Diabetic retinopathy (DR) is a leading cause of vision-loss globally. Of an estimated 285 million people with diabetes mellitus worldwide, approximately one third have signs of DR and of these, a further one third of DR is vision-threatening DR, including diabetic macular edema (DME). The identification of established modifiable risk factors for DR such as hyperglycemia and hypertension has provided the basis for risk factor control in preventing onset and progression of DR. Additional research investigating novel risk factors has improved our understanding of multiple biological pathways involved in the pathogenesis of DR and DME, especially those involved in inflammation and oxidative stress. Variations in DR prevalence between populations have also sparked interest in genetic studies to identify loci associated with disease susceptibility. In this review, major trends in the prevalence, incidence, progression and regression of DR and DME are explored, and gaps in literature identified. Established and novel risk factors are also extensively reviewed with a focus on landmark studies and updates from the recent literature.

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Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss

Diabetes retinopathy (DR) is a leading cause of vision loss in middle-aged and elderly people globally. Early detection and prompt treatment allow prevention of diabetes-related visual impairment. Patients with diabetes require regular follow-up with primary care physicians to optimize their glycaemic, blood pressure and lipid control to prevent development and progression of DR and other diabetes-related complications. Other risk factors of DR include higher body mass index, puberty and pregnancy, and cataract surgery. There are weaker associations with some genetic and inflammatory markers. With the rising incidence and prevalence of diabetes and DR, public health systems in both developing and developed countries will be faced with increasing costs of implementation and maintenance of a DR screening program for people with diabetes. To reduce the impact of DR-related visual loss, it is important that all stakeholders continue to look for innovative ways of managing and preventing diabetes, and optimize cost-effective screening programs within the community.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/ceo.12696

Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review.

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.

Genetics of diabetes mellitus and diabetes complications.

With increasing global prevalence of diabetes, diabetic retinopathy (DR) is set to be the principle cause of vision impairment in many countries. DR affects a third of people with diabetes and the prevalence increases with duration of diabetes, hyperglycemia, and hypertension—the major risk factors for the onset and progression of DR. There are now increasing data on the epidemiology of diabetic macular edema (DME), an advanced complication of DR, with studies suggesting DME may affect up to 7 % of people with diabetes. The risk factors for DME are largely similar to DR, but dyslipidemia appears to play a more significant role. Early detection of DR and DME through screening programs and appropriate referral for therapy is important to preserve vision in individuals with diabetes. Future research is necessary to better understand the potential role of other risk factors such as apolipoproteins and genetic predisposition to shape public health programs.

Current Epidemiology of Diabetic Retinopathy and Diabetic Macular Edema

http://www.icoph.org/dynamic/attachments/taskforce_documents/prevalence_of_diabetic_retinopathy_in_various_ethnic_groups__a_worldwide_perspective.pdf

Prevalence of diabetic retinopathy in various ethnic groups: a worldwide perspective.

To identify genetic loci for severe diabetic retinopathy, 286 Mexican-Americans with type 2 diabetes from Starr County, Texas, completed physical examinations including fundus photography for diabetic retinopathy grading. Individuals with moderate-to-severe non-proliferative and proliferative diabetic retinopathy were defined as cases. Direct genotyping was performed using the Affymetrix GeneChip Human Mapping 100 K Set, and SNPs passing quality control criteria were used to impute markers available in HapMap Phase III Mexican population (MXL) in Los Angeles, California. Two directly genotyped markers were associated with severe diabetic retinopathy at a P-value less than .0001: SNP rs2300782 () mapped to an intron region of CAMK4 (calcium/calmodulin-dependent protein kinase IV) on chromosome 5, and SNP rs10519765 () on chromosomal 15q13 in the FMN1 (formin 1) gene. Using well-imputed markers based on the HapMap III Mexican population, we identified an additional 32 SNPs located in 11 chromosomal regions with nominal association with severe diabetic retinopathy at P-value less than .0001. None of these markers were located in traditional candidate genes for diabetic retinopathy or diabetes itself. However, these signals implicate genes involved in inflammation, oxidative stress and cell adhesion for the development and progression of diabetic retinopathy.

/pdf/identification-of-diabetic-retinopathy-genes-through-a-2v40xzknmj.pdf

Identification of Diabetic Retinopathy Genes through a Genome-Wide Association Study among Mexican-Americans from Starr County, Texas

OBJECTIVE—Diabetic retinopathy is a major cause of blindness. To determine whether retinopathy itself or only its severity aggregates in families, we examined the occurrence and severity of diabetic retinopathy in Mexican-American siblings with type 2 diabetes. RESEARCH DESIGN AND METHODS—Using stereoscopic fundus photography of seven standard fields, we measured retinopathy in 656 type 2 diabetic patients from 282 Mexican-American families from Starr County, Texas. Retinopathy severity was scored using the Early Treatment of Diabetic Retinopathy Study system and classified as no retinopathy, early nonproliferative diabetic retinopathy (NPDR-E), moderate-to-severe nonproliferative diabetic retinopathy (NPDR-S), or proliferative diabetic retinopathy (PDR). RESULTS—Of 249 siblings of randomly selected probands with retinopathy, 169 (67.9%) had retinopathy, compared with 95 of 125 siblings of unaffected probands (76.0%; P = 0.11). Proband retinopathy class was associated (P = 0.03) with sibling retinopathy class, with significant odds ratios (ORs) for NPDR-E versus no retinopathy (OR 0.57 [95% CI 0.35–0.93]) and PDR versus NPDR-E (2.02 [1.13–3.63]); the contrast of NPDR-S versus NPDR-E approached significance (1.78 [0.99–3.20]). With the more severe classes (PDR and NPDR-S) combined in one group and the less severe ones (none and NPDR-E) in another, more severe proband retinopathy was associated with more severe sibling retinopathy (1.72 [1.03–2.88]). CONCLUSIONS—More severe diabetic retinopathy showed evidence of familial aggregation, but the occurrence of diabetic retinopathy per se did not. The factors involved in the onset of diabetic retinopathy may differ from those involved in its progression to more severe forms.

https://care.diabetesjournals.org/content/diacare/28/5/1163.full.pdf

Familial Aggregation of Severity of Diabetic Retinopathy in Mexican Americans From Starr County, Texas

We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions.

https://diabetes.diabetesjournals.org/content/diabetes/56/4/1167.full.pdf

Victor H. Gonzalez

Papers

Identification of Diabetic Retinopathy Genes through a Genome-Wide Association Study among Mexican-Americans from Starr County, Texas

Familial Aggregation of Severity of Diabetic Retinopathy in Mexican Americans From Starr County, Texas

A genome-wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County, Texas.

Adverse Association between Diabetic Retinopathy and Cardiac Structure and Function