Sequence Variation in DDAH1 and DDAH2 Genes Is Strongly and Additively Associated with Serum ADMA Concentrations in Individuals with Type 2 Diabetes

Copyright: © 2010 Abhary et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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

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 x 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 x 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 PCSK.2 (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

Genetic study of Diabetic Retinopathy: recruitment methodology and analysis of baseline characteristics

ARC and NHMRC funded authors may self-archive the author accepted version of their paper (authors manuscript) after a 12-month embargo period from publication in an open access institutional repository.BACKGROUND: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence, 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 (GWAS) analysis to detect genetic risk variants of DR. METHODS: 1669 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 hypoglycemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. RESULTS: 683 diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR (NPDR), proliferative DR (PDR) or diabetic macular edema (DME) were included in this analysis. 812 individuals with DM but no DR or minimal NPDR 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 BMI. DME was associated with T2DM (p<0.001), whereas PDR 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 GWAS to detect genetic risk variants for DR.This work was funded by a grant from the Ophthalmic Research Institute of Australia, and Project Grant #595918 from the National Health and Medical Research Council (NHMRC) of Australia. JEC is supported in part by a NHMRC Practitioner Fellowship and KPB by a Career Development Fellowship. Research conducted at Moorfields Eye Hospital was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology

Inappropriate behaviours experienced by doctors while undertaking specialty training

Purpose To explore inappropriate behaviours experienced during specialty training in Australia and their implications for doctors\u27 training experiences and outcomes. This is a subset of data from a larger study exploring experiences of doctors in Australian specialty training - a qualitative study of enablers, stressors and supports. Methods In this qualitative study, registrars in specialist training programmes in Australia were invited and interviewed between August 2015 and August 2016. Semistructured open-ended questions were used to explore topics of relevance to their workplace, training, support service use and personal lives. Interviews were transcribed verbatim, de-identified and content and thematic analysis undertaken. Recruitment was ceased when data saturation was reached and no new themes emerged. Key themes related to inappropriate behaviours experienced during specialty training are reported in this study. Results 17 participants were recruited (including one Indigenous and one international medical graduate). A total of six specialty training programmes across multiple states at various locations across Australia were represented in this cohort. Almost all participants reported confronting (personally experienced or witnessed) inappropriate behaviours during their training, perpetrated most commonly by senior doctors. Key themes of inappropriate behaviour that emerged were belittling and humiliation, sexually inappropriate behaviour, inappropriate behaviour as part of the \u27culture\u27 of medicine, reluctance to raise concerns due to fear of recrimination, and impacts of inappropriate behaviour. Conclusion Varying inappropriate behaviours were experienced by doctors in specialty training, having implications for their psychological well-being. A multidimensional and multisystem approach is required in the management of this serious issue

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

© 2009 by The Association for Research in Vision and Ophthalmology, Inc.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.Sotoodeh Abhary, Kathryn P. Burdon, Aanchal Gupta, Stewart Lake, Dinesh Selva, Nikolai Petrovsky and Jamie E. Crai

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

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