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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1560-1564
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Association between diabetic retinopathy and genetic variations
in  2 1 integrin, a platelet receptor for collagen
Yumiko Matsubara,
Mitsuru Murata,
Taro Maruyama,
Makoto Handa,
Norihiko Yamagata,
Gentaro Watanabe,
Takao Saruta, and
Yasuo Ikeda
From the Department of Medicine, School of Medicine, Keio
University, Tokyo; Saitama Social Insurance Hospital, Saitama, Blood
Center, Keio University, Tokyo; and the Hibiya Medical Center, Sakura
Bank, Tokyo, Japan.
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Abstract |
Platelets might be involved in the pathogenesis of diabetic
microangiopathy. Wide interindividual variations in the density of a
platelet collagen receptor ( 2 1 integrin or glycoprotein Ia/IIa)
are reportedly associated with polymorphism(s) in the gene encoding the
subunit of the receptor, including a Bgl II polymorphism in intron
7. The aim of the present study was to determine the relationship
between the Bgl II polymorphism and the susceptibility to diabetic
microangiopathy. A case-control study comparing 227 patients with type
II diabetes mellitus (119 with versus 108 without diabetic retinopathy)
as well as 169 nondiabetic subjects demonstrated that genotypes with
Bgl II (+) allele had a significant increase in the risk for
retinopathy. The odds ratio for Bgl II (+/+) to Bgl II ( /)
was 3.41 (95% CI, 1.49-7.78, P = .0036) when analysis was
confined to those with a disease duration of diabetes of 10 years or
more. The present study suggests that the presence of a Bg II (+)
allele is a genetic risk factor for diabetic retinopathy.
(Blood. 2000;95:1560-1564)
© 2000 by The American Society of Hematology.
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Introduction |
The platelet membrane glycoprotein (GP) Ia/IIa,
 21 integrin, serves as a platelet receptor for
collagen.1-4 It mediates platelet primary adhesion to
subendothelial tissues, which is an essential first step in thrombus
formation. The gene encoding 2 integrin has at least 8 polymorphisms, including 2 silent polymorphisms located within the I
domain,5 224Phe (TTT/TTC) due to a T/C
transition at nucleotide 807 (807T/C) and 246Thr (ACA/ACG)
due to an A/G transition at nucleotide 873 (873A/G) (numbers according
to Takada et al6), and a Bgl II restriction fragment length
polymorphism (Bgl II, +/) within intron 7.7 These 3 polymorphisms are in linkage disequilibrium, the Bgl II (+) allele
being linked to the 807T allele and 873A allele and the Bgl II
() allele being linked to the 807C allele and 873G allele.7 It was reported that the platelet 21 density
and the extent of platelet adhesion to collagen were higher in
individuals with the 807T-(873A- or Bgl II (+)-) homozygote than in
individuals with the 807C-(873G- or Bgl II ()-)
homozygote.7,8 Frequency of the 807T allele was reported to
be 33.6%, 31.4%, and 53.9% in the healthy Caucasians, African
Americans, and Native Americans, respectively.9
Relationships between these polymorphisms and the prevalence of
myocardial infarction or stroke have been reported, and the 807T allele
has been shown to be at risk.10-12
Platelets from diabetic patients are hyperreactive to aggregating
agents, such as adenosine diphosphate, collagen, and thrombin. There is
increased secretion of -thromboglobulin and platelet factor 4, which
are markers of platelet activation in vivo.13-15 The values
of platelet activation markers in diabetic patients without
microangiopathy are higher than those in patients without microangiopathy.16,17 Also, the importance of platelets for the development of diabetic retinopathy or nephropathy is supported by
several studies indicating the beneficial effects of antiplatelet therapy.13,18-21 Thus, platelets are thought to be involved
in the development of diabetic retinopathy or nephropathy, although the
mechanisms underlying the association between platelet functions and
microangiopathies are incompletely known.15
For the development of diabetic retinopathy and nephropathy, disease
duration of diabetes and glycemic control are major determinants. Some
diabetic patients, however, do not develop these complications, even
after a long duration of diabetes.13 Familial clustering of
diabetic retinopathy22 and nephropathy23 has
been demonstrated. These observations suggest that some modulating
factors for the risk of diabetic retinopathy or nephropathy are
genetically transmitted.
To examine a hypothesis that a genetic variation on 21 integrin
is associated with the development of diabetic microangiopathy, we
analyzed the association between the Bgl II polymorphism and the
susceptibility to retinopathy or nephropathy among patients with type
II diabetes mellitus. We also investigated genotype distributions of
the PLA1/A2 polymorphism24 of integrin IIb3 (GP
IIb/IIIa), a platelet membrane receptor for fibrinogen and von
Willebrand factor.
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Patients and methods |
Study subjects
Informed consent was obtained from all subjects enrolled into the
study. Normal subjects (n = 169; 135 males, 34 females), recruited at
Hibiya Medical Center (Tokyo, Japan), Fuji Electronics (Tokyo, Japan),
and Keio University Hospital (Tokyo, Japan) for their regular checkups,
were analyzed. The mean age was 47.1 ± 5.9 years
(mean ± SD). They had no clinical or laboratory evidence of
either past vascular disorders or any form of diabetes.
Patients were genetically unrelated 227 Japanese subjects who had had a
diagnosis of type II diabetes mellitus, as defined by World Health
Organization criteria,25 and were followed up on a regular
basis at an outpatient clinic of Saitama Social Insurance Hospital
(Saitama, Japan). They were divided into 2 groups (Table 1). The first group included 119 patients
with retinopathy (35 patients with retinopathy without nephropathy,
group B; and 84 patients with both retinopathy and nephropathy,
group C). The second group consisted of 108 patients without
retinopathy or nephropathy (group A). The group A patients were
selected to match groups B and C patients in terms of age at diagnosis
of diabetes, sex, and disease duration after diagnosis of diabetes.
Diabetic retinopathy was diagnosed by independent diabetic
ophthalmologists using standard fundus photos and was classified as
simple, preproliferative, and proliferative (either treated with
photocoagulation or not). Diabetic nephropathy was diagnosed using the
following criteria: (1) urinary excretion of albumin per gram (urinary
albumin index; UAI)  30 mg/g and (2) the presence of retinopathy,
which indicates diabetic microangiopathy. It was classified as
microalbuminuria (UAI, 30-299 mg/g), overt proteinuria (UAI 300 mg/g), and chronic renal failure. Diabetic patients with UAI  20 mg/g
were classified as "no nephropathy." Those with UAI between 21 and 29 mg/g were assumed to be in the "gray zone" and were
excluded from the study. Those with UAI 30 mg/g but without
retinopathy were also excluded from the study because proteinuria is
observed in diabetic patients with reasons other than diabetic
nephropathy.26 Clinical data, including age at diagnosis of
diabetes, disease duration after diagnosis of diabetes, body mass index
(BMI) at diagnosis of diabetes, hemoglobin (Hb) A1C,
antihypertensive drug treatment, and hyperlipidemia were collected from
medical records of the patients.
Genotyping of Bgl II polymorphism and PLA1/A2 polymorphism
Genomic DNA was isolated from peripheral blood leukocytes in 227 patients with type II diabetes mellitus and 169 normal subjects, as
described previously.27 For genotyping of the Bgl II
polymorphism, a 600-bp DNA fragment that contains the Bgl II
(+/) polymorphism was amplified using polymerase chain reaction
(PCR) with a DNA thermal cycler (Perkin Elmer, Takara Biomedicals,
Chiba, Japan). Briefly, the reaction was performed in a
final volume of 100 µL containing 1 µg genomic DNA, 10 mM Tris (pH
8.3), 50 mM KCl, 1.5 mM MgCl2, 0.001% gelatin, 0.2 mM each
of deoxynucleotide triphosphate, and 2.5 U Taq polymerase.
The 2 oligonucleotide primers7 were
5'-GATTTAACTTTCCCGACTGCCTTC (nucleotide number 2789-2812) and
5'-CATAGGTTTTTGGGGAACAGGTGG (nucleotide number 3346-3369). PCR
conditions of 34 cycles in this study were as follows: the first 2 cycles were 94°C for 1 minute, 69°C for 1 minute, and 72°C
for 1 minute; the second 2 cycles were 94°C for 1 minute, 67°C
for 1 minute, and 72°C for 1 minute; the remaining 30 cycles were
94°C for 1 minute, 65°C for 1 minute, and 72°C for 1 minute. Amplified DNA was digested with a restriction enzyme Bgl II
(Takara Shuzo, Osaka, Japan) at 37°C for 3 hours,
followed by an electrophoresis on a 2% agarose gel. The PCR products
containing Bgl II (+) would be cut into visible fragments of 200 bp and
400 bp, whereas those containing Bgl II () would not be cut.
Genotyping of the PLA1/A2 polymorphism was performed essentially as
described.24
Statistics
Student's t test was used to compare age at diagnosis of
diabetes, disease duration after diagnosis of diabetes, BMI at
diagnosis of diabetes, and HbA1C at diagnosis of diabetes
between subgroups of patients. Analyses of genotype frequency counts
were performed using the chi-square test. Multiple logistic regression
analysis was performed to evaluate the relationship between those with versus those without retinopathy (categorical variable, yes or no) and
other variables. Independent variables included in the analysis
were Bgl II genotype (categorical variable, +/+, +/, /), sex (categorical variable, male or female), age at
diagnosis of diabetes (quantitative variable), disease duration from
diagnosis of diabetes (quantitative variable), and BMI at diagnosis of
diabetes (quantitative variable). Analysis of variance (ANOVA) was used for the comparison of the mean values of current HbA1C
levels among the 3 Bgl II genotypes. All statistical analyses were
performed using Statview (version 5.0, for Macintosh, Abacus Concepts,
Berkeley, CA). Variability in sampling associated with the estimated
odds ratio (OR) was assessed by 2-sided 95% confidence intervals (CI). An OR (95% CI) greater than 1 was considered to be significant. A
P value less than 0.05 was considered to be statistically significant.
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Results |
Bgl II polymorphism and susceptibility to diabetic retinopathy or
nephropathy
To explore the clinical significance of the Bgl II polymorphism, we
performed a cross-sectional study comparing diabetic patients with
(n = 119) and without (n = 108 retinopathy. Genotyping was performed also on 169 nondiabetic subjects. The clinical
characteristics of 227 patients are shown in Table 1. The 2 groups were
well matched with regard to gender distribution, age at diagnosis of diabetes, disease duration after diagnosis of diabetes,
HbA1C at diagnosis of diabetes, and BMI at diagnosis of diabetes.
Table 2 shows Bgl II genotype distribution
in patients and normal subjects. The genotype distribution in each
group shown in Table 2 was in Hardy-Weinberg equilibrium. The frequency
of the Bgl II (+/+, +/) genotype in group B plus C patients
(69.7%) was significantly higher than that in group A patients
(55.6%, OR [95% CI] = 1.84 [1.07-3.16], P = .0270).
The frequency of Bgl II (+/+, +/) genotype in group C patients
(71.4%) was significantly higher than in group A plus B patients
(58.0%, OR = 1.81 [1.02-3.22], P = .0437), or in group A
patients (55.6%, OR = 2.00 [1.10-3.65], P = .0242). When
the analysis was confined to those patients with a disease duration of
10 years or more, the frequency of Bgl II (+/+, +/) genotype was
72.4% for group B plus C patients, 55.1% for group A patients, 73.9%
for group C patients, and 58.1% for group A plus B patients
(OR = 2.14 [1.20-3.82], P = .0102, group B plus C versus
group A patients; OR = 2.04 [1.06-3.94], P = .0262, group C versus group A plus B patients; OR = 2.31 [1.20-4.44], P = .0120, group C versus group A patients). These
observations suggest that patients with the Bgl II (+/+, +/)
genotype have an increased risk for diabetic retinopathy or
nephropathy. For normal subjects, the frequency of the Bgl II (+/+,
+/) genotype was 65.7% and the frequency of the Bgl II
(/) genotype was 34.3%.
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Table 2.
Genotype distribution of 2 integrin Bgl II
polymorphism in patients with type II diabetes and in normal
subjects
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Next, the dose effect of the Bgl II (+) allele on the risk for
retinopathy or nephropathy was analyzed in diabetic patients with a
disease duration of 10 years or more. It was shown that the
greater the number of the Bgl II (+) allele, the greater the risk
for diabetic retinopathy or nephropathy. For retinopathy, the
frequencies of Bgl II (+/+) genotype were 23.5% and 11.2% for group B
plus C and group A patients, respectively, and the frequencies of Bgl
II (+/) genotype were 48.9% and 43.9% for group B plus C and
group A patients, respectively. The ORs (95% CI) to Bgl II
(/) were 1.82 (0.98-3.38, P = .0580) and 3.41 (1.49-7.78, P = .0036) for Bgl II (+/) and Bgl II
(+/+) genotypes, respectively (see Table 2). For nephropathy, the
frequencies of Bgl II (+/+) genotype were 21.7% and 14.7% for group C
and group A plus B patients, respectively, and the frequencies of Bgl
II (+/) genotype were 52.2% and 43.4% for group C and group A
plus B patients, respectively. The ORs (95% CI) to Bgl II
(/) were 1.93 (0.99-3.76, P = .0533) and 2.38 1.02 -5.54, P = .0444) for Bgl II (+/) and Bgl II
(+/+) genotypes, respectively (see Table 2).
Increased frequency of Bgl II (+)-containing allele was observed in all
stages of diabetic microangiopathies, that is, genotype distributions
did not differ significantly among different stages of retinopathy and
nephropathy (data not shown).
As shown in Table 3, a multiple logistic
regression model with a dependent variable (presence or absence of
retinopathy) and several independent variables (Bgl II genotype, sex,
age at diagnosis of diabetes, disease duration after diagnosis of
diabetes, and BMI at diagnosis of diabetes) had an adjusted OR of 1.515 (95% CI, 1.020-2.251, P = .0397) for the relation between
retinopathy and the presence of the Bgl (+) allele, suggesting that the
Bgl II genotype is an independent predictor of retinopathy. To examine whether the relation of the Bgl II genotype to nephropathy shown in
Table 2 depended on the relationship between the genotype and
retinopathy, we analyzed the genotype distribution only in patients
with retinopathy, comparing those with and without nephropathy. The
genotype frequency for Bgl II (+/+, +/) was 71.4% and 65.7% for group C and group B, respectively, which were not significantly different (P > .05). Thus, the Bgl II genotype is
associated with the prevalence of retinopathy independent of the other
variables, but it is not independently associated with the prevalence
of nephropathy.
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Table 3.
Odds ratios adjusted by multiple logistic regression
analysis for the association with retinopathy among patients with type
II diabetes mellitus
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Current disease status of patients in relation to the Bgl II genotype
is shown in Table 4. No significant
difference was observed among 3 Bgl II genotypes with regard to
HbA1C, prevalence of antihypertensive drug treatment, or
hyperlipidemia, either in group A patients or group B plus C patients
although the mean of HbA1C and the prevalence of
antihypertensive drug treatment in group B plus C patients were higher
than those in group A patients.
We next analyzed the genotype distribution of the PLA1/A2 polymorphism
among 154 diabetic patients (82 with retinopathy, 72 without
retinopathy). However, we found no subject with the PLA1/A2 or PLA2/A2
genotypes, that is, all patients had the PLA1/A1 genotype. This result
is consistent with previous reports that the PLA2 allele is rare in
Japan.28,29
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Discussion |
Several epidemiologic and experimental studies indicate that disease
duration of diabetes and glycemic control are major determinants for
the development of diabetic retinopathy or
nephropathy.30-32 In the presence of prolonged
hyperglycemia, alteration in retinal or renal blood flow, metabolic
changes, hemostatic abnormality, or nonenzymatic glycosylation of
long-lived tissue proteins are observed.14,33-36 These
changes are associated with vascular dysfunction in
microcirculation,13,36-40 which are thought to contribute
to the occurrence or progression of diabetic retinopathy and nephropathy.
Platelets might be involved in the occurrence of diabetic retinopathy
and nephropathy. Hyperreactive platelets in diabetic patients would be
more likely to interact with an exposed subendothelium of damaged
vessels and enhance microthrombus formation or small vessel occlusion
in vivo. This, in turn, might alter retinal or renal blood flow.
Moreover, evidence indicating the beneficial effect of antiplatelet
therapy18-21 on retinopathy and nephropathy suggests the
involvement of platelets in the pathogenesis of microangiopathy. The
focus in the present study was on platelet adhesion, which is a first
critical step for primary thrombus formation and leads to intracellular
activation processes.
This study shows that the Bgl II polymorphism is associated with the
prevalence of retinopathy among patients with type II diabetes
mellitus. The Bgl II (+/+, +/) genotypes increased the risk of
retinopathy and nephropathy, but the association between the Bgl II
genotype and nephropathy was not independent of retinopathy. However,
because the majority of diabetic patients with retinopathy suffer from
concomitant nephropathy, the Bgl II genotype could be also regarded as
a predictor of nephropathy. The Bgl II polymorphism has been reportedly
associated with platelet 21 density, the extent of platelet
adhesion to collagen, and the prevalence of myocardial infarction or
stroke.7,8,10-12 This study is the first to demonstrate an
association between the Bgl II polymorphism and diabetic retinopathy.
The amount of nonenzymatically glycosylated collagen, which more easily
interacted with platelets, was higher in diabetic patients than in
nondiabetic controls.33,41 It is possible that Bgl II
(+)-containing platelets can more easily interact with nonenzymatically
glycosylated collagen and accelerate the occurrence of retinopathy. In
addition, our findings might affect antiplatelet drug treatment for
diabetic retinopathy. For instance, patients with the Bgl II
(+/, +/+) genotype might benefit more from antiplatelet
therapies. Although the role for 21 integrin in the development
of diabetic retinopathy is not fully understood, our data suggest a
contribution of platelets in the development of diabetic retinopathy.
The PLA1/A2 polymorphism has recently been highlighted because of its
association with thrombotic disorders.42 The PLA2 allele,
however, was reported to be extremely rare in Japanese populations.28,29 In agreement with these reports, we did
not observe the genotypes with the PLA2 allele among 154 diabetic patients. Therefore, it remains unclear whether the PLA1/A2
polymorphism might affect the susceptibility to microangiopathy in
patients with type II diabetes mellitus.
In conclusion, Bgl II polymorphism of the subunit of 21
integrin is associated with the prevalence of retinopathy in
patients with type II diabetes mellitus. The present study will aid in early identification of risk or possibly prevention and will direct studies on more beneficial uses of antiplatelet drugs for diabetic microangiopathy.
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Acknowledgments |
We thank Dr Thomas J. Kunicki, Scripps Research Institute, CA, for
providing the detailed protocol on Bgl II genotyping. We also thank Dr
Koichi Kawano and Dr Nobuo Aoki, Kyorin Universtiy, Tokyo, Japan, for
providing samples from healthy subjects.
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Footnotes |
Submitted April 26, 1999; accepted October 26, 1999.
Reprints: Mitsuru Murata, Department of Medicine,
School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; e-mail: murata{at}mc.med.keio.ac.jp.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction