the study. Individuals on medication that may
cause secondary DM were also excluded. The control individuals had
a fasting plasma glucose level of <6.05 mmol/l (110 mg/dl), a
blood hemoglobin A1c content of <6.2% and had no history of DM
or of receiving anti-diabetic medication.
Selection and genotyping of
polymorphisms
SNPs that were recently identified as susceptibility
loci for CHD in Caucasian populations were searched for by
meta-analyses of GWASs (13,14).
These SNPs were examined with the dbSNP database (National Center
for Biotechnology Information; http://www.ncbi.nlm.nih.gov/SNP/) to find SNPs with a
minor allele frequency of >0.015 in a Japanese population.
Finally, 29 SNPs (data not shown) were selected and the association
with type 2 DM was examined. Wild-type and variant alleles of the
SNPs were determined from the original sources.
Venous blood (7 ml) was collected into tubes
containing 50 mmol/l ethylenediaminetetraacetic acid (disodium
salt) and genomic DNA was isolated with a kit (Genomix; Talent,
Trieste, Italy). Genotypes of the 29 SNPs were determined at
G&G Science (Fukushima, Japan) by a method that combines
polymerase chain reaction and sequence-specific oligonucleotide
probes with suspension array technology (Luminex Corporation,
Austin, TX, USA). The overall call rate of genotyping of 29 SNPs
was 99%. The detailed genotyping methodology was performed as
described previously (17).
Statistical analysis
The χ2 test was used to compare the
categorical variables, whereas the Mann-Whitney U test was used for
analysis of the quantitative data. Allele frequencies of each SNP
were compared between subjects with type 2 DM and controls by the
χ2 test. A false discovery rate (FDR) was calculated to
compensate for multiple comparisons of genotypes, and FDR≤0.05 was
considered to indicate a statistical significance for association.
Multivariable logistic regression analysis was performed with type
2 DM as a dependent variable and age, gender (0, women; 1, men),
body mass index (BMI) and the genotype of SNP as independent
variables. The SNP was assessed according to dominant (the combined
group of heterozygotes and variant homozygotes verses wild-type
homozygotes), recessive (variant homozygotes verses the combined
group of wild-type homozygotes and heterozygotes) and two additive
[additive 1 (heterozygotes verses wild-type homozygotes) and
additive 2 (variant homozygotes verses wild-type homozygotes)]
genetic models. As fasting plasma glucose level and blood
hemoglobin A1c content were not normally distributed (P<0.01 by
the Kolmogorov-Smirnov Lilliefors test), these parameters were
compared among genotypes by the non-parametric Kruskal-Wallis test.
Statistical analysis was performed with JMP version 11 and JMP
Genomics version 6.0 software (SAS Institute, Cary, NC, USA).
Results
Clinical characteristics of the study
subjects
The clinical characteristics of the study subjects
are shown in Table I. Age, the
frequency of males, BMI, the prevalence of smoking, myocardial
infarction, dyslipidemia and hypertension, as well as serum
concentrations of triglycerides and creatinine, were higher,
whereas the serum concentrations of high-density lipoprotein (HDL)
cholesterol were lower in subjects with type 2 DM compared to
controls.
 | Table ICharacteristics of the subjects with
type 2 diabetes mellitus (DM) and controls. |
Table I
Characteristics of the subjects with
type 2 diabetes mellitus (DM) and controls.
| Characteristic | Type 2 DM | Controls | P-value |
|---|
| No. of subjects | 1444 | 2313 | |
| Age, years | 65.8±10.1 | 63.1±11.3 | <0.0001 |
| Gender, male/female
(%) | 67.0/33.0 | 57.1/42.9 | <0.0001 |
| Body mass index,
kg/m2 | 24.1±3.7 | 23.6±3.4 | 0.0005 |
| Current or former
smoker, % | 30.3 | 25.5 | 0.0013 |
| Myocardial
infarction, % | 66.3 | 36.5 | <0.0001 |
| Dyslipidemia,
% | 55.7 | 42.1 | <0.0001 |
| Hypertension,
% | 75.5 | 56.9 | <0.0001 |
| Serum
triglycerides, mmol/l | 1.79±1.39 | 1.43±0.87 | <0.0001 |
| Serum
HDL-cholesterol, mmol/l | 1.25±0.35 | 1.39±0.43 | <0.0001 |
| Serum
LDL-cholesterol, mmol/l | 3.14±1.01 | 3.10±0.87 | 0.6136 |
| Serum creatinine,
µmol/l | 93.8±106.1 | 84.0±99.1 | <0.0001 |
| Fasting plasma
glucose, mmol/l | 10.46±3.91 | 4.96±0.64 | <0.0001 |
| Blood hemoglobin
A1c, % | 7.8±2.0 | 6.0±1.2 | <0.0001 |
Associations of SNPs to type 2 DM
Allele frequencies were compared between subjects
with type 2 DM and controls by the χ2 test and five SNPs
with P<0.05 are shown in Table
II. Among these SNPs, rs964184 (C→G) of the ZPR1 zinc finger
gene (ZPR1) was significantly (FDR≤0.05) associated with the
prevalence of type 2 DM. The genotype distributions of five SNPs
were in Hardy-Weinberg equilibrium (P>0.05) among subjects with
type 2 DM and controls.
| Table IIComparison of the single-nucleotide
polymorphism (P<0.05) allele frequencies by the χ2
test between subjects with type 2 diabetes mellitus (DM) and
controls. |
Table II
Comparison of the single-nucleotide
polymorphism (P<0.05) allele frequencies by the χ2
test between subjects with type 2 diabetes mellitus (DM) and
controls.
| Variables | Type 2 DM (%) | Controls (%) | P-value
(allele) | FDR (allele) |
|---|
| rs964184 | | | 0.0017 | 0.050 |
|
CC | 728 (50.4) | 1289 (55.7) | | |
|
CG | 601 (41.6) | 869 (37.6) | | |
|
GG | 115 (8.0) | 155 (6.7) | | |
| Minor allele
frequency | 0.29 | 0.26 | | |
| Hardy-Weinberg
P | 0.5585 | 0.6024 | | |
| rs12190287 | | | 0.0101 | 0.119 |
|
CC | 472 (32.7) | 833 (36.0) | | |
|
CG | 696 (48.2) | 1100 (47.6) | | |
|
GG | 276 (19.1) | 380 (16.4) | | |
| Minor allele
frequency | 0.43 | 0.40 | | |
| Hardy-Weinberg
P | 0.4960 | 0.5996 | | |
| rs11556924 | | | 0.0123 | 0.119 |
|
CC | 1394 (96.5) | 2191 (94.7) | | |
|
CT | 49 (3.4) | 121 (5.2) | | |
|
TT | 1 (0.1) | 1 (0) | | |
| Minor allele
frequency | 0.02 | 0.03 | | |
| Hardy-Weinberg
P | 0.4044 | 0.6098 | | |
| rs6725887 | | | 0.0249 | 0.179 |
|
TT | 1413 (98.2) | 2280 (99.0) | | |
|
TC | 26 (1.8) | 22 (1.0) | | |
|
CC | 0 (0) | 0 (0) | | |
| Minor allele
frequency | 0.009 | 0.005 | | |
| Hardy-Weinberg
P-value | 0.7295 | 0.8178 | | |
| rs2075650 | | | 0.0309 | 0.179 |
|
AA | 1042 (72.2) | 1576 (68.3) | | |
|
AG | 359 (24.9) | 666 (28.9) | | |
|
GG | 42 (2.9) | 65 (2.8) | | |
| Minor allele
frequency | 0.15 | 0.17 | | |
| Hardy-Weinberg
P | 0.1051 | 0.5933 | | |
Multivariable logistic regression analysis with
adjustment for age, gender and BMI revealed that rs964184 of
ZPR1 was significantly associated with type 2 DM in the
dominant and additive 1 and 2 models, with the minor G
allele representing a risk factor for this condition (Table III). As hypertriglyceridemia is an
important risk factor for type 2 DM, additional multivariable
logistic regression analysis was performed with adjustment for
serum triglycerides concentrations or hypertriglyridemia (serum
concentration of triglycerides ≥1.65 mmol/l or taking
anti-dyslipidemic medication) in addition to age, gender and BMI
(Table III). rs964184 was also
significantly associated with type 2 DM in the dominant and
additive 1 models in this analysis.
| Table IIIMultivariable logistic regression
analysis of rs964184 of ZPR1 zinc finger gene and type 2 diabetes
mellitus with additional adjustments to age, gender and BMI. |
Table III
Multivariable logistic regression
analysis of rs964184 of ZPR1 zinc finger gene and type 2 diabetes
mellitus with additional adjustments to age, gender and BMI.
| Dominant | Recessive | Additive 1 | Additive 2 |
|---|
|
|
|
|
|
|---|
| Additional
adjustments | P-value | OR (95% CI) | P-value | OR (95% CI) | P-value | OR (95% CI) | P-value | OR (95% CI) |
|---|
| None | 0.0012 | 1.25
(1.09–1.43) | 0.1134 | 1.23
(0.95–1.59) | 0.0036 | 1.23
(1.07–1.42) | 0.0280 | 1.35
(1.03–1.75) |
| Serum
concentrations of triglycerides | 0.0209 | 1.18
(1.02–1.35) | 0.4105 | 1.12
(0.86–1.45) | 0.0304 | 1.18
(1.01–1.35) | 0.1923 | 1.20
(0.91–1.57) |
|
Hypertriglyceridemia | 0.0101 | 1.19
(1.04–1.37) | 0.2677 | 1.16
(0.89–1.50) | 0.0188 | 1.19
(1.03–1.37) | 0.1047 | 1.25
(0.95–1.64) |
Associations of rs964184 to fasting
plasma glucose level and blood hemoglobin A1c content
Finally, the associations of rs964184 genotypes to
fasting plasma glucose level and blood hemoglobin A1c content were
examined by the Kruskal-Wallis test (Table IV). rs964184 was significantly
associated with the two parameters and the G allele was
associated with the increases in fasting plasma glucose level and
in blood hemoglobin A1c content.
| Table IVAssociation of rs964184 of ZPR1 zinc
finger gene to fasting plasma glucose level and blood hemoglobin
A1c content as determined by the Kruskal-Wallis test. |
Table IV
Association of rs964184 of ZPR1 zinc
finger gene to fasting plasma glucose level and blood hemoglobin
A1c content as determined by the Kruskal-Wallis test.
| Genotype of
rs964184 | |
|---|
|
| |
|---|
| Parameter | CC | CG | GG | P-value |
|---|
| Fasting plasma
glucose, mmol/l | 6.9±3.3 |
7.1±3.4a |
7.3±3.8a | 0.0076 |
| Blood hemoglobin
A1c, % | 6.8±1.8 | 6.9±1.7 |
7.3±2.2a | 0.0132 |
Discussion
The associations of 29 SNPs identified as
susceptibility loci for CHD by meta-analyses of GWASs to type 2 DM
were examined and it was observed that rs964184 of ZPR1 was
significantly associated with type 2 DM in Japanese individuals.
The prevalence of type 2 DM, fasting plasma glucose level and blood
hemoglobin A1c content were increased by 18.0, 6.7 and 7.4%,
respectively, for individuals with the GG genotype of
rs964184 compared to those with the CC genotype.
rs964184 is located in the intron region of
ZPR1 at chromosome 11q23.3. ZPR1 is an essential regulatory
protein for cell proliferation and signal transduction and may have
multiple physiological functions (18,19).
The most relevant transcription factor that binds to the promoter
region of ZPR1 is peroxisome proliferator-activated receptor
γ, which plays an important role in insulin sensitivity and obesity
(20,21). The promoter region of ZPR1 is
also bound by hepatocyte nuclear factor 4α, which activates a
variety of genes involved in glucose, fatty acid and cholesterol
metabolism (22).
ZPR1 is located ~1.6 kb upstream of the
APOA5-A4-C3-A1 gene complex. Previous studies have shown
that several polymorphisms in or near APOA5 are
significantly associated with serum triglycerides concentrations
(23–26). rs964184 of ZPR1 has been
associated with serum triglycerides and this may be attributable to
linkage disequilibrium with functional SNPs in APOA5, which
influence metabolism of chylomicrons, very-low-density lipoprotein
and HDL (27). As an increase in
serum triglycerides concentration is an important risk factor for
type 2 DM (28), a multivariable
logistic regression analysis was performed with adjustment for
serum triglycerides levels or hypertriglyceridemia in addition to
age, gender and BMI. There was a significant association of
rs964184 with type 2 DM in this analysis, indicating that the
association was independent, at least in part, of serum
triglycerides levels in the study. The previous GWASs suggested
that APOA5 polymorphisms may also play an important role in
the development of type 2 DM (29,30). A
subgroup analysis by ethnicity of a meta-analysis revealed a
significant association of the −1131T→C polymorphism of
APOA5 with type 2 DM in Asian populations (31). This observation may support the
hypothesis that rs964184 of ZPR1 is associated with type 2
DM through the interaction with APOA5 in Japanese
individuals.
Although the contribution of rs964184 to the
increased susceptibility to type 2 DM was examined in several GWASs
mainly with Caucasians, the significant association was not
detected (32,33). The reason for the discrepancy
between the previous studies and the present results remains
unclear. The variations in the minor G allele frequencies
due to the ethnic differences may be, at least in part, responsible
for this discrepancy. The frequencies of the CG and
GG genotypes of rs9645184 were 23.7 and 2.4%, respectively,
in Caucasian populations (32),
whereas in the present study population they were 39.1 and 7.2%,
respectively. The G allele of rs964184 was therefore higher
in the present population (26.8%) compared to the Caucasian
population (13–14%) (23,33,34).
In addition, the prevalence of type 2 DM in the present population
was 38.2%, which was more than twice that reported previously
(32). The higher frequency of the
G allele and the higher prevalence of type 2 DM in the
present population compared to those in the previous studies
(33,34) may increase the statistical power to
detect the association of rs964184 with type 2 DM.
In conclusion, the results indicate that rs964184
(C→G) of ZPR1 may be a susceptibility locus for type 2 DM in
Japanese individuals. Validation of these findings is required in
other independent subject panels or ethnic groups.
Acknowledgements
The present study was supported by a Collaborative
Research Grant from the Gifu Prefectural General Medical Center
(no. H24-26 to Y.Y.) and a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan (no. 24590746 to Y.Y.).
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