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Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.

ABSTRACT: BACKGROUND:Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight-threatening complications of diabetes mellitus and leading causes of adult-onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes. METHODS:Caucasian Australians with type 2 diabetes were evaluated in a genome-wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non-retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates. RESULTS:The top ranked SNP for DME was rs1990145 (p?=?4.10?×?10-?6, OR?=?2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p?=?3.87?×?10-?6, OR?=?0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p?=?0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK2 (p?=?0.007) in the PDR cohort. CONCLUSION:This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology.

SUBMITTER: Graham PS

PROVIDER: S-EPMC5941644 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.

Graham Patricia S PS Kaidonis Georgia G Abhary Sotoodeh S Gillies Mark C MC Daniell Mark M Essex Rohan W RW Chang John H JH Lake Stewart R SR Pal Bishwanath B Jenkins Alicia J AJ Hewitt Alex W AW Lamoureux Ecosse L EL Hykin Philip G PG Petrovsky Nikolai N Brown Matthew A MA Craig Jamie E JE Burdon Kathryn P KP

BMC medical genetics 20180508 1

<h4>Background</h4>Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight-threatening complications of diabetes mellitus and leading causes of adult-onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as se ...[more]

PMID: 29739359

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Project description:ImportancePrevious studies on the relationship between diabetic retinopathy (DR) and cardiovascular disease (CVD) focused on the early stages of DR. Understanding whether patients with type 2 diabetes and severe stages of DR (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]) have a higher risk of CVD will allow physicians to more effectively counsel patients.ObjectiveTo examine the association of severe stages of DR (DME and PDR) with incident CVD in patients with type 2 diabetes.Data sourcesEnglish-language publications were reviewed for articles evaluating the relationship of DR and CVD in MEDLINE, EMBASE, Current Contents, and the Cochrane Library from inception (January 1, 1950) to December 31, 2014, using the search terms diabetic retinopathy OR macular edema AND stroke OR cerebrovascular disease OR coronary artery disease OR heart failure OR myocardial infarction OR angina pectoris OR acute coronary syndrome OR coronary artery disease OR cardiomyopathy.Study selectionAmong 656 studies screened for eligibility, 7604 individuals were included from 8 prospective population-based studies with data on photographic-based DR grading, follow-up visits, and well-defined incident CVD end point.Data extraction and synthesisTwo independent reviewers conducted a systematic search of the 4 databases, and a single pooled database was developed. Incidence rate ratios (IRRs) were estimated for patients with DME, PDR, and vision-threatening DR, compared with persons without these conditions, by using individual participant data followed by a standard inverse-variance meta-analysis (2-step analysis). The review and analyses were performed from January 1, 2009, to January 1, 2017.Main outcome and measuresIncident CVD, including coronary heart disease, stroke, or death from cardiovascular causes.ResultsAmong 7604 patients with type 2 diabetes, the prevalence of DME was 4.6% and PDR, 7.4%. After a mean follow-up of 5.9 years (range, 3.2-10.1 years), 1203 incident CVD events, including 916 coronary heart disease cases, were reported. Persons with DME or PDR were more likely to have incident CVD (IRR, 1.39; 95% CI, 1.16-1.67) and fatal CVD (IRR, 2.33; 95% CI, 1.49-3.67) compared with those without DME or PDR.Conclusions and relevancePatients with type 2 diabetes and DME or PDR have an increased risk of incident CVD, which suggests that these persons should be followed up more closely to prevent CVD.

Project description:Importance:The comorbidity of chronic kidney disease and diabetic retinopathy (DR) is well known. However, to our knowledge, no cohort study has demonstrated the effect of chronic kidney disease on the development or progression of DR. Objective:To investigate the association of chronic kidney disease with the development of DR and diabetic macular edema (DME) in type 2 diabetes. Design, Setting, and Participants:This 8-year prospective cohort study that was conducted in 2 medical centers in Taiwan included 2135 patients with type 2 diabetes. Exposures:The baseline and mean follow-up renal profiles including serum creatinine level, estimated glomerular filtration rate (eGFR), and urinary albumin/creatinine ratio (ACR). Main Outcomes and Measures:Diabetic retinopathy and DME were detected with nonmydriatic fundus photography. Cox regression analyses was used to evaluate the hazard ratios (HRs) for the renal profiles of new-onset DR, proliferative DR, and DME. Results:The mean (SD) age of the study participants was 63.4 (11.9) years and 1025 (48%) were women. A higher serum creatinine level (HR of 2.358 for an increase of 1 mg/dL [to convert to micromoles per liter, multiply by 76.25]; 95% CI, 1.901-2.924; P < .001), an estimated glomerular filtration rate of less than 60 mL/min/1.73m2 (40-60: HR, 2.235; 95% CI, 1.351-4.035; P = .002; 30-45: HR, 2.625; 95% CI, 1.436-4.798; P = .002; <30: HR, 5.488; 95% CI, 2.739-10.993; P < .001), and a urinary albumin to creatinine ratio (ACR) of more than 30 mg/g (31-300: HR, 3.202; 95% CI, 2.029-5.053; P < .001; >300: HR, 6.652; 95% CI, 3.922-11.285; P < .001) at baseline were all associated with the development of proliferative DR. A baseline urinary ACR of more than 30 mg/g (31-300: HR, 1.563; 95% CI, 1.078-2.267; P = .02; >300: HR, 2.707; 95% CI, 1.640-4.470; -2.707; P < 0.001) was associated with the development of DME. After adjusting the baseline values, the mean follow-up renal profiles, including a higher serum creatinine level (HR, 2.369 per mg/dL; 95% CI, 1.704-3.293; P < .001), an estimated glomerular filtration rate of less than 30 mL/min/1.73m2 (HR, 4.215; 95% CI, 1.265-14.039; P = .02), and a urinary ACR of more than 30 mg/g (31-300: HR, 2.344; 95% CI, 1.200-4.503; P = .01; >300: HR, 4.193; 95% CI, 1.638-10.735; P = .003) were still correlated with new-onset PDR during the follow-up periods. Conclusions and Relevance:Abnormal renal profiles at baseline, including a high serum creatinine level, low estimated glomerular filtration rate, and high urinary ACR, were associated with the development of PDR in patients with type 2 diabetes. A high baseline urinary ACR was associated with DME. Abnormal mean follow-up renal profiles were still correlated with new-onset PDR after adjusting for baseline values. Aggressive treatment for chronic kidney disease may have a role in preventing the deterioration of DR.

Project description:PurposeTo study the association between different hypoglycemic regimens and postoperative diabetic macular edema (DME).MethodsA secondary analysis based on a retrospective cohort study.ResultsIn this secondary analysis, 124 eyes from patients with proliferative diabetic retinopathy (PDR) who underwent pars plana vitrectomy (PPV) between January 2008 and September 2012 were included. We found that compared with oral hypoglycemic medication, oral hypoglycemic medication plus insulin treatment revealed an insignificant relationship with postoperative DME (odds ratio [OR]=0.8, 95% confidence interval [CI]: 0.12-5.21, P=0.8167), only insulin treatment revealed a significant association with postoperative DME (OR=0.10, 95% CI: 0.01-0.84, P=0.0337) after adjusted age, sex. After adjusted age, sex, diabetes mellitus (DM) duration, glycosylated hemoglobin (HbA1c), the results did not have obvious changes (OR=0.61, 95% CI: 0.09-4.26, P=0.6187; OR=0.07, 95% CI: 0.01-0.65, P=0.0197). Furthermore, after adjusted age, sex, DM duration, HbA1c, hypertension, intraoperative retinal photocoagulation, vitreous hemorrhage, macular detachment, fibrovascular membrane, intraocular lens implantation and microincision vitrectomy surgery, the results were consistent (OR=0.66, 95% CI: 0.05-9.49, P=0.7621; OR=0.06, 95% CI: 0.00-0.81, P=0.0342). The same trend was observed in these adjusted models as well (p for trend was 0.0254, 0.0141, and 0.0311, respectively).ConclusionIn conclusion, our results of the secondary analysis should be interpreted as a significant association between insulin treatment and reduced risks of postoperative DME in Japanese PDR patients with PPV surgery, compared with oral medications. Well glycemic control with longstanding insulin therapy may be beneficial to reduce the risks of postoperative DME in PDR patients. Our investigation calls for large-scale and long-term prospective clinical studies for a full evaluation of the exact role of insulin in the progression of postoperative DME.

Dataset Information

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.

Publications

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.

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