Open Access

High prevalence of diabetic retinopathy and lack of association with integrin α2 gene polymorphisms in patients with type 2 diabetes from Northeastern Mexico

  • Authors:
    • Ana Cecilia Cepeda‑Nieto
    • María Teresa Esquivel‑Contreras
    • Francisco Duran‑Iñiguez
    • Mauricio Andrés Salinas‑Santander
    • Hugo Leonid Gallardo‑Blanco
    • Sandra Cecilia Esparza‑González
    • Alejandro Zugasti‑Cruz
    • Jesús Antonio Morlett‑Chávez
    • Luis Tlaloc Córdova‑Alvelais
  • View Affiliations

  • Published online on: May 26, 2015     https://doi.org/10.3892/etm.2015.2520
  • Pages: 435-444
  • Copyright: © Cepeda‑Nieto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Diabetic retinopathy (DR) is one of the primary causes of blindness in the working age population and is characterized by angiogenesis in the retina. Platelets have been suggested to be involved in the pathogenesis of diabetic microvascular complications. The integrin receptor for collagen/laminin, α2β1, mediates platelet primary adhesion to subendothelial tissues, which is an essential first step in thrombus formation. The gene encoding the α2 subunit of α2β1 integrin has ≥8 polymorphisms, including a BglII/NdeI restriction fragment length polymorphism. To explore the prevalence of DR in a population from Northeastern Mexico, unrelated, hospitalized patients who had received a diagnosis of type 2 diabetes mellitus (DM2) at least 10 years previously were recruited (n=177). DR was diagnosed in a masked manner by independent ophthalmologists using fundus images captured using a non‑mydriatic retinal camera. A total of 121 patients with DM2 (68%) had some degree of DR development (DR patients), and 56 patients with DM2 (32%) did not exhibit any sign of DR (No‑DR patients). The results showed that after 15 years of DM2 progression, there is an increased risk of DR (P=0.0497; odds ratio, 1.993). In addition, insulin therapy and family history of DM2 were significantly associated with DR. In order to detect a possible association between DR and BglII/NdeI α2 gene polymorphisms, a comparative cross‑sectional study between DR and No‑DR patients was conducted. The α2 gene was genotyped by polymerase chain reaction‑restriction fragment length polymorphism assay. Statistical analysis revealed no association between BglII/NdeI genotypes and the development of DR in this group of patients. In conclusion, the present data indicate a high prevalence of DR in the Mexican population and suggest that the damage in DR is due to other factors, such as the duration of the DM2, and is not linked to BglII/NdeI α2 gene polymorphisms.

Introduction

The most common complication of type 2 diabetes mellitus (DM2) is diabetic retinopathy (DR), which is a microvascular complication of the retina and remains one of the leading causes of blindness throughout the world (1). The characteristic features of DR include increased vascular permeability and hemostatic abnormalities, which may result in vascular occlusion, irrespective of antidiabetic treatment, and, ultimately, retinal non-perfusion and neovascularization (2). Platelets have been suggested be involved in the pathogenesis of DR (3,4).

DR can be classified into early- and late-stage categories. The early stage of DR, also known as non-proliferative diabetic retinopathy (NPDR), is associated with edema, fluid leakage and restricted blood flow into the eye, in the absence of abnormal neovascularization. By contrast, advanced-stage DR, or proliferative diabetic retinopathy (PDR), is characterized by neovascularization and fibrous tissue formation (5).

Population-based studies in different countries have found the prevalence of DR in individuals diagnosed or undiagnosed with DM2 to range from 17.6% in India to 54% in Iran (68); however, these data are scarce, as these studies rely on sophisticated diagnostic equipment (714). The reported prevalence rate of DR in a Mexican-American population aged ≥40 years was found to be 48% (15,16). In Mexico, a study reported 38.9% DR prevalence in a population from Southern Mexico (17). The high prevalence in Southern Mexico is consistent with data from another study undertaken in Mexico, in which the DR prevalence was 51% (18).

In Coahuila, Mexico, the number of patients with DM2 has increased over recent years (19); therefore, the number of patients with DR is also increasing. To date, there are no recent reports concerning DR prevalence in Northeastern Mexico, and thus investigating the DR prevalence in this region is one of the purposes of this research.

Evidence from ethnic and family studies has suggested that there may be genetic susceptibility for DR. In the Diabetes Control and Complications Trial, a 3.1-fold increased risk of severe retinopathy was found for subjects with retinopathy-positive relatives, and a correlation for the severity of retinopathy was present among all family members (20). Similar results for the clustering of DR-positive individuals within families were also observed among Southern Indians and Mexican Americans with DM2 (21,22). In the FIND-Eye study, the overall broad-sense heritability for DR was found to be 27%, compared with 24% in Mexican-American families (23). The role of genetics in DR is believed to be responsible for the fact that certain diabetic individuals avoid retinal complications, even following a long history of uncontrolled diabetes, while others rapidly develop DR, despite tight metabolic control (24).

Considerable research has been performed to identify the genetic markers that are associated with the risk of developing DR using an indirect approach, such as case-control association studies, in a number of ethnic populations. In these studies several candidate genes with different functions have been reported to be associated with DR (3,2533); however, only a fraction of these studies have shown a consistent association with DR or its severity in different populations (25,3437).

The pathogenesis of DR is linked with vascular permeability, tissue ischemia and angiogenesis (5). Alterations in platelet function are frequent in patients with DM2 and contribute to the pathogenesis and progression of vascular complications (3,14,38,39). Following vascular injury, circulating blood platelets are exposed to subendothelial collagen, a protein that stimulates the matrix adhesion and activation required for platelet thrombus formation. The firm adhesion of platelets to collagen requires the involvement of collagen receptors, such as integrin α2β1 (38,40). Given the important role of integrin receptors in vascular processes and their complications, these receptors are considered a good candidate for investigations into a possible association with the DR in patients with DM2.

Integrin receptors are heterodimeric molecules composed of non-covalently associated α and β subunits that mediate cell-cell and cell-matrix adhesion (38,40). α2β1, also known as the platelet membrane glycoprotein Ia-IIa complex or ITGA2, is a membrane glycoprotein expressed in megakaryocytes and blood platelets. This receptor acts as a platelet receptor for collagen (38,40) and mediates the primary adhesion of platelets to subendothelial tissues, which is a crucial first step in the formation of thrombi. The expression levels of the integrin α2β1 in platelets vary significantly among normal individuals, whereas the levels of other integrin receptors do not (40,41).

The gene encoding the α2 subunit of α2β1 integrin has ≥8 polymorphisms, including two conservative changes in the amino acid coding region of α2 at nucleotides 807 (TTT/TTC at codon Phe224) and 873 (ACA/ACG at codon Thr246) of the cDNA sequence (41). These DNA sequence polymorphisms, referred to as 807C and 807T for the 807C/873G and 807T/873A pairs, respectively, in the α2 gene coding region are linked with two polymorphic sites in the α2 gene intron G (3,160 A/G and 3,090 T/C), which correspond to the recognized sites by BglII and NdeI restriction enzymes, respectively (41).

The BglII and NdeI recognition sites in intron G of the α2 gene are used to genotype three different α2 gene alleles defined by eight nucleotide polymorphisms, including the 807C and 807T polymorphisms, using BglII/NdeI restriction analysis (41). The allele BglII (+)/NdeI (+) has been linked to 807T polymorphism, which is associated with high levels of platelet integrin α2β1 expression, while allele BglII (-)/NdeI (-) has been linked to 807C polymorphism and is associated with low levels of platelet integrin α2β1 (3,4,41).

Associations between the BglII polymorphism and the prevalence of DR have been reported in Japanese (3) and Caucasian (25) diabetic patients, and the BglII (+) allele in these two ethnic groups has been shown to be a risk factor for DR; however, the association between the BglII/NdeI polymorphism and the prevalence of DR has not yet been studied in patients with DM2 from Northeastern Mexico. The aim of the present study, therefore, was to test the hypothesis that a genetic variation in the α2 integrin gene is associated with the development of DR by analyzing the possible association between the intronic polymorphic sites BglII and NdeI of the α2 gene and the susceptibility to DR among Mexican diabetic patients with ≥10 years of DM2 history.

Materials and methods

Study subjects

A comparative cross-sectional hospital study was performed to analyze the clinical characteristics of DR and to explore the genetic association between DR and polymorphic variants of the α2 gene. Unrelated Mexican patients who had been diagnosed with DM2 ≥10 years previously (n=177; 108 males, 69 females) were recruited at the Mexican Social Security Institute (IMSS) Hospital (Saltillo, Mexico). Diabetes was defined according to the report of the expert committee on the diagnosis and classification of diabetes mellitus (42). Only DM2 patients were included in this study, and the study was performed in accordance with the ethics standards of the Dr Gonzalo Valdés University Hospital of the Autonomous University of Coahuila (Saltillo, Mexico). The University Hospital-Autonomous University of Coahuila Institutional Review Board approved and registered the study under the code FM001-10.

Informed consent was obtained from all subjects enrolled following an explanation of the nature of the study. Patients with known DM2 for a duration of <10 years, patients who had not voluntarily agreed to participate in the study and those who did not have a laboratory workup were excluded from the study.

Clinical data collection and study group classification

DR was diagnosed in a masked manner by independent ophthalmologists using fundus images captured using a Canon CR-DGi non-mydriatic retinal camera with the Eye Q Prime software (Canon USA, Inc., Lake Success, NY, USA) in patients with a DM2 duration of ≥10 years. Patients with DM2 but without DR (No-DR group, n=56) were compared with DM2 patients with DR of either the NPDR or PDR subtype (DR group, n=121) according to Early Treatment Diabetic Retinopathy Study (ETDRS) criteria (5).

The following clinical and biochemical characteristics were analyzed for all patients with DM2 (No-DR and DR groups): Age (years), gender, duration of diabetes (years), systolic and diastolic pressure (mmHg), fasting plasma glucose (mg/dl), cholesterol (mg/dl), triglycerides (mg/dl), cataracts, glaucoma and insulin use. Documented information also included family history of DM, hypertension, cardiovascular disease, dyslipidemia and renal failure. Peripheral blood was obtained from all patients with DM2 following a 12-h fast for biochemical analysis.

DNA extraction

Peripheral venous blood samples (5 ml) were obtained from the DR and No-DR patients and were collected in EDTA tubes (BD Vacutainer®; Becton Dickinson, Mexico City, Mexico). The samples were centrifuged using a refrigerated centrifuge (Thermo Fisher Scientific, Inc., Waltham, MA, USA), and the buffy coat was processed for high-molecular weight genomic DNA isolation by the salting-out method, and suspended in Tris-EDTA (pH 7.8; Mallinckrodt Baker, Inc., Phillipsburg, NJ, USA), at a final concentration of 0.1–1.0 µg/µl.

Genotyping for the α2 gene 3,160 A/G and 3,090 T/C polymorphisms

Genotyping for the α2 gene was performed to analyze the possible genetic association between DR and the polymorphic variants of the α2 gene. The 3,160 A/G and 3,090 T/C polymorphism of the α2 intron G region were tested. The α2 gene was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, as previously reported (41), using an MJ Mini™ Gradient Thermal Cycler (Bio-Rad, Hercules, CA, USA), followed by BglII and NdeI [New England Biolabs (NEB), Ipswich, MA, USA] restriction enzyme analysis. In brief, the method for the PCR was as follows: 250 ng genomic DNA, 0.5 µM primers (forward, 5′-GAT TTA ACT TTC CCG ACT GCC TTC-3′ and reverse, 5′-CAT AGG TTT TTG GGG AAC AGG TGG-3′), 0.2 mM deoxyribonucleotide triphosphates (Invitrogen Life Technologies, Carlsbad, CA, USA), 1.5 mM MgCl2 and 2.5 units of Taq DNA polymerase (Invitrogen Life Technologies) were combined to form the reaction mixture. The 600-bp segment of intron G encompassing the BglII and NdeI sites was amplified from genomic DNA in a final volume of 25 µl using the following conditions: 2 cycles of 94°C for 1 min, 69°C for 1 min and 72°C for 1 min; 2 cycles of 94°C for 1 min, 67°C for 1 min and 72°C for 1 min; and 30 cycles of 94°C for 1 min, 65°C for 1 min and 72°C for 1 min. The PCR samples (∼1 µg) were digested overnight with BglII and NdeI (NEB) at 37°C in a temperature-controlled water bath (Bio-Rad). The digested amplicons were analyzed by electrophoresis in 2% agarose gels using ethidium bromide (Invitrogen Life Technologies) and a 2UV™ transilluminator (UVP, LLC, Upland, CA, USA).

The 3,160 A allele, BglII (+), and the 3,090 T allele, NdeI (+), of the α2 gene result in the gain of restriction sites for the enzymes BglII and NdeI, respectively (41). When the 3,160 A allele or and 3,090 T allele were present, the 600-bp PCR product was digested with BglII or NdeI enzyme, respectively, generating two fragments of 400 and 200 bp (41). The 3,160 G allele, BglII (-), and the 3,090 C allele, Nde I (-), were detected by an absence of cuts by the BglII or NdeI enzyme, respectively, leaving the 600-bp PCR fragment intact.

Statistical analysis

All collected data were organized in a database in preparation for statistical calculations. Quantitative variables (age, systolic and diastolic pressure, total cholesterol levels, triglyceride and fasting plasma glucose levels) were compared between the No-DR and DR patients with DM2 using a Student's t-test, and the results are presented as the mean ± standard deviation. The risk factors for DR were analyzed using the GraphPad Prism version 4.0 software for Windows (GraphPad Software, Inc., San Diego, CA, USA). Fisher's exact tests were used for univariate analysis to compare the clinical and biochemical characteristics, as well as the family history data, between No-DR and DR diabetic patients. The estimated odds ratio (OR) was assessed by two-sided 95% confidence intervals (CI). The difference was considered statistically significant when P≤0.05.

The polymorphism statistical analyses were performed using the SNP and Variation Suite version 8.1.5 (Golden Helix, Inc., Bozeman, MT, USA) and the Epi Info™ 7 statistical program (USD Inc., Stone Mountain, GA, USA). Analyses of allele and genotype frequency counts were performed using the χ2 test. For the validation of the genotypes, the Hardy-Weinberg equilibrium (HWE) was analyzed using a Fisher's exact test (significant deviation from HWE at P>0.05).

To analyze the association between the DR genotypes and the clinical, biochemical and family history data of the DM2 patients, multiple logistic regression analysis was performed to fit the binary response, using regression coefficients for continuous predictors and indicator coefficients for categorical predictors. Association studies were performed by genotypic tests with correlation to assess the ORs, 95% CI and P-value. The Bonferroni P-value and false discovery rate (FDR) were calculated to exclude spurious associations. An OR (95% CI) >1 and a P-value P≤0.05 were considered significant.

Results

Clinical characteristics of the study population

The aim of this study was to explore the prevalence of DR and a possible association between DR and two α2 gene polymorphisms. The analyzed population comprised clinically diagnosed DM2 patients who attended the IMSS Hospital (Northwestern Mexico). Patients that had been diagnosed with DM2 ≥10 years previously (n=177; 108 males, 69 females) were selected for the study and examined by a certified ophthalmologist.

Fundus images were captured using a Canon CR-DGi non-mydriatic retinal camera using the Eye Q Prime software (Canon USA, Inc.). All images were analyzed and the DR progress was determined. A total of 121 patients with DM2 had some degree of DR development (DR group, 68%) and 56 patients with DM2 did not exhibit any sign of DR (No-DR group, 32%). Among the patients with DM2 who developed DR, 41.32% had NPDR and 58.67% had PDR, according to the ETDRS criteria (5).

The baseline characteristics of the 177 patients with DM2 are summarized in Table I. No significant difference between the No-DR and DR groups was found for the variables analyzed (age, cholesterol, triglycerides, glucose, systolic/diastolic blood pressure). The majority of the patients were male (DR group, 60%; No-DR group, 62%), and no significant difference in gender was found between the No-DR and DR groups (Table II). The age of the patients ranged from 28 to 89 years, with a median age of 59.68 years. More than half (85%) of the participants had an age of >50 years. The majority of the No-DR (87.5%) and DR (85.71%) patients were in the >50 years age group (Table II).

Table I.

Baseline characteristics of the type 2 diabetic patients.

Table I.

Baseline characteristics of the type 2 diabetic patients.

CharacteristicNo-DR groupDR groupP-value
Age, years 61.6±11.48 58.7±9.510.0616
Total cholesterol, mg/dl 223.2±70.83 232.7±71.780.2668
Tryglicerides, mg/dl 198.4±93.12 188.0±123.100.3189
Glucose, mg/dl 165.5±64.63 168.0±74.110.9321
Systolic blood pressure, mmHg 119.3±15.24 123.9±19.040.6873
Diastolic blood pressure, mmHg 76.1±10.62 76.9±12.860.2384

[i] Data are presented as the mean ± standard deviation. DR, diabetic retinopathy.

Table II.

Analysis of risk factors for DR in patients with DM2.

Table II.

Analysis of risk factors for DR in patients with DM2.

VariableNo DR, n (%)DR, n (%)P-value
Gender
  Male35 (62.50)73 (60.33)0.8693
  Female21 (37.50)48 (39.66)
Agea
  <50 years7 (12.50)17 (14.28)0.8181
  ≥50 years49 (87.50)102 (85.71)
Duration of DM2a
  <15 years36 (65.45)58 (48.74)0.0497
  ≥15 years19 (34.54)61 (51.26)
Hypertension
  Yes36 (64.29)80 (66.12)0.8655
  No20 (35.71)41 (33.88)
Cataract
  Yes18 (32.14)49 (40.50)0.3204
  No38 (67.86)72 (59.50)
Glaucoma
  Yes3 (5.36)14 (11.57)0.2745
  No53 (94.64)107 (88.43)
Kidney disease
  Yes6 (10.71)26 (21.49)0.0957
  No50 (89.29)95 (78.51)
Insulin therapy
  Yes9 (16.07)39 (32.23)0.0290
  No47 (83.93)82 (67.77)
Dyslipidemia
  Yes33 (58.93)79 (65.29)0.5027
  No23 (41.07)42 (34.71)
Glycemia
  Yes44 (78.57)89 (73.55)0.5758
  No12 (21.43)32 (26.45)

a Missing data. DR, diabetic retinopathy; DM2, type 2 diabetes mellitus.

The majority of studies on DR indicate the importance of the duration of the diabetes when considering a higher incidence and progression of DR (26,4345). In the present study it was found that there was an increased risk of DR in cases of DM2 with a duration of ≥15 years (OR, 1.993; 95% CI, 1.028–3.863; P=0.0497). Other clinical characteristics, such as hypertension, glaucoma, cataract, renal disease, dyslipidemia and glycemic control, showed no association with the presence of DR in the analyzed patients (P>0.05) (Table II); however, a significant association was found between the use of insulin therapy and the presence of DR (P=0.0290) with an OR value of 0.4026 (95% CI, 0.1793–0.9040) (Table II).

Regarding the family history of the patients, a significant association between DR and a family history of DM2 was found (P=0.0291), with an OR value of 0.4561 (95% CI, 0.2280–0.9127) (Table III). Other variables in the family history were not associated with the presence of DR (P>0.05) (Table III).

Table III.

Family characteristics associated with DR in the patients with DM2.

Table III.

Family characteristics associated with DR in the patients with DM2.

CharacteristicNo-DR group, n (%)DR group, n (%)P-value
DR
  Yes9 (16.07)31 (25.62)0.1802
  No47 (83.93)90 (74.38)
DM2
  Yes35 (62.50)95 (78.51)0.0291
  No21 (37.50)26 (21.49)
Dyslipidemia
  Yes23 (41.07)49 (40.50)1.0000
  No33 (58.93)72 (59.50)
Hypertension
  Yes33 (58.93)70 (57.85)1.0000
  No23 (41.07)51 (42.15)
Cardiovascular disease
  Yes23 (41.07)42 (34.71)0.5027
  No33 (58.93)79 (65.29)
Kidney disease
  Yes6 (10.71)19 (15.70)0.4884
  No50 (89.29)102 (84.30)

[i] DR, diabetic retinopathy; DM2, type 2 diabetes mellitus.

Genotypes and DR susceptibility

The alleles of the α2 gene in Mexican patients with DM2 were identified using the BglII/NdeI sites with RFLP assays. The statistical results obtained from the PCR-RFLP studies are shown in Table IV. With both polymorphisms, the heterozygous genotypes were the most prevalent in the DR [BglII (A/G), 74.4%; NdeI (T/C), 94.2%] and No-DR [BglII (A/G), 62.5%; NdeI (T/C), 96.4%] patients. Homozygous genotypes for BglIII (+) and NdeI (+) were not found in the DM2 population tested. Statistical analysis revealed no association between heterozygous BglII/NdeI genotypes or BglII/NdeI-negative genotypes and the development of DR in this patient group (P>0.05) (Table IV).

Table IV.

Genotype and allele frequencies of α2 integrin BglII and NdeI polymorphisms in patients with and without DR.

Table IV.

Genotype and allele frequencies of α2 integrin BglII and NdeI polymorphisms in patients with and without DR.

A, BglII

Genotypes and allelesNo-DR group, n (%)DR group, n (%)χ2OR95% CIP-value
Genotypes
  GG21 (37.50)31 (25.60)2.58951.73620.87–3.430.1076
  AG35 (62.50)90 (74.40)2.58950.57600.29–1.140.1076
  AA0 (0)0 (0)
Alleles
  G77 (68.75)152 (62.80)1.17941.30170.81–2.110.2775
  A35 (31.25)90 (37.20)1.17940.76820.47–1.230.2775

B, NdeI

Genotypes and allelesNo-DR group, n (%)DR group, n (%)χ2OR95% CIP-value

Genotypes
  CC2 (3.60)7 (5.80)0.38650.60470.08–2.820.5341
  TC54 (96.40)114 (94.20)0.38651.65360.35–11.950.5341
  TT0 (0)0 (0)
Alleles
  C58 (51.80)28 (52.90)0.03750.95670.61–1.500.8464
  T54 (48.20)14 (47.10)0.03751.04520.66–1.640.8464

[i] DR, diabetic retinopathy; OR, odds ratio; CI, confidence interval.

In order to assess the HWE, the data were analyzed using the Fisher's exact test. For BglII, the P-values in the No-DR and DR groups were 0.000423 and 1.204×10−12, respectively; for NdeI, the P-values in the No-DR and DR groups were 1.080×10−13 and 7.966×10−27, respectively. In all HWE analyses, the P-value was <0.05, indicating that the genotypes were not in HWE in the No-DR and DR patients.

Genetic polymorphisms and family history of diseases

In addition to the clinical data, a family history of the DM2-related conditions showed no statistically significant associations with the genotypes obtained by the RFLP assays (P>0.05) (Table V). In the initial analyses, a significant association with DR was observed for family history of cardiovascular disease (BglII AG genotype: OR, 2.14; 95% CI, 1.04–4.40; P=0.037) and hypertension (BglII GG genotype: OR, 2.39; 95% CI, 1.08–5.29; P=0.029); however, the significance of the association between these genotypes and cardiovascular disease susceptibility or hypertension was lost following the application of the Bonferroni correction and FDR (P>0.05) (Table V).

Table V.

Association of BglII and NdeI genotypes with clinical and biochemical characteristics in patients with DM2.

Table V.

Association of BglII and NdeI genotypes with clinical and biochemical characteristics in patients with DM2.

A, BglII (risk allele, A; no-risk allele, G)

Frequency of AA/AG/GG genotypes, n (%)

VariableDR patientsNo-DR patients P-valuecOR (95% CI)
Cataract0 (0.0)/44 (65.7)/23 (34.3)0 (0)/81 (73.6)/29 (26.4)0.2610.68 (0.35–1.32)
Duration of DM2 (≥15 years)a0 (0.0)/58 (72.5)/22 (27.5)0 (0)/76 (80.8)/18 (19.1)0.1920.62 (0.31–1.27)
Dyslipidemiaa0 (0.0)/56 (77.8)/16 (22.2)0 (0.0)/69 (65.7)/36 (34.3)0.0841.83 (0.92–3.63)
Cardiovascular diseasea0 (0.0)/52 (80.0)/13 (20.0)0 (0.0)/73 (65.2)/39 (34.8)0.0372.14 (1.04–4.40)
Hypertensiona0 (0.0)/75 (72.8)/28 (27.2)0 (0.0)/64 (73.6)/10 (26.4)0.0292.39 (1.08–5.29)
DM2a0 (0.0)/95 (73.1)/35 (26.9)0 (0.0)/30 (63.8)/17 (36.2)0.2341.54 (0.76–3.13)
B, NdeI (risk allele, T; no-risk allele, C)

Frequency of TT/TC/CC genotypes, n (%)

VariableDR patientsNo-DR patients P-valuecOR (95% CI)

Cataract0 (0.0)/62 (92.5)/5 (7.5)0 (0.0)/106 (96.4)/4 (3.6)0.2620.47 (0.12–1.81)
Duration of DM2 (≥15 years)b0 (0.0)/74 (92.5)/6 (7.5)0 (0.0)/89 (94.7)/5 (5.3)0.5600.69 (0.20–2.31)
Dyslipidemiaa0 (0.0)/69 (95.8)/3 (4.2)0 (0.0)/99 (94.3)/6 (5.7)0.6461.39 (0.34–5.76)
Cardiovascular diseasea0 (0.0)/62 (95.4)/3 (4.6)0 (0.0)/106 (94.6)/6 (5.4)0.8291.17 (0.28–4.84)
Hypertensiona0 (0.0)/97 (94.1)/6 (5.8)0 (0.0)/71 (95.9)/3 (4.0)0.5960.68 (0.17–2.82)
DM2a0 (0.0)/124 (95.4)/6 (4.6)0 (0.0)/44 (93.6)/3 (6.4)0.6371.41 (0.34–5.88)

a Family history data

b missing data

c correlation/trend P-value. DM2, type 2 diabetes mellitus; OR, odds ratio; CI, confidence interval.

Discussion

DM2 is a growing health problem in Mexico and represents a significant cause of mortality and complications such as diabetic foot, nephropathy and retinopathy. An increase in the number of diabetic patients has been predicted; therefore, it is expected that the incidence of patients with DR will show a corresponding increase (19).

The present study comprised a comparative cross-sectional hospital study in Northeastern Mexico with patients who had a history of DM2 of ≥10 years. The patients with DM2 were clinically examined by an ophthalmologist to determine if they had DR. The prevalence of DR in the analyzed Mexican population with DM2 was 68%. To date, there have been no reports of a prevalence of DR as high as that found in this study. A high prevalence (DR 48%) has been reported in a Mexican-American population aged ≥40 years living in Arizona (15) and Latinos living in California (16). The prevalence of DR found in the present study is higher than the last records found for a Mexican population, which gave prevalences of 38.9% (17) and 51% (18); however, this coincides with the exponential increase in obesity and DM2 in the country.

Population-based studies have been conducted in several countries using photographic evidence of DR. These studies have reported a DR prevalence of 10–20% in France (9), 22% in Australia (10) and Barbados (46), 27% in Fiji (11), 54% in Iran (7), 37% in China (47), 11% in India (48) and 24.8% in the USA (12).

Although the mechanisms underlying the development of DR have yet to be elucidated, numerous risk factors have been described, including poor glycemic control, longer diabetes duration, hypertension, hyperlipidemia and albuminuria (45,49). Previous studies have found a significant correlation between elevated serum cholesterol/triglycerides and the risk and severity of DR (50,51). By contrast, other studies have shown an absence of significant correlation between elevated serum cholesterol/triglycerides and the risk of DR (25,52,53). In the present study it was found that although the levels of glucose, cholesterol and triglyceride in the patients with DM2 were above levels considered normal, these abnormal results appeared to have no association with the development of DR (P>0.05) (Table I). Hyperglycemia was observed in 73.55% of patients in the DR group and 78.57% of patients in the No-DR group (P=0.5758) (Table II). Compared with values reported in other studies (5457), the prevalence of dyslipidemia (including isolated triglyceridemia, isolated cholesterolemia and mixed) was high, with the condition affecting 65.29% of patients in the DR group and 58.93% in the No-DR group.

Another DR risk factor analyzed was the duration of DM2. The importance of this factor to a higher incidence and progression of DR has been previously reported (26,43,44,58). Consistent with these studies, the present results revealed that patients who had a DM2 history of >15 years had an increased risk of DR (OR, 1.993; 95% CI, 1.028–3.863; P=0.0497) (Table II). Conversely, the age factor did not represent a DR risk, which coincided with a previous report analyzing the correlation between age and the severity of the DR (59).

Regarding gender, it was found that males predominated in both the DR and No-DR groups, which demonstrated that gender was not a risk factor for the development of DR (Table II). Others studies have shown an inconsistency when investigating whether gender is a risk factor for the development of DR; while some studies found a higher prevalence of DR in women (51,60), other studies have claimed that the severity of the disease is associated with the male gender (53,59). Furthermore, studies of the prevalence of DR have indicated that the disease occurs in similar proportions among men and women (26,61,62). Further studies are required to determine the causes of this inconsistency in the prevalence of DR according to gender in different populations.

Contradictory results have also been found for hypertension. While there are reports indicating that hypertension is not a risk factor for DR (44,60), a larger number of studies argue for a link between the presence of hypertension and the development of DR (26,53,59). In addition, several studies have reported an association between DR and the systolic, but not diastolic, blood pressure (43,5052). In the present study, a significant correlation between the blood pressure values and the development of the DR was not found (P>0.05) (Table II); however, the fact that any hypertension in the analyzed patients was already controlled by medical specialists could have affected the present results.

Another widely studied factor is the use of insulin in patients with DM2 to control the disease. Insulin therapy was found to be significantly associated with DR in the patients with DM2 in the present study (P=0.0290) (Table II); however, the OR obtained indicates that insulin therapy is not a risk factor for DR (OR, 0.4026; 95% CI, 0.1793–0.9040). This finding suggests that, in the Mexican population analyzed, treatment with insulin prevented the development of DR in DM2 patients receiving insulin therapy, compared with DM2 patients that did not receive this therapy. The present results differed from studies with Japanese (52) and Iranian (53) patients with DM2, which reported insulin therapy to be a DR risk factor.

Concerning the genetic analysis, PCR-RFLP assays were used to analyze two polymorphisms in intron G of the α2 gene (3,160 A/G and 3,090 T/C) using BglII and NdeI restriction enzymes; these polymorphisms were found to be associated with the presence of DR in the diabetic patients. The results obtained for the genotyping of the α2 gene are the first, to the best of our knowledge, to be made for the Mexican population. The distribution of the BglII/NdeI genotypes, as well as the frequency of the respective alleles, in the DR and No-DR patients was similar (Table IV). With both polymorphisms, the heterozygous genotypes were the most prevalent in the DR and No-DR patients. Statistical analysis revealed no association between the BglII/NdeI genotypes and the development of DR in this patients group (P>0.05) (Table IV).

The fact that this study did not find a significant correlation between the BglII/NdeI genotypes of the α2 gene and DR in the analyzed Mexican population marks an important precedent in this type of study aimed at finding the genes associated with diabetic complications in Mexican population. This finding, together with the absence of the BglII (3,160 A/A) and NdeI (3,090 T/T) genotypes in the analyzed population with DM2 reflects the ethnic differences and genetic heterogeneity among populations. Furthermore, it was observed in the present study that the BglII/NdeI polymorphisms were not in HWE. Deviation from the HWE was noted in both groups (DR and No-DR); the fact that there was deviation from the HWE in the No-DR group indicated that one or more of the model requirements may have been violated. If the possibility of genotyping error is discarded it can be assumed that there are other factors that influenced this outcome and that directly affected the observed allele frequencies. We suggest that the existence of inbreeding in the group analyzed and the insufficient sample size could have been the possible causes of this result, as well as the factors influencing this outcome that directly affected the observed allele frequencies. In the case of inbreeding, although the selection criteria excluded a family relationship between patients, at the level of the population analyzed this phenomenon could be occurring. Furthermore, it was observed that the genotypic frequencies of the BglII and NdeI polymorphisms showed no significant difference in the two study groups (DR and No-DR). Another factor that cannot be ruled out is the sample size, and particularly the group size of the No-DR patients. Given the vast problem of DM2 in the Mexican population and the lack of adequate control of this disease, there were few patients who had a ≥10-year history of DM2 who did not exhibit some degree of DR.

The present results differed from similar studies in Asian and Caucasian populations, where there was a significant correlation between the presence of the BglII genotype (A/A) and the BglII (A) allele in the development of DR (3,25). To date, few studies have reported genes associated with DR, and the reported results are inconsistent (63). DM2 is a multigenic and multifactorial disease; therefore the DR depends on the factors driving the DM2 (59,63). Similar results to those described in the present study can be found in the literature, particularly in an analysis conducted on the association between the α2β1 807T allele and the development of DR in French patients with DM2, giving support to the present findings (64).

The polymorphisms in the G intronic region containing the BglII and NdeI recognition sites are used to infer the α2 gene haplotypes, including polymorphisms 807C and 873T of exons 7 and 8, respectively. These polymorphisms have been associated with differences in the platelet α2β1 receptor density (41,65) and several diseases, such as retinal diseases (66,67), colorectal cancer (68) and ischemic stroke risk (69). Based on the HWE results obtained in the present study, and considering that i) the method of Kritzik et al (41), which was used in the present study to detect the α2 gene polymorphisms 807C and 873T, is an indirect detection method; and ii) the intronic region, where the recognition sites of BglII and NdeI are present, is the gene region with most susceptibility to variations, we suggest that the intronic BglII and NdeI polymorphic sites in the Mexican population are not linked to exonic 807C and 873T nucleotide polymorphic sites and therefore cannot detect the α2 gene haplotypes reported (41).

In conclusion, the results of the present study indicate a high prevalence of DR that had not been previously described in patients with type 2 diabetes from Northeastern Mexico. No significant association was detected between the frequencies of the genotypes and alleles for the α2 gene polymorphisms BglII and NdeI and the development of DR in the DM2 population. The duration of DM2 ≥15 years was the only risk factor linked with the development of DR.

Acknowledgements

This study was supported by the SEP-PROMEP and the General Coordination of Graduate Studies and Research of the Autonomous University of Coahuila. The authors would like to acknowledge Dr Tania Batallar-Gómez for providing blood samples from the patients and Dr Carmen Aleida Flores-Flores for suggestions in the preparation of written English. The authors would also like to thank the patients with DM2 for their participation in the study.

References

1 

Foster A and Resnikoff S: The impact of Vision 2020 on global blindness. Eye (Lond). 19:1133–1135. 2005. View Article : Google Scholar : PubMed/NCBI

2 

Congdon NG, Friedman DS and Lietman T: Important causes of visual impairment in the world today. JAMA. 290:2057–2060. 2003. View Article : Google Scholar : PubMed/NCBI

3 

Matsubara Y, Murata M, Maruyama T, et al: Association between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagen. Blood. 95:1560–1564. 2000.PubMed/NCBI

4 

Kunicki TJ, Kritzik M, Annis DS and Nugent DJ: Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood. 89:1939–1943. 1997.PubMed/NCBI

5 

Early Treatment Diabetic Retinopathy Study Research Group, . Grading diabetic retinopathy from stereoscopic color fundus photographs - an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 98:786–806. 1991. View Article : Google Scholar : PubMed/NCBI

6 

Yau JW, Rogers SL, Kawasaki R, et al Meta-Analysis for Eye Disease (META-EYE) Study Group: Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 35:556–564. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Hosseini SM, Maracy MR, Amini M and Baradaran HR: A risk score development for diabetic retinopathy screening in Isfahan-Iran. J Res Med Sci. 14:105–110. 2009.PubMed/NCBI

8 

Ramavat PR, Ramavat MR, Ghugare BW, Vaishnav RG and Joshi MU: Prevalence of diabetic retinopathy in western Indian type 2 diabetic population: A hospital-based cross-sectional study. J Clin Diagn Res. 7:1387–1390. 2013.PubMed/NCBI

9 

Delcourt C, Massin P and Rosilio M: Epidemiology of diabetic retinopathy: Expected vs reported prevalence of cases in the French population. Diabetes Metab. 35:431–438. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Tapp RJ, Shaw JE, Harper CA, et al AusDiab Study Group: The prevalence of and factors associated with diabetic retinopathy in the Australian population. Diabetes Care. 26:1731–1737. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Brian G, Fischer-Harder K, et al: Diabetic eye disease among adults in Fiji with self-reported diabetes. Clin Experiment Ophthalmol. 38:867–874. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Wong TY, Klein R, Islam FM, Cotch MF, Folsom AR, Klein BE, Sharrett AR and Shea S: Diabetic retinopathy in a multi-ethnic cohort in the United States. Am J Ophthalmol. 141:446–455. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Klein R, Klein BE, Moss SE and Linton KL: The Beaver Dam Eye Study. Retinopathy in adults with newly discovered and previously diagnosed diabetes mellitus. Ophthalmology. 99:58–62. 1992. View Article : Google Scholar : PubMed/NCBI

14 

Ferreiro JL, Gómez-Hospital JA and Angiolillo DJ: Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res. 7:251–259. 2010. View Article : Google Scholar : PubMed/NCBI

15 

West SK, Muñoz B, Klein R, et al: Risk factors for Type II diabetes and diabetic retinopathy in a Mexican-American population: Proyecto VER. Am J Ophthalmol. 134:390–398. 2002. View Article : Google Scholar : PubMed/NCBI

16 

Varma R, Torres M, Peña F, et al Los Angeles Latino Eye Study Group: Prevalence of diabetic retinopathy in adult Latinos: The Los Angeles Latino eye study. Ophthalmology. 111:1298–1306. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Polack S, Yorston D, López-Ramos A, et al: Rapid assessment of avoidable blindness and diabetic retinopathy in Chiapas, Mexico. Ophthalmology. 119:1033–1040. 2012. View Article : Google Scholar : PubMed/NCBI

18 

González Villalpando ME, González Villalpando C, Arredondo Pérez B and Stern MP: Diabetic retinopathy in Mexico. Prevalence and clinical characteristics. Arch Med Res. 25:355–360. 1994.PubMed/NCBI

19 

INEGI, . Statistics About the World Diabetes Day. National Institute of Statics and Geography. https://www.inegi.org.mx/inegi/default.aspx?s=inegi&c=2894&pred=1Accessed. November 14–2013, (In Spanish).

20 

The Diabetes Control and Complications Trial Research Group, . Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes. 46:1829–1839. 1997. View Article : Google Scholar : PubMed/NCBI

21 

Rema M, Saravanan G, Deepa R and Mohan V: Familial clustering of diabetic retinopathy in South Indian Type 2 diabetic patients. Diabet Med. 19:910–916. 2002. View Article : Google Scholar : PubMed/NCBI

22 

Hallman DM, Huber JC Jr, Gonzalez VH, Klein BE, Klein R and Hanis CL: Familial aggregation of severity of diabetic retinopathy in Mexican Americans from Starr County, Texas. Diabetes Care. 28:1163–1168. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Arar NH, Freedman BI, Adler SG, et al Family Investigation of Nephropathy and Diabetes Research Group: Heritability of the severity of diabetic retinopathy: The FIND-Eye study. Invest Ophthalmol Vis Sci. 49:3839–3845. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Barnett AH: Pathogenesis of diabetic microangiopathy: An overview. Am J Med. 90((6A)): 67S–73S. 1991. View Article : Google Scholar : PubMed/NCBI

25 

Petrovic MG, Hawlina M, Peterlin B and Petrovič D: BglII gene polymorphism of the alpha2beta1 integrin gene is a risk factor for diabetic retinopathy in Caucasians with type 2 diabetes. J Hum Genet. 48:457–460. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Buraczynska M, Ksiazek P, Baranowicz-Gaszczyk I and Jozwiak L: Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patients. Nephrol Dial Transplant. 22:827–832. 2007. View Article : Google Scholar : PubMed/NCBI

27 

Li H, Louey JW, Choy KW, et al: EDN1 Lys198Asn is associated with diabetic retinopathy in type 2 diabetes. Mol Vis. 14:1698–1704. 2008.PubMed/NCBI

28 

Costa V, Casamassimi A, Esposito K, et al: Characterization of a novel polymorphism in PPARG regulatory region associated with type 2 diabetes and diabetic retinopathy in Italy. J Biomed Biotechnol. 2009:1269172009. View Article : Google Scholar : PubMed/NCBI

29 

Nakamura S, Iwasaki N, Funatsu H, Kitano S and Iwamoto Y: Impact of variants in the VEGF gene on progression of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 247:21–26. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Cho H and Sobrin L: Genetics of diabetic retinopathy. Curr Diab Rep. 14:5152014. View Article : Google Scholar : PubMed/NCBI

31 

Uhlmann K, Kovacs P, Boettcher Y, Hammes HP and Paschke R: Genetics of diabetic retinopathy. Exp Clin Endocrinol Diabetes. 114:275–294. 2006. View Article : Google Scholar : PubMed/NCBI

32 

Zhang T, Pang C, Li N, Zhou E and Zhao K: Plasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: A meta-analysis. BMC Med. 11:1–9. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Qian-Qian Y, Yong Y, Jing Z, Dong-Hong F, et al: Association between a 27-bp variable number of tandem repeat polymorphism in intron 4 of the eNOS gene and risk for diabetic retinopathy Type 2 diabetes mellitus: A meta-analysis. Curr Eye Res. 39:1052–1058. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Abhary S, Hewitt AW, Burdon KP and Craig JE: A systematic meta-analysis of genetic association studies for diabetic retinopathy. Diabetes. 58:2137–2147. 2009. View Article : Google Scholar : PubMed/NCBI

35 

Liu L, Yu Q, Wang H, et al: Association of intercellular adhesion molecule 1 polymorphisms with retinopathy in Chinese patients with Type 2 diabetes. Diabet Med. 23:643–648. 2006. View Article : Google Scholar : PubMed/NCBI

36 

Qiu M, Xiong W, Liao H and Li F: VEGF-634G>C polymorphism and diabetic retinopathy risk: A meta-analysis. Gene. 518:310–315. 2013. View Article : Google Scholar : PubMed/NCBI

37 

McAuley AK, Wang JJ, Dirani M, et al: Replication of genetic loci implicated in diabetic retinopathy. Invest Ophthalmol Vis Sci. 55:1666–1671. 2014. View Article : Google Scholar : PubMed/NCBI

38 

Plow EF, Meller J and Byzova TV: Integrin function in vascular biology: A view from 2013. Curr Opin Hematol. 21:241–247. 2014. View Article : Google Scholar : PubMed/NCBI

39 

Caunedo-Almagro P: Hemostatic alterations in diabetes mellitus. Rev Cubana Hematol Inmunol Hemoter. 21:1–9. 2005.(In Spanish).

40 

Saboor M, Ayub Q, Ilyas S and Moinuddin: Platelet receptors: An instrumental of platelet physiology. Pak J Med Sci. 29:891–896. 2013. View Article : Google Scholar : PubMed/NCBI

41 

Kritzik M, Savage B, Nugent DJ, et al: Nucleotide polymorphisms in the alpha2 gene define multiple alleles that are associated with differences in platelet alpha2 beta1 density. Blood. 92:2382–2388. 1998.PubMed/NCBI

42 

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, . Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 26 (Suppl 1):S5–S20. 2003. View Article : Google Scholar : PubMed/NCBI

43 

Ray D, Mishra M, Ralph S, et al: Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes. 53:861–864. 2004. View Article : Google Scholar : PubMed/NCBI

44 

West SK, Klein R, Rodriguez J, et al Proyecto VER: Diabetes and diabetic retinopathy in a Mexican-American population: Proyecto VER. Diabetes Care. 24:1204–1209. 2001. View Article : Google Scholar : PubMed/NCBI

45 

Maghbooli Z, Pasalar P, Keshtkar A, Farzadfar F and Larijani B: Predictive factors of diabetic complications: a possible link between family history of diabetes and diabetic retinopathy. J Diabetes Metab Disord. 13:552014. View Article : Google Scholar : PubMed/NCBI

46 

Leske MC, Wu SY, Hennis A, et al Barbados Eye Study Group: Hyperglycemia, blood pressure, and the 9-year incidence of diabetic retinopathy: The Barbados Eye Studies. Ophthalmology. 12:799–805. 2005. View Article : Google Scholar

47 

Wang FH, Liang YB, Zhang F, et al: Prevalence of diabetic retinopathy in rural China: The Handan Eye Study. Ophthalmology. 116:461–467. 2009. View Article : Google Scholar : PubMed/NCBI

48 

Nirmalan PK, Katz J, Robin AL, et al: Prevalence of vitreoretinal disorders in a rural population of southern India: The Aravind Comprehensive Eye Study. Arch Ophthalmol. 122:581–586. 2004. View Article : Google Scholar : PubMed/NCBI

49 

Singh R, Ramasamy K, Abraham C, Gupta V and Gupta A: Diabetic retinopathy: An update. Indian J Ophthalmol. 56:178–188. 2008.PubMed/NCBI

50 

van Leiden HA, Dekker JM, Moll AC, et al: Blood pressure, lipids, and obesity are associated with retinopathy: The Hoorn Study. Diabetes Care. 25:1320–1325. 2002. View Article : Google Scholar : PubMed/NCBI

51 

Hallman DM, Boerwinkle E, Gonzalez VH, et al: A genome-wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County, Texas. Diabetes. 56:1167–1173. 2007. View Article : Google Scholar : PubMed/NCBI

52 

Awata T, Inoue K, Kurihara S, et al: A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 51:1635–1639. 2002. View Article : Google Scholar : PubMed/NCBI

53 

Javadi MA, Katibeh M, Rafati N, et al: Prevalence of diabetic retinopathy in Tehran province: A population-based study. BMC Ophthalmol. 9:122009. View Article : Google Scholar : PubMed/NCBI

54 

Martinez-Hervas S, Carmena R, Ascaso JF, et al: Prevalence of plasma lipid abnormalities and its association with glucose metabolism in Spain: The di@bet.es study. Clin Investig Arterioscler. 26:107–114. 2014. View Article : Google Scholar : PubMed/NCBI

55 

Arauz A, Romano JG, Ruiz-Franco A, et al: Differences in lipid profiles in two Hispanic ischemic stroke populations. Int J Stroke. 9:394–399. 2014. View Article : Google Scholar : PubMed/NCBI

56 

Escobedo-de la Peña J, de Jesús-Pérez R, Schargrodsky H and Champagne B: Prevalence of dyslipidemias in Mexico city and Its relation to other cardiovascular risk factors. Results from the CARMELA study. Gac Med Mex. 150:128–136. 2014.(In Spanish). PubMed/NCBI

57 

Tóth PP, Potter D and Ming EE: Prevalence of lipid abnormalities in the United States: The National Health And Nutrition Examination Survey 2003–2006. J Clin Lipidol. 6:325–330. 2012. View Article : Google Scholar : PubMed/NCBI

58 

Rodríguez-Villalobos E, Ramírez-Barba EJ and Cervantes-Aguayo F: The incidence and opportunity for the diagnosis of diabetic retinopathy. Salud Publica Mex. 36:275–280. 1994.(In Spanish). PubMed/NCBI

59 

Chatziralli IP, Sergentanis TN, Keryttopoulos P, et al: Risk factors associated with diabetic retinopathy in patients with diabetes mellitus type 2. BMC Res Notes. 3:1532010. View Article : Google Scholar : PubMed/NCBI

60 

Prado-Serrano A, Guido-Jiménez M and Camas-Benítez J: Prevalence of diabetic retinopathy in a Mexican population. Rev Mex Oftalmol. 83:261–266. 2009.(In Spanish).

61 

Kempen JH, O'Colmain BJ, Leske MC, et al Eye Diseases Prevalence Research Group: The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 122:552–563. 2004. View Article : Google Scholar : PubMed/NCBI

62 

Smith TST, Szetu J and Bourne RR: The prevalence and severity of diabetic retinopathy, associated risk factors and vision loss in patients registered with type 2 diabetes in Luganville, Vanuatu. Br J Ophthalmol. 91:415–419. 2007. View Article : Google Scholar : PubMed/NCBI

63 

Kuo JZ, Wong TY and Rotter JI: Challenges in elucidating the genetics of diabetic retinopathy. JAMA Ophthalmol. 132:96–107. 2014. View Article : Google Scholar : PubMed/NCBI

64 

Arsène S, Pouplard C, Perrodeau E, et al: No association between the ITGA2 807T allele and retinopathy in french patients with type 2 diabetes. Thromb Res. 128:293–295. 2011. View Article : Google Scholar : PubMed/NCBI

65 

Jacquelin B, Tarantino MD, Kritzik M, et al: Allele-dependent transcriptional regulation of the human integrin alpha2 gene. Blood. 97:1721–1726. 2001. View Article : Google Scholar : PubMed/NCBI

66 

Dinauer DM, Friedman KD and Hessner MJ: Allelic distribution of the glycoprotein Ia (alpha2-integrin) C807T/G873A dimorphisms among caucasian venous thrombosis patients and six racial groups. Br J Haematol. 107:563–565. 1999. View Article : Google Scholar : PubMed/NCBI

67 

Dodson PM, Haynes J, Starczynski J, et al: The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: A novel risk factor for retinal vein occlusion. Eye (Lond). 17:772–777. 2003. View Article : Google Scholar : PubMed/NCBI

68 

Gerger A, Hofmann G, Langsenlehner U, et al: Integrin alpha-2 and beta-3 gene polymorphisms and colorectal cancer risk. Int J Colorectal Dis. 24:159–163. 2009. View Article : Google Scholar : PubMed/NCBI

69 

Wu G, Xi Y, Yao L, et al: Genetic polymorphism of ITGA2 C807T can increase the risk of ischemic stroke. Int J Neurosci. 124:841–851. 2014. View Article : Google Scholar : PubMed/NCBI

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Cepeda‑Nieto AC, Esquivel‑Contreras MT, Duran‑Iñiguez F, Salinas‑Santander MA, Gallardo‑Blanco HL, Esparza‑González SC, Zugasti‑Cruz A, Morlett‑Chávez JA and Córdova‑Alvelais LT: High prevalence of diabetic retinopathy and lack of association with integrin α2 gene polymorphisms in patients with type 2 diabetes from Northeastern Mexico. Exp Ther Med 10: 435-444, 2015
APA
Cepeda‑Nieto, A.C., Esquivel‑Contreras, M.T., Duran‑Iñiguez, F., Salinas‑Santander, M.A., Gallardo‑Blanco, H.L., Esparza‑González, S.C. ... Córdova‑Alvelais, L.T. (2015). High prevalence of diabetic retinopathy and lack of association with integrin α2 gene polymorphisms in patients with type 2 diabetes from Northeastern Mexico. Experimental and Therapeutic Medicine, 10, 435-444. https://doi.org/10.3892/etm.2015.2520
MLA
Cepeda‑Nieto, A. C., Esquivel‑Contreras, M. T., Duran‑Iñiguez, F., Salinas‑Santander, M. A., Gallardo‑Blanco, H. L., Esparza‑González, S. C., Zugasti‑Cruz, A., Morlett‑Chávez, J. A., Córdova‑Alvelais, L. T."High prevalence of diabetic retinopathy and lack of association with integrin α2 gene polymorphisms in patients with type 2 diabetes from Northeastern Mexico". Experimental and Therapeutic Medicine 10.2 (2015): 435-444.
Chicago
Cepeda‑Nieto, A. C., Esquivel‑Contreras, M. T., Duran‑Iñiguez, F., Salinas‑Santander, M. A., Gallardo‑Blanco, H. L., Esparza‑González, S. C., Zugasti‑Cruz, A., Morlett‑Chávez, J. A., Córdova‑Alvelais, L. T."High prevalence of diabetic retinopathy and lack of association with integrin α2 gene polymorphisms in patients with type 2 diabetes from Northeastern Mexico". Experimental and Therapeutic Medicine 10, no. 2 (2015): 435-444. https://doi.org/10.3892/etm.2015.2520