Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM).It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM). METHODS: Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE) were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs) and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies. RESULTS: Among the nine loci (15 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012), compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032). Combining the two cohorts gave an allelic P < 0.003 and dominant P = 0.0013). Combined analysis with the Sankara Nethralaya cohort gave an allelic P = 0.0003 and dominant P = 0.00011 with an OR = 0.49 (0.34 - 0.70) for the minor allele. In HTRA1, rs11200638 (G>A), showed marginal significance with DR (P = 0.055) while rs10490924 in LOC387715 gave a P = 0.07. No statistical significance was observed for SNPs in the other 7 genes studied. CONCLUSIONS: This study confirms significant association of one polymorphism only (rs2070600 in RAGE) with DR in an Indian population which had T2DM.

Software for reading and grading diabetic retinopathy: Aravind Diabetic Retinopathy Screening 3.0.

OBJECTIVE: To evaluate the validity and reproducibility of software for reading digital images and grading diabetic retinopathy. RESEARCH DESIGN AND METHODS: A prospective, comparative observational study was conducted on a series of patients with type 2 diabetes who presented at the retina clinic of a tertiary care center in India. A total of 210 eyes of 105 patients were allocated to one of three ophthalmologists, who performed dilated indirect and direct ophthalmoscopy and subsequently assessed the digital images of the same group of patients who were masked to the patient's identity. The interobserver and intertest agreement between clinical assessments and grading of diabetic retinopathy using the software was estimated. RESULTS: Moderate nonproliferative diabetic retinopathy (NPDR) was most frequently diagnosed, both clinically and on evaluating digital images. The overall agreement between the clinical grading of diabetic retinopathy and the grading of images was 81.3% (kappa = 0.69, SE 0.04, P < 0.0001); there was good agreement (81.3%) for NPDR (kappa = 0.61, SE 0.05, P < 0.0001), but agreement was not as good (54.6%) for proliferative diabetic retinopathy (kappa = 0.29, SE 0.11, P = 0.005). Clinically significant macular edema was diagnosed in 33.3% (70 of 210) of eyes clinically and in 40.2% (84 of 209) of eyes by grading images, and there was good agreement (89.5%) between the two (kappa = 0.77, SE 0.07, P < 0.0001). CONCLUSIONS: Aravind Diabetic Retinopathy Screening 3.0 is a simple and valid tool to assist in the detection of sight-threatening retinopathy and could supplement dilated fundus examinations by ophthalmologists on patients to detect diabetic retinopathy.

Macular ischaemia as a marker for nephropathy in diabetic retinopathy.

PURPOSE: To determine whether diabetic macular ischaemia is associated with ischaemic heart disease (IHD), hyperlipidaemia, hypertension (HTN) and nephropathy. METHODS: Prospective case-control study from January to December 2001, involving 102 type 2 diabetic patients (aged 40-80 years), 59 with unilateral / bilateral macular ischaemia and 43 concurrent controls. Diabetic retinopathy was graded and macular ischaemia assessed by fundus examination, central fundus photography and fluorescein angiography. Systemic examination and laboratory investigations were done to evaluate systemic diseases. The associations were analysed by Chi-square test and Student's t-test. The significance of the variables as independent risk factors was tested by logistic regression analysis. RESULTS: Macular ischaemia was not associated with IHD (P=1.00); HTN (P=1.00) and hyperlipidaemia (P=0.30). Nephropathy was significantly associated with macular ischaemia (P=0.025; odds ratio [OR]: 2.62; 95% confidence interval [CI]: 1.16-5.9). The association remained significant after controlling for age, gender, duration of diabetes, severity of retinopathy, HTN, IHD and hyperlipidaemia. Further, the association with nephropathy was not affected by the presence of macular isachaemia in one or both the eyes (P=0.39). CONCLUSION: Macular ischaemia may serve as a marker for nephropathy in type 2 diabetes mellitus irrespective of the severity of retinopathy.

Atypical manifestations of diabetic retinopathy.

PURPOSE OF REVIEW: As the prevalence of diabetes mellitus increases globally, recognition of the atypical manifestations of diabetic retinopathy will become increasingly important. RECENT FINDINGS: In addition to the inherent variability in the spectrum of diabetic retinopathy, coexisting systemic or ocular conditions can dramatically alter the retinal manifestations of diabetes mellitus in any given patient. SUMMARY: We review here the clinical features and treatment implications associated with the atypical manifestations of diabetic retinopathy.

Familial exudative vitreoretinopathy (FEVR). Clinical profile and management.

PURPOSE: To report our experience with the diagnosis and management of Familial Exudative Vitreoretinopathy (FEVR) in a predominantly older Indian population.. METHODS: This prospective interventional non-comparative case series included 38 patients of FEVR and their 23 family members. The diagnosis was established by clinical examination, fluorescein angiography and family screening. Prophylactic photocoagulation/cryotherapy or surgical treatment was done depending on the severity of the disease. RESULTS: The mean age of the patients was 23.6 years. The fundus/fluorescein angiographic findings in 116 eyes of our 61 patients (6 eyes phthisical) were as follows: forty eight (41.4%) eyes had only peripheral avascular zone, 8 (6.9%) eyes had peripheral new vessels, and 35 (30.1%) eyes had retinal detachments (RD)--10 (8.6%) exudative, 5 (4.3%) tractional and 20 (17.2%) rhegmatogenous. Prophylactic photocoagulation or cryotherapy was done in 34 eyes for retinal holes, local exudative detachments and bleeding new vessels. All the eyes retained stable vision over a mean follow-up of 16 months. Only 14 RDs were suitable for surgery: scleral buckling, vitrectomy or both. The reattachment rate was 85.7% (12 of 14) and the best-corrected visual acuity (BCVA) improved to 5/60 or better in 50% of these eyes over a 2-year follow-up. CONCLUSIONS: FEVR appears to be more common than reported. Timely diagnosis and intervention is essential in view of the lifelong progression of the disease, late exacerbations, frequent involvement of family members, and poor surgical results. A high index of suspicion, family screening and early prophylaxis are recommended to prevent avoidable blindness from this underdiagnosed disease.