MicroRNA-Related Genetic Variants Are Associated With Diabetic Retinopathy in Type 1 Diabetes Mellitus.

Purpose: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). Methods: All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Results: Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Conclusions: Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.

Mitochondrial haplogroups are not associated with diabetic retinopathy in a large Australian and British Caucasian sample.

Mitochondrial haplogroups H1, H2 and UK have previously been reported to be associated with proliferative diabetic retinopathy (PDR) in Caucasian patients with diabetes. We aimed to replicate this finding with a larger sample and expand the analysis to include different severities of DR, and diabetic macular edema (DME). Caucasian participants (n = 2935) with either type 1 or type 2 diabetes from the Australian Registry of Advanced Diabetic Retinopathy were enrolled in this study. Twenty-two mitochondrial single nucleotide polymorphisms were genotyped by MassArray and haplogroups reconstructed using Haplogrep. Chi square tests and logistic regressions were used to test associations between haplogroup and DR phenotypes including any DR, non-proliferative DR (NPDR), proliferative DR (PDR) and DME. After stratifying the samples in type 1 and type 2 diabetes groups, and adjusting for sex, age, diabetes duration, concurrent HbA1c and hypertension, neither haplogroups H1, H2, UK, K or JT were associated with any DR, NPDR, PDR or DME.

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

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.

A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients.

AIMS: This study aimed to investigate whether the single-nucleotide polymorphism (SNP) rs2910164 residing within microRNA-146a (miR-146a) is associated with diabetic microvascular complications diabetic nephropathy (DN), proliferative diabetic retinopathy (PDR) or diabetic macular oedema (DME) in either Caucasian patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus. METHODS: Caucasian patients with T1DM (n = 733) or T2DM (n = 2215) were recruited from ophthalmology, renal and endocrine clinics in Australia and the UK. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be on treatment with oral hypoglycaemic drugs or insulin. In total, 890 participants had DN (168 with T1DM and 722 with T2DM), 731 had PDR (251 with T1DM and 480 with T2DM) and 1026 had DME (170 with T1DM and 856 with T2DM). Participants were genotyped for SNP rs2910164 in miR-146a. Analyses investigating association were adjusted for relevant clinical covariates including age, sex, DM duration, HbA1c and hypertension. RESULTS: A significant association was found between the C allele of rs2910164 and DN in the T1DM group (OR 1.93; CI 1.23-3.03; P = 0.004), but no association found in the T2DM group (OR 1.05; CI 0.83-1.32; P = 0.691). In the subset of T2DM patients, the C allele was specifically associated with DME (OR 1.25; CI 1.03-1.53; P = 0.025). No association with DME was found in the T1DM group (OR 0.87; CI 0.54-1.42); P = 0.583), or with PDR for either type of DM. CONCLUSIONS: Rs2910164 is significantly associated with microvascular complications DN in patients with T1DM and DME in patients with T2DM.

Promoter polymorphism at the tumour necrosis factor/lymphotoxin-alpha locus is associated with type of diabetes but not with susceptibility to sight-threatening diabetic retinopathy.

AIM: To investigate, in a large cohort of 2494 individuals with diabetes mellitus, whether functional single nucleotide polymorphisms in the promoter region of tumour necrosis factor (TNF) and lymphotoxin-alpha (LTA) genes are associated with type of diabetes or presence of diabetic retinopathy. METHODS: A total of 334 type 1 diabetes and 999 type 2 diabetes participants with sight-threatening diabetic retinopathy, and 260 type 1 diabetes and 901 type 2 diabetes participants with no diabetic retinopathy or minimal non-proliferative diabetic retinopathy, were genotyped for two single nucleotide polymorphisms (rs1800629 and rs361525). RESULTS: The A allele of rs1800629 was associated with type 1 diabetes (p < 0.001; odds ratio = 0.62). After adjustment for age, sex, diabetes duration, HbA1c, hypertension and nephropathy, no significant association was found between rs1800629 or rs361525 and sight-threatening diabetic retinopathy. CONCLUSION: An association between the A allele of rs1800629 and type of diabetes was found. No association was found between two promoter variants of TNF and LTA, and diabetic retinopathy in a large cohort of Caucasian patients with type 1 diabetes and type 2 diabetes.

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene.

AIMS/HYPOTHESIS: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. METHODS: Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. RESULTS: The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. CONCLUSIONS/INTERPRETATION: Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.

Common Sequence Variation in the VEGFC Gene Is Associated with Diabetic Retinopathy and Diabetic Macular Edema.

PURPOSE: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional, case control study. PARTICIPANTS: White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. METHODS: Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. MAIN OUTCOME MEASURES: Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, individually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. RESULTS: Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001; OR, 0.67; confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001; OR, 0.62; CI, 0.47-0.81), and rs2333526 (P = 0.005; OR, 0.69; CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004; OR, 0.53; CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. CONCLUSIONS: Significant associations were found between VEGFC tag SNPs (individually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.

Genetic study of diabetic retinopathy: recruitment methodology and analysis of baseline characteristics.

BACKGROUND: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study sample to be used for genome-wide association analysis to detect genetic risk variants of DR. METHODS: One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. Individuals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. RESULTS: Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve individuals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P < 0.001), whereas proliferative DR was associated with T1DM (P < 0.001). CONCLUSIONS: Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR.

Relationship between DDAH gene variants and serum ADMA level in individuals with type 1 diabetes.

Asymmetric dimethylarginine (ADMA) levels are elevated in diabetes and likely contribute to diabetic complications such as retinopathy and nephropathy. The DDAH enzymes are primarily responsible for ADMA metabolism. Polymorphisms in the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes have been previously associated with serum ADMA levels in type 2 diabetes (T2DM). We sought to determine whether they are also associated with ADMA levels in individuals with type 1 diabetes (T1DM). Serum ADMA concentrations were measured in 196 individuals with T1DM. Twenty-six tag SNPs in the DDAH1 gene and 10 in the DDAH2 gene were genotyped. One SNP in the DDAH1 gene (rs3738111) and one in the DDAH2 gene (rs805293) showed a correlation with serum ADMA levels; however, neither survived correction for multiple testing. We found limited evidence that genetic polymorphisms in DDAH genes influence serum ADMA levels in individuals with T1DM. This differs to findings in T2DM and may be due to underlying differences in the cohorts or to fundamental differences in the pathogenesis of the two types of diabetes.

Elevation of serum asymmetrical and symmetrical dimethylarginine in patients with advanced glaucoma.

PURPOSE: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are the dimethylated isomeric derivatives of the amino acid L-arginine. ADMA is an endogenous inhibitor of nitric oxide synthase (NOS), while SDMA is a competitive inhibitor of cellular uptake of L-arginine, the substrate for NOS. As such, these metabolites are associated with endothelial dysfunction. As the nitric oxide pathway and endothelial dysfunction have been implicated in glaucoma, the aim of this study was to investigate serum ADMA, SDMA, and L-arginine levels in individuals with advanced glaucoma compared with normal controls. In addition, we have investigated genetic variation in the DDAH1 and DDAH2 genes, encoding the enzymes responsible for degradation of ADMA, for association with ADMA level in glaucoma patients and controls. METHODS: Two hundred eleven patients with advanced glaucoma and 295 normal controls were recruited. Liquid chromatography-tandem mass spectrometry was used to measure the serum ADMA, SDMA, and L-arginine levels of participants. Single nucleotide polymorphisms in the DDAH1 and DDAH2 genes reportedly associated with ADMA level were genotyped in all individuals. RESULTS: A significant increase in both serum ADMA and SDMA concentration was detected in advanced glaucoma cases compared with controls (P ≤ 0.0001). No significant change was detected in serum L-arginine concentration. No association of polymorphisms in DDAH1 and DDAH2 with either ADMA level or glaucoma was detected. CONCLUSIONS: The serum levels of two dimethylarginines, ADMA and SDMA, are associated with advanced glaucoma. These data further implicate the nitric-oxide pathway in glaucoma pathogenesis.

Incidence of diabetic retinopathy in indigenous Australians within Central Australia: the Central Australian Ocular Health Study.

BACKGROUND: To estimate the incidence of diabetic retinopathy (DR) within the indigenous Australian population living in Central Australia. DESIGN: Clinic-based cohort study. PARTICIPANTS: One thousand eight hundred eighty-four individuals aged ≥20 years living in one of 30 remote communities within the statistical local area of 'Central Australia'. METHODS: Among those with diabetes mellitus (DM) (n = 1040), 432 (42%) were reviewed between 6 months and 3 years (median 21 months) after the initial examination. DR in participants with DM was graded using the Early Treatment of Diabetic Retinopathy Study classification. Baseline results were compared with those at follow-up. MAIN OUTCOME MEASURES: The incidence of any DR and vision-threatening DR (clinically significant macular oedema and/or proliferative DR) in at least one eye. RESULTS: Of those with DM but without DR at baseline, 8.41% (9.42% of those aged 40 years or older) per year developed DR. Meanwhile, 0.7% (0.92% for those aged ≥40 years) of those with no DR at baseline developed vision-threatening DR per year, increasing to 8.4% per year for those with minimal or mild non-proliferative DR, and 28.2% per year for those with moderate or severe non-proliferative DR at baseline. CONCLUSION: Our study has estimated the annual incidence rates of DR among indigenous Australians living within Central Australia. These rates are similar to those from the non-indigenous population, and highlight the need for good surveillance and service provision in a population where the prevalence of diabetes is very high and the logistics of screening are complex.

Prevalence and associations of diabetic retinopathy in indigenous Australians within central Australia: the Central Australian Ocular Health Study.

PURPOSE: To determine the prevalence and associations of diabetic retinopathy (DR) within the indigenous Australian population living in central Australia. METHODS: 1884 individuals aged 20 years or older, living in one of 30 remote communities within the statistical local area of 'central Australia' were recruited for this study. This equated to 36% of those aged 20 years or older and 67% of those aged 40 years or older within this district. Participants were recruited as they presented to the eye clinic at each remote community. Following dilated slit-lamp fundoscopy, the amount of DR in participants with diabetes mellitus (DM) was quantified using the Early Treatment of Diabetic Retinopathy Study criteria. The presence of any DR and vision-threatening DR (clinically significant macular oedema and/or proliferative DR) in one or both eyes was presented. RESULTS: Of those with diabetes, 22.2% (25.4% of those aged 40 years or older) had any DR and 7.0% (8.4% of those aged 40 years or older) had vision-threatening DR. Both the presence of any DR and vision-threatening DR were associated with advancing age and HbA1c level, but neither subcategory was associated with sex or self-reported hypertension. CONCLUSION: Our study has shown similar prevalence rates for DR in indigenous Australians compared with non-indigenous Australians. However, as DM is far more prevalent among indigenous Australians, the proportion of those affected by DR across the population should be considerably higher when compared with non-indigenous Australians.

Aldose reductase gene polymorphisms and diabetic retinopathy susceptibility.

OBJECTIVE: Aldose reductase (ALR) is involved in diabetic microvascular damage via the polyol pathway. A recent meta-analysis found genetic variation in the ALR gene (AKR1B1) to be significantly associated with diabetic retinopathy (DR). We investigated the genetic association of AKR1B1 with DR. RESEARCH DESIGN AND METHODS: The study enrolled 909 individuals with diabetes. Participants were genotyped for an AKR1B1 (CA)n microsatellite and 14 tag single nucleotide polymorphisms, and ophthalmological assessment was performed. RESULTS: A total of 514 individuals were found to have DR. rs9640883 was significantly associated with DR (P = 0.0005). However, AKR1B1 variation was not independently associated with DR development after adjusting for relevant clinical parameters. rs9640883 was associated with duration of diabetes (P = 0.002). CONCLUSION: Many previous reports have failed to account for known risk factors for DR. The commonly reported association of AKR1B1 with DR may be due to an association of the gene with younger age at onset of diabetes.

Sequence variation in DDAH1 and DDAH2 genes is strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes.

BACKGROUND: Asymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) is an ADMA degrading enzyme that has two isoforms: DDAHI and DDAHII. We sought to determine whether serum ADMA levels in type 2 diabetes are influenced by common polymorphisms in the DDAH1 and DDAH2 genes. METHODOLOGY/PRINCIPAL FINDINGS: Relevant clinical parameters were measured and peripheral whole blood obtained for serum and genetic analysis on 343 participants with type 2 diabetes. Serum ADMA concentrations were determined by mass spectroscopy. Twenty six tag SNPs in the DDAH1 and 10 in the DDAH2 gene were genotyped in all subjects and tested for association with serum ADMA levels. Several SNPs and haplotypes in the DDAH genes were strongly associated with ADMA levels. Most significantly in the DDAH1 gene, rs669173 (p = 2.96x10(-7)), rs7521189 (p = 6.40x10(-7)), rs2474123 (p = 0.00082) and rs13373844 (p = 0.00027), and in the DDAH2 gene, rs3131383 (p = 0.0029) and the TGCCCAGGAG haplotype (p = 0.0012) were significantly associated with ADMA levels. Sub-analysis by diabetic retinopathy (DR) status revealed these variants were associated with ADMA levels predominantly in participants without DR. Combined analysis of the most strongly associated SNPs in DDAH1 (rs669173) and DDAH2 (rs3131383) revealed an additive effect (p = 1.37x10(-8)) on ADMA levels. CONCLUSIONS/SIGNIFICANCE: Genetic variation in the DDAH1 and 2 genes is significantly associated with serum ADMA levels. Further studies are required to determine the pathophysiological significance of elevated serum ADMA in type 2 diabetes and to better understand how DDAH gene variation influences ADMA levels.

Association between erythropoietin gene polymorphisms and diabetic retinopathy.

OBJECTIVE: To determine whether sequence variation in the erythropoietin gene (EPO) is associated with the development of diabetic retinopathy (DR). METHODS: This was a multicenter study based on 518 subjects with long-standing diabetes mellitus (DM), 173 with type 1 DM (T1DM) and 345 with type 2 DM (T2DM). Study groups consisted of 233 control subjects with no DR, 155 subjects with nonproliferative DR, 126 with proliferative DR, and 90 with clinically significant macular edema. Subjects with end-stage renal disease were excluded. DNA extracted from blood of each subject was genotyped for 3 EPO single-nucleotide polymorphisms (SNPs). RESULTS: All 3 SNPs in EPO were associated with overall DR status in the combined T1DM and T2DM and T2DM alone groups (CC genotype of rs507392, P < .008; GG genotype of rs1617640, P < .008; and CC genotype of rs551238, P < .008) in the multivariate analysis. The GCC haplotype was also associated with overall DR status in the combined DM and T2DM alone groups (P = .008) by multivariate analysis. All SNPs and the GCC haplotype were also associated with proliferative DR and clinically significant macular edema in the combined DM and T2DM alone groups. No associations were found with T1DM alone. CONCLUSION: Sequence variation in EPO is associated with the risk of DR independent of duration of DM, degree of glycemic control, and nephropathy. CLINICAL RELEVANCE: Identifying EPO genetic markers for high risk of developing DR could lead to the possibility of developing novel treatments or preventive therapies.

Diabetic retinopathy is associated with elevated serum asymmetric and symmetric dimethylarginines.

OBJECTIVE: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and l-arginine directly influence nitric oxide production. Our objective was to test whether serum ADMA, SDMA, or l-arginine levels correlate with diabetic retinopathy subtype or severity. RESEARCH DESIGN AND METHODS: A total of 162 subjects with type 1 diabetes and 343 with type 2 diabetes, of whom 329 subjects had no diabetic retinopathy, 27 had nonproliferative diabetic retinopathy (NPDR), 101 had proliferative diabetic retinopathy (PDR), and 107 had clinically significant macular edema (CSME), were recruited. Blinding diabetic retinopathy was defined as severe NPDR, PDR, or CSME. Serum ADMA, SDMA, and l-arginine concentrations were determined by mass spectroscopy. RESULTS: In multivariate analysis, blinding diabetic retinopathy, PDR, and nephropathy were associated with significantly increased serum levels of ADMA (P < 0.001), SDMA (P < 0.001), and l-arginine (P = 0.001). Elevated ADMA (P < 0.001) and SDMA (P < 0.001) were also significantly associated with CSME. CONCLUSIONS: Severe forms of diabetic retinopathy are associated with elevated serum ADMA, SDMA, and l-arginine. Further investigation is required to determine whether these findings are of clinical relevance.

A systematic meta-analysis of genetic association studies for diabetic retinopathy.

OBJECTIVE: Diabetic retinopathy is a sight-threatening microvascular complication of diabetes with a complex multifactorial pathogenesis. A systematic meta-analysis was undertaken to collectively assess genetic studies and determine which previously investigated polymorphisms are associated with diabetic retinopathy. RESEARCH DESIGN AND METHODS: All studies investigating the association of genetic variants with the development of diabetic retinopathy were identified in PubMed and ISI Web of Knowledge. Crude odds ratios (ORs) and 95% CIs were calculated for single nucleotide polymorphisms and microsatellite markers previously investigated in at least two published studies. RESULTS: Twenty genes and 34 variants have previously been studied in multiple cohorts. The aldose reductase (AKR1B1) gene was found to have the largest number of polymorphisms significantly associated with diabetic retinopathy. The z-2 microsatellite was found to confer risk (OR 2.33 [95% CI 1.49-3.64], P = 2 x 10(-4)) in type 1 and type 2 diabetes and z+2 to confer protection (0.58 [0.36-0.93], P = 0.02) against diabetic retinopathy in type 2 diabetes regardless of ethnicity. The T allele of the AKR1B1 promoter rs759853 variant is also significantly protective against diabetic retinopathy in type 1 diabetes (0.5 [0.35-0.71], P = 1.00 x 10(-4)), regardless of ethnicity. These associations were also found in the white population alone (P < 0.05). Polymorphisms in NOS3, VEGF, ITGA2, and ICAM1 are also associated with diabetic retinopathy after meta-analysis. CONCLUSIONS: Variations within the AKR1B1 gene are highly significantly associated with diabetic retinopathy development irrespective of ethnicity. Identification of genetic risk factors in diabetic retinopathy will assist in further understanding of this complex and debilitating diabetes complication.

Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy.

PURPOSE: Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that plays a role in angiogenesis and microvascular permeability. This study was conducted to determine whether common sequence variation in the VEGFA gene plays a role in the development of diabetic retinopathy (DR). METHOD: Five hundred fifty-four subjects with diabetes mellitus (DM) including 190 type 1 DM (T1DM) and 364 type 2 DM (T2DM) were recruited. The study group consisted of 235 participants without DR, 158 with nonproliferative DR (NPDR), 132 with proliferative DR (PDR), and 93 with clinically significant macular edema (CSME). Blinding DR was defined as severe NPDR, PDR, or CSME. Fifteen VEGFA tag single-nucleotide polymorphisms (SNPs) were genotyped in all subjects and tested for association with blinding DR. RESULTS: Multiple tag SNPs in the VEGFA gene were associated with blinding DR. After controlling for sex, HbA1c, and duration of disease, in T1DM, the AA genotype of rs699946 (P = 0.007, odds ratio [OR], 4.1; 95% confidence interval [CI], 1.5-11.4) and the GG genotype of rs833068 (P = 0.017, OR, 3.1; 95% CI, 1.3-7.2) were most significantly associated. In T2DM, the C allele of rs3025021 (P = 0.002; OR, 3.8; 95% CI, 1.5-10.0) and the G allele of rs10434 (P = 0.002; OR, 2.6; 95% CI, 1.3-5.3) were most significantly associated with blinding DR. Haplotype analyses suggested an important role for the haplotype TCCGCG in blinding DR (P = 0.0004). CONCLUSIONS: Sequence variation in the VEGFA gene is associated with risk of developing blinding DR in T1DM and T2DM. Identifying specific genetic markers will allow for refined screening algorithms and earlier intervention in patients at highest risk.

An interdisciplinary course for trainee psychiatrists: feedback and implications.

OBJECTIVE: To describe a course for trainee psychiatrists, designed to encourage critical thinking within an interdisciplinary framework. Trainees' responses to the course, and the implications of these for teaching, learning and clinical practice, are considered. METHOD: Trainees were interviewed, and their responses subjected to content analysis. RESULTS: To some extent, the course appears to have met its objectives. However, some trainees found parts of the course content threatening, and reported negative perceptions of teaching staff and the process of critical appraisal. CONCLUSIONS: Challenging taken for granted beliefs in psychiatry is a fundamental skill, which should be fostered in trainee psychiatrists if the profession is to move forwards as an intellectual and clinical discipline. The lessons learned from the course we describe may be useful to others who wish to pursue integrated, interdisciplinary teaching methods.

Psychiatric aspects of detention: illustrative case studies.

OBJECTIVE: Although the two political systems cannot be equated, the psychiatric and psychosocial issues raised by people detained under the migration regulations of the present Australian government, and those detained under the security legislation of the last apartheid government in South Africa, are similar in many aspects. METHOD: We present two case scenarios representative of the cumulative clinical experience of the authors in their work (as part of their routine clinical practice and medical school experience) with asylum seekers and political detainees in acute psychiatric units in both South Africa and Australia. RESULTS: Similar issues raised included the validity of a psychiatric diagnosis in these patients and the debate this conundrum provoked among the multidisciplinary teams. The pressures placed on clinicians by politicians in terms of clinical management of hospitalized detainees raised similar ethical questions across both countries. The clinical syndromes of depression and posttraumatic stress disorder were similar. The effect of the 'non-person' status conferred upon refugees by the 'temporary protection visa' could be equated with the effect of 'banning orders' imposed on opponents of the Apartheid regime. CONCLUSIONS: In South Africa, political detainees entered into the struggle expecting to face hardship and torture at the hands of the government of the time. Asylum seekers flee to Australia expecting support from a democratic system and generally had not prepared themselves for further incarceration and yet another political struggle. Despite this seemingly fundamental difference, the experiences of detainees across two very different political systems are remarkably similar.