Type 2 Diabetes Genetic Variants and Risk of

Diabetic Retinopathy
Yong He Chong, MSc,1,2 Qiao Fan, PhD,2 Yih Chung Tham, PhD,1 Alfred Gan, MSc,1 Shu Pei Tan, BSc,1
Gavin Tan, MMed,1 Jie Jin Wang, PhD,3 Paul Mitchell, MD, PhD,3 Tien Yin Wong, FRCS, PhD,1,2,4,*
Ching-Yu Cheng, MD, PhD1,2,4,*

Purpose: Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy
(DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR.
Design: Case-control genetic association study.
Participants: We evaluated the aggregate effects of multiple type 2 diabeteseassociated genetic variants on
the risk of DR among 1528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study, of
whom 547 (35.8%) had DR.
Methods: Participants underwent a comprehensive ocular examination, including dilated fundus photog-
raphy. Retinal photographs were graded using the modified Airlie House classification system to assess the
presence and severity of DR following a standardized protocol. We identified 76 previously discovered type 2
diabeteseassociated single nucleotide polymorphisms (SNPs) and constructed multilocus genetic risk scores
(GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect
estimates on DR. Two GRSs were generated: an overall GRS that included all 76 discovered type 2
diabeteseassociated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be
associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the
GRSs with DR were determined using logistic regression analyses. Discriminating ability of the GRSs was
determined by the area under the receiver operating characteristic curve (AUC).
Main Outcome Measures: Odds ratios on DR.
Results: Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with
participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were 2.00-fold more likely to
have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity
levels. However, addition of the GRSs to traditional risk factors improved the AUC only modestly by 3% to 4%.
Conclusions: Type 2 diabeteseassociated genetic loci were significantly associated with higher risks of DR,
independent of traditional risk factors. Our findings may provide new insights to further our understanding of the
genetic pathogenesis of DR. Ophthalmology 2016;-:1e7 ª 2016 by the American Academy of Ophthalmology

Supplemental material is available at www.aaojournal.org.

Diabetic retinopathy (DR) is the most common microvas-
cular complication of diabetes mellitus1 and is a leading
cause of preventable blindness in working-aged adults
worldwide.2 The global prevalence of DR, proliferative DR
(PDR), and vision-threatening DR among individuals with
diabetes is estimated to be 35%, 7%, and 12%, respec-
tively.3 DR has also been estimated to be the cause of 2.6%
of cases of blindness worldwide.4
Our understanding of the pathophysiology of DR is
incomplete and constantly evolving with research. Risk
factors such as hyperglycemia, hypertension, and prolonged
diabetes duration are well established but explain less than
50% of the risk of DR.3,5e9 Genetic susceptibility to DR has
also been suspected.10 Previous studies have shown racial
and ethnic differences11 and familial aggregation in
DR,12,13 suggesting a role for genetic factors in DR devel-
opment. Several candidate gene studies and genome-wide
association studies (GWAS) have also identified potential
genetic loci associated with DR.14e22 However, few results
have been consistently replicated across different
populations.
Because DR is the most common microvascular
complication of type 2 diabetes,2 it is reasonable to postulate
that both diseases share a common genetic background.
Type 2 diabetes is a multifactorial disease influenced by
many different genetic variants with heritability estimated
to be between 40% and 80%.23 Over the past decade,
GWAS have identified over 70 susceptibility loci for type
2 diabetes.24e29 Of note, 3 of the type 2 diabetes risk loci
(near TCF7L2, PPARG, and KCNJ11) have previously been
shown to be associated with DR,30e32 further suggesting
that type 2 diabetes susceptibility genes may have an in-
fluence on DR development.
In this study, we hypothesized that individuals with more
risk alleles of type 2 diabetes are more likely to have DR.
We aimed to evaluate the association between the aggregate

ª 2016 by the American Academy of Ophthalmology http://dx.doi.org/10.1016/j.ophtha.2016.11.016 1

Published by Elsevier Inc. ISSN 0161-6420/16
 Ophthalmology Volume -, Number -, Month 2016
effects of multiple type 2 diabetes genetic variants with DR,
through the construct of multilocus genetic risk scores
(GRSs), in a population-based, multiethnic study.
Methods
Study Population
The Singapore Epidemiology of Eye Diseases (SEED) Study is a
population-based cross-sectional study of 3 major ethnic groups in
Singapore: Malays (2004e2006), Indians (2007e2009), and
Chinese (2009e2011). The detailed study methodology has been
previously described.33,34 In brief, 4168 Malays, 4497 Indians, and
4605 Chinese aged 40 to 80 years were selected using an age-
stratified random sampling strategy and invited to participate in
the study. From these, a total of 10 033 participated, including
3280 Malays (response rate of 78.7%), 3400 Indians (75.6%), and
3353 Chinese (72.8%), giving an overall response rate of 75.6%.
For this analysis, we focused on all participants with diabetes,
defined as persons having a random glucose of 11.1 mmol/L or
higher, using diabetic medication, or having a self-reported history
of diabetes. Ethics approval was obtained from the SingHealth
Centralised Institutional Review Board. Written informed consent
was obtained from all participants and the study was conducted in
accordance with the Declaration of Helsinki.
Diabetic Retinopathy and Risk Factor
Assessments
DR was assessed through standardized retinal photographs using a
digital retinal camera (Canon CR-DGi with a 10-D SLR back;
Canon, Tokyo, Japan) at the Singapore Eye Research Institute.
After pupil dilation, 2 retinal photographs, centered at the optic
disc and macula, were taken from both eyes. Photographs were
sent to the University of Sydney and graded for retinopathy by
masked, trained graders. DR was considered present if any char-
acteristic lesion as defined by the Early Treatment Diabetic Reti-
nopathy Study severity scale (i.e., microaneurysms, hemorrhages,
cotton wool spots, intraretinal microvascular abnormalities, hard
exudates, venous beading, and new vessels) was present in either
eye.11 DR severity was based on the worse eye and was graded
according to the modified Airlie House classification system35 as
follows: level 10, DR absent; levels 14e15, questionable DR;
level 20, minimal non-PDR (NPDR); level 35, mild NPDR; level
43, moderate NPDR; level 47, moderately severe NPDR; level
53, severe NPDR; level 61, mild PDR; level 65, moderate PDR;
level 71, severe PDR; and levels 81 and 85, advanced PDR.
All participants underwent a standardized interview for
collection of demographic data, lifestyle risk factors, and medical
history (e.g., diabetes duration). Blood pressure was measured
according to the protocol used in the Multi-Ethnic Study of
Atherosclerosis11 and was taken with the study participants seated
and after 5 minutes of rest. Systolic and diastolic blood pressure
were measured with a digital automatic blood pressure monitor.
Blood pressure was measured on 2 occasions 5 minutes apart. If
the blood pressures differed by more than 10 mmHg systolic and
5 mmHg diastolic, a third measurement was made. The blood
pressure of the individual was then taken as the mean between
the 2 closest readings. Hypertension was defined as systolic
blood pressure of 140 mmHg or more, diastolic blood pressure
of 90 mmHg or more, or use of antihypertensive medication.
Nonfasting venous blood samples were collected to measure
serum glycosylated hemoglobin (HbA1c) levels and for DNA
extraction.
2
Genotyping and Genetic Ancestry Inference
Genome-wide genotyping was performed using Illumina Human
610 Quad BeadChips (Illumina Inc, San Diego, CA) based on the
manufacturer’s protocols in 7584 of the SEED participants. The
detailed data quality control procedure has been previously
described.36 Genotype imputation was carried out using the
Markov Chain Haplotyping software package,37 using 1000
Genomes Project as reference panels.
Individual genetic ancestry was inferred using principal
component (PC) analysis to account for spurious associations
owing to ancestral differences of individual single nucleotide
polymorphisms (SNPs). This was carried out using the smartPCA
program (EIGENSTRAT software version 4.2).38 The details of the
PC analysis have been previously described.39
Statistical Analysis
A 2-stage approach was adopted for analysis. First, we adopted a
candidate gene approach by identifying and selecting 76 type 2
diabeteseassociated SNPs identified in the most recent and largest-
to-date meta-analysis of type 2 diabetes GWAS by the DIAbetes
Genetics Replication And Meta-analysis (DIAGRAM) Con-
sortium.24 To determine the association between DR and each type
2 diabetes susceptibility locus in our study population, we
performed logistic regression analyses between the individual
SNPs with DR under additive genetic models adjusting for age,
gender, and the first 3 PCs in each ethnic group. We then
obtained the combined effect estimates of individual SNPs by
performing random-effect meta-analysis using individual-level
data across the 3 ethnic groups. Next, we evaluated the aggregate
effects of the type 2 diabetes susceptibility loci by constructing 2
GRSs: (1) an overall GRS that included all 76 SNPs identified by
the DIAGRAM Consortium, and (2) an Asian-specific GRS that
included a subset of 55 SNPs showing nominally significant as-
sociation (P < 0.05) in East and/or South Asian ancestry groups
from the DIAGRAM Consortium’s aggregated meta-analysis. This
was achieved by summing the number of risk alleles for each of the
type 2 diabeteseassociated SNPs for each GRS, weighted by the
estimated individual SNP effect size on DR (logarithm of the odds
ratio).40 Multivariable logistic and ordinal logistic regression
analyses were performed to determine the association between
GRSs with DR and DR severity levels, respectively, adjusting
for diabetes duration, HbA1c, and hypertension (collectively
termed “traditional DR risk factors”). In the ordinal logistic
regression analyses, the dependent outcome variable DR severity
level was coded accordingly on an ordinal scale as 0 (DR
absent), 1 (questionable DR), 2 (minimal NPDR), 3 (mild
NPDR), 4 (moderate NPDR), 5 (moderately severe NPDR), 6
(severe NPDR), 7 (mild PDR), 8 (moderate PDR), 9 (severe
PDR), or 10 (advanced PDR).
To evaluate the discriminating ability of the GRSs for DR
compared with traditional risk factors, we calculated the area under
the receiver operating characteristic curve (AUC) for 2 different
models: the first model consisted of traditional DR risk factors and
the second model consisted of both the traditional risk factors plus
the GRSs. The difference in AUCs between models was compared
using C-statistic. All statistical analyses were performed using
Stata 14 (StataCorp LP, College Station, TX).
Results
Of the 7584 study participants in the SEED study with genome-
wide genotype information, after excluding participants without
diabetes (n ¼ 5805) and participants with diabetes with missing
 Chong et al 
Effects of Diabetic Genes on DR

Table 1. Summary of Demographic and Clinical Characteristics of

the Diabetic Study Participants (N ¼ 1528)

With DR Without DR
(N [ 547) (N [ 981) P Value

Age, years 62.6 (8.8) 62.5 (9.6) 0.811

Gender, female 267 (48.8) 477 (48.6) 0.944
Ethnicity
Malay 172 (31) 308 (31) 0.316
Indian 279 (51) 471 (48)
Chinese 96 (18) 202 (21)
Diabetes duration, years 13.7 (9.8) 8.2 (7.6) <0.001
Age at diabetes onset, years 49.0 (11.0) 54.3 (10.6) <0.001
HbA1c, % 8.1 (1.7) 7.5 (1.5) <0.001
Systolic BP, mmHg 149.3 (22.9) 142.9 (20.9) <0.001
Diastolic BP, mmHg 77.3 (10.8) 77.2 (9.6) 0.938

BP ¼ blood pressure; DR ¼ diabetic retinopathy; HbA1c ¼ serum

glycosylated hemoglobin.
Data are presented as means (standard deviation) or number (%), as
appropriate.

relevant clinical data (n ¼ 251), a total of 1528 participants with

diabetes (480 Malays, 750 Indians, and 298 Chinese) were
included in the analysis. Of these, 547 participants (35.8%) were
assessed to have DR. The baseline demographic and clinical
characteristics of the included participants are shown in Table 1.
Overall, participants with DR tended to be older and female.
They also had significantly longer diabetes duration as well as
higher HbA1c and systolic blood pressure levels (all P < 0.001).
A summary of the 76 type 2 diabeteseassociated SNPs previ-
ously reported by the DIAGRAM Consortium used for the con-
struction of the overall GRS is shown in Table 2 (available at http://
www.aaojournal.org). These 76 SNPs’ associations with DR
among the study participants are shown in Table 3 (available at
http://www.aaojournal.org). The frequencies of both the overall
GRS and the Asian-specific GRS were approximately normally
distributed (Fig 1A, B). The mean, standard deviation (SD), and
range of the GRSs are shown in Table 4. In general, the mean
(SD) of the overall GRS was 1.11 (0.45) among participants
with DR and 0.93 (0.45) among controls; that of the Asian-
specific GRS in participants with DR was 0.33 (0.40)
and 0.47 (0.39) in controls.
Table 5 shows the associations of the GRSs with DR. The mean
SD number of risk alleles carried by the individuals in the highest
tertile of the overall GRS was 92.62.6, compared with 81.22.6
carried by those in the lowest tertile (P < 0.001). Similarly, the
mean SD number of risk alleles carried by individuals in the
highest tertile of the Asian-specific GRS was 66.42.4,
compared with 56.42.3 in the lowest tertile (P < 0.001). In
general, participants with higher scores of both GRSs were
significantly associated with increased odds of having DR, after
adjusting for ethnicity, diabetes duration, HbA1c, and hypertension
(all P trend < 0.001) (Fig 2). When adjusting for ethnicity and the
traditional DR risk factors, participants in the top tertile of the
overall GRS were 2.56 times (95% confidence interval [CI]:
1.92e3.40; P ¼ 1.5  1010) more likely to have DR compared
with participants in the lowest tertile. Similarly, participants in
the top tertile of the Asian-specific GRS were 2.00 times (95%
CI: 1.51e2.65; P ¼ 1.3  106) more likely to have DR compared
Figure 1. Distribution of genetic risk scores. A, Overall genetic risk score.
B, Asian-specific genetic risk score. DR ¼ diabetic retinopathy.
with participants in the lowest tertile. Similar trends were consis-
tently observed across the 3 ethnic groups of Malay, Indian, and
Chinese (Table 6 [available at http://www.aaojournal.org]).
The associations of the GRSs with DR severity are shown in
Table 7. Both GRSs were associated with higher DR severity levels
after adjusting for ethnicity, diabetes duration, HbA1c, and
hypertension (all P < 0.001). This association between GRSs
and DR severity was similarly observed across the 3 ethnic
groups (Table 8 [available at http://www.aaojournal.org]).
A sensitivity analysis was conducted that included only controls
with a diabetes duration of at least 5 years (n ¼ 547 cases, 548
controls). The mean diabetes duration was 13.7 and 12.8 years in
cases and controls, respectively. Similar to the original finding, this
sensitivity analysis showed that higher scores of both GRSs were
significantly associated with increased odds of having DR, and that
both GRSs were associated with higher DR severity levels
(Tables 9 and 10 [available at http://www.aaojournal.org]).
To determine the discriminatory accuracy of the GRSs
compared with the traditional DR risk factors, we compared the
difference in AUC estimates in the models consisting of traditional
DR risk factors (age, gender, ethnicity, diabetes duration, HbA1c,
and hypertension) and the model consisting of traditional DR risk
factors and the GRSs (Table 11). The AUC in the model consisting

3
 Ophthalmology Volume -, Number -, Month 2016

Table 4. Summary of Genetic Risk Score Characteristics Across Ethnic Groups

Total (N [ 1528; 547 Malay (N [ 480; 172 Indian (N [ 750; 279 Cases, Chinese (N [ 298; 96 Cases,
Cases, 981 Controls) Cases, 208 Controls) 471 Controls) 202 Controls)
GRS Mean (Range) SD Mean (Range) SD Mean (Range) SD Mean (Range) SD

Overall GRS
Case 1.11 (0.29 to 2.39) 0.45 1.13 (0.11 to 2.29) 0.42 1.03 (0.29 to 2.39) 0.47 1.32 (0.28e2.23) 0.40
Control 0.93 (0.48 to 2.39) 0.45 0.93 (0.17 to 2.20) 0.41 0.86 (0.48 to 2.39) 0.46 1.12 (0.18 to 2.33) 0.42
Asian-specific GRS
Case 0.33 (1.45 to 0.94) 0.40 0.36 (1.45 to 0.74) 0.39 0.36 (1.42 to 0.94) 0.40 0.21 (1.07 to 0.69) 0.37
Control 0.47 (1.78 to 0.64) 0.39 0.52 (1.43 to 0.54) 0.39 0.49 (1.78 to 0.53) 0.39 0.38 (1.52 to 0.64) 0.37

GRS ¼ genetic risk score; SD ¼ standard deviation.

Cases are individuals with diabetic retinopathy (DR); controls are those without DR.

of the traditional DR risk factors only was 0.71 (95% CI:
0.68e0.74). In the model consisting of both the traditional DR
risk factors and the GRSs, the AUC increased by 0.03 (P value
for AUC difference of overall GRS ¼ 2.0  104) and 0.02
(P value for AUC difference of Asian-specific GRS ¼ 2.2  103).
Discussion
In this multiethnic, population-based study, we showed
that persons with a greater number of genetic risk loci for
type 2 diabetes were more likely to have DR, using
multilocus GRSs constructed from 76 type 2 dia-
beteseassociated genetic variants. This association was
independent of traditional risk factors for DR and may be
clinically relevant in predicting the risk of developing DR
among patients with diabetes and the disease progression
upon diagnosis of diabetes. Overall, our findings showed
that participants in the top tertile of the overall GRS had a
2.5-fold increased risk of having DR compared with those
in the lowest tertile. Similarly, participants in the top
tertile of the Asian-specific GRSs also had a 2.0-fold
increased risk of having DR compared with those in the
lowest tertile.
However, the effect of individual type 2 diabetese
associated SNPs on DR susceptibility was modest. Of note,
there was no significant association found between the SNPs
in the loci of TCF7L2, PPARG, and KCNJ11 and DR, in
contrast to the findings from previous studies. This high-
lights the challenges in identifying genetic risk factors of
DR, as reasons such as small sample sizes and the lack of
uniform assessment across studies preclude the replication
of results across populations. However, our findings showed
that the cumulative effect of the type 2 diabeteseassociated
SNPs had significantly stronger associations with DR. Such
association consistently mirrors the polygenic, complex
nature of DR, which was previously postulated. On the other
hand, duration of diabetes and HbA1c are strong predictors
for DR development. In our study, duration of diabetes was
self-reported and HbA1c was based on a 1-time measure-
ment only. As such, although we adjusted for duration of
diabetes and HbA1c in our analysis, our observed associa-
tion may reflect a possible effect of diabetes severity,
mediated though longer duration of diabetes and higher
levels of HbA1c, leading to the development of DR.
Our findings showed that the GRSs were associated with
higher DR severity levels. This suggests that genetic factors
may play a prominent role in the development of DR and the

Table 5. Association Between Genetic Risk Scores and Diabetic Retinopathy

Model 1* Model 2y
GRS OR (95% CI) P Value OR (95% CI) P Value

Overall GRS (range)

1st tertile (0.45 to 0.81) 1.00 (Reference) e 1.00 (Reference) e
2nd tertile (0.81 to 1.21) 1.55 (1.18e2.03) 1.6  103 1.48 (1.10e1.97) 8.4  103
3rd tertile (1.21 to 2.39) 2.64 (2.01e3.45) 1.8  1012 2.56 (1.92e3.40) 1.5  1010
P for trend ¼ 1.4  1012 P for trend ¼ 1.1  1010
Asian-specific GRS (range)
1st tertile (1.78 to 0.58) 1.00 (Reference) e 1.00 (Reference) e
2nd tertile (0.58 to 0.25) 1.49 (1.14e1.95) 3.2  103 1.43 (1.07e1.89) 0.014
3rd tertile (0.25 to 0.94) 2.17 (1.66e2.82) 9.4  109 2.00 (1.51e2.65) 1.3  106
P for trend ¼ 9.1  109 P for trend ¼ 1.2  106

CI ¼ confidence interval; GRS ¼ genetic risk score; OR ¼ odds ratio.

*Adjusted for ethnicity.
y
Adjusted for ethnicity, diabetes duration, serum glycosylated hemoglobin, and hypertension.

4
 Chong et al 
Effects of Diabetic Genes on DR

Table 11. Area-Under-the-Curve Estimates for Diabetic Reti-

nopathy Using Traditional and Genetic Risk Score Prediction
Models

Overall GRS Asian-Specific GRS

Model including traditional 0.71 (0.68e0.74) 0.71 (0.68e0.74)

risk factors*
Model including traditional 0.74 (0.71e0.76) 0.73 (0.70e0.76)
risk factors and GRS
4
P difference 2.0  10 2.2  103

GRS ¼ genetic risk score.

*Traditional risk factors consist of age, gender, ethnicity, diabetes duration,
serum glycosylated hemoglobin, and hypertension.
Data are area under the curve (95% confidence interval) unless otherwise
indicated.

existing risk factors. This finding of modest risk discrimi-

Figure 2. Proportions and odds ratios (OR) of diabetic retinopathy (DR)
in sextile groups of genetic risk scores, with the first sextile as the reference
group. A, Overall genetic risk score; B, Asian-specific genetic risk score.
eventual severity of the disease. Although the absolute AUC
estimates for the GRS models are possibly overestimated
owing to the concurrent use of study population in score
construction, our purpose in performing the AUC analysis
was to evaluate the discriminating ability of the GRSs for
DR compared with traditional risk factors. In this regard, we
showed a modest increase in AUC from the addition of the
GRSs to traditional risk factors, indicating the robustness of
nation improvement using genetic markers has been
observed in other multifactorial, complex diseases such as
glaucoma,40 which are influenced by numerous genetic
variants. Current DR screening methods include regular
dilated slit-lamp biomicroscopy eye examinations, mydri-
atic or nonmydriatic retinal photography, and tele-retinal
screening.41 However, studies have shown a high
prevalence of undiagnosed DR, ranging from 25% in an
American inpatient population42 to 83% in the SEED
population,43 suggesting that current screening methods
may be inadequate. Early diagnosis and treatment have
been shown to reduce the risk of DR progression and
blindness.44,45 Clinically, the GRSs may be helpful in pre-
dicting patients with diabetes’ risk of developing DR and
the disease progression upon diagnosis of diabetes. How-
ever, given the polygenic nature of complex diseases such as
DR and the cost of genotyping, further discovery of more
novel genes for type 2 diabetes or DR and cheaper cost of
genotyping will be needed to more robustly improve the
clinical usefulness of genetic variants in predicting DR.
We showed that there was no significant difference in
association between the GRSs and DR among the 3 ethnic
groups of Malays, Indians, and Chinese. Combined with
previous studies that showed no significant difference in the
prevalence of DR among these 3 ethnic groups in the
SEED population,43 these results suggest similar genetic
susceptibility across the 3 ethnic groups of Malays,
Indians, and Chinese.

Table 7. Association between Genetic Risk Score and Diabetic Retinopathy Severity Level

Model 1* Model 2y
GRS b (95% CI) P Value b (95% CI) P Value
12
Overall GRS 0.83 (0.60e1.06) 2.2  10 0.74 (0.50e0.98) 1.2  109
Asian-specific GRS 0.87 (0.60e1.12) 9.7  1011 0.74 (0.47e1.01) 9.9  108

GRS ¼ genetic risk score.

b represents the change in diabetic retinopathy severity level in the ordered log-odds scale for each standard unit increase in GRS.
*Adjusted for ethnicity.
y
Adjusted for ethnicity, diabetes duration, serum glycosylated hemoglobin, and hypertension.

5
 Ophthalmology Volume -, Number -, Month 2016
Study Strengths and Limitations
The strengths of this study include a large, population-based
sample and standardized methodology and assessment of
DR based on retinal photographs. Although the type 2
diabetes genetic susceptibility variants had modest individ-
ual effects on DR, our study design allowed for the identi-
fication of stronger combined effects using the GRS
approach. A limitation of this study was that it included only
Asian ethnicities. As such, further validation of the GRSs is
required in other populations of different ethnicities for
further generalization of the current findings. Given that DR
regression has been known to occur, especially in patients
with minimal or mild NPDR, it is also possible that some
controls may have previously had mild forms of the disease
that have since regressed.
In conclusion, our findings showed that persons with type
2 diabetes with more disease genetic risk alleles were more
likely to have DR, independent of traditional DR risk factors.
This suggests complex genetic susceptibility to both diabetes
and DR, providing new insights into the genetic pathogenesis
of microvascular complications in type 2 diabetes.
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Footnotes and Financial Disclosures
Originally received: August 17, 2016.
Final revision: November 11, 2016.
Accepted: November 11, 2016.
Available online: ---. Manuscript no. 2016-106.
1
Singapore Eye Research Institute, Singapore National Eye Centre,
Singapore.
2
Duke-NUS Medical School, Singapore.
3
Centre for Vision Research, Westmead Institute for Medical Research,
University of Sydney, Sydney, Australia.
4
Department of Ophthalmology, Yong Loo Lin School of Medicine, Na-
tional University of Singapore, Singapore.
*Both Tien Yin Wong and Ching-Yu Cheng contributed equally to this
work.
Financial Disclosure(s):
Supported by the National Medical Research Council (NMRC), Singapore
(grants 0796/2003, 1176/2008, 1149/2008, STaR/0003/2008, 1249/2010,
CG/SERI/2010, CIRG/1371/2013, and CIRG/1417/2015), and Biomedical
Research Council, Singapore (08/1/35/19/550 and 09/1/35/19/616).
C.Y.C.: Supported by an award from NMRC (CSA/033/2012). The funding
organization had no role in the design or conduct of this research.
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Author Contributions:
Conception and design: Wong, Cheng
Analysis and interpretation: Chong, Fan, Tham, Gan, S.P. Tan, G. Tan,
Wong, Cheng
Data collection: Wang, Mitchell, Wong, Cheng
Obtained funding: Not applicable
Overall responsibility: Chong, Fan, Tham, Gan, S.P. Tan, G. Tan, Wang,
Mitchell, Wong, Cheng
Abbreviations and Acronyms:
AUC ¼ area under the receiver operating characteristic curve;
CI ¼ confidence interval; DIAGRAM ¼ DIAbetes Genetics Replication
And Meta-analysis; DR ¼ diabetic retinopathy; GRS ¼ genetic risk score;
GWAS ¼ genome-wide association study; HbA1c ¼ serum glycosylated
hemoglobin; NPDR ¼ nonproliferative diabetic retinopathy;
PC ¼ principal component; PDR ¼ proliferative diabetic retinopathy;
SD ¼ standard deviation; SEED ¼ Singapore Epidemiology of Eye Dis-
eases; SNP ¼ single nucleotide polymorphism.
Correspondence:
Ching-Yu Cheng, MD, PhD, Singapore Eye Research Institute, The
Academia, 20 College Road, Discovery Tower Level 6, Singapore, 169856.
E-mail: chingyu.cheng@duke-nus.edu.sg.