Risk factors for retinopathy in type 1 diabetes

Background Diabetic retinopathy is the leading cause of acquired visual disability among people of working age in all industrialised countries. Established risk factors for diabetic retinopathy include the duration of diabetes, glycaemic control, blood pressure and dyslipidaemia. However, these risk factors explain less than half of the risk for diabetic retinopathy. It is, thus, obvious that a large proportion of the risk remains to be explored. Aim The aim of the present study was to investigate potential risk factors that could affect the development of severe forms of retinopathy in type 1 diabetes. Patients and Methods The study patients were drawn from the large FinnDiane (Finnish Diabetic Nephropathy study) database. The FinnDiane study is an observational cohort study which since 1997 has collected comprehensive data on patients with type 1 diabetes at 92 centers throughout Finland with the aim of identifying genetic and environmental risk factors for diabetic complications. The patients retinopathy status were verified from ophthalmic and medical files and fundus photographs when available and graded with the ETDRS-scale. All patients underwent a thorough clinical characterisation of their clinical diabetes status by the attending physician at the participating study centers. Results Proliferative diabetic retinopathy showed significant familial clustering in siblings with type 1 diabetes and the heritability h2 adjusted for conventional risk factors suggested a significant genetic contribution to the risk. The siblings first affected by type 1 diabetes had a lower risk of proliferative retinopathy as compared to the siblings later affected by type 1 diabetes. The risk of both proliferative retinopathy and clinically significant macular edema were modified by the patient s age at onset of type 1 diabetes. The patients with higher age at onset of type 1 diabetes had a lower risk of proliferative retinopathy but conversely, a higher risk of clinically significant macular edema. The HbA1c variability was lower in those patients with higher age at onset of type 1 diabetes and the patients with lower HbA1c variability had a lower cumulative incidence and risk of laser treatment and proliferative retinopathy. Conclusion In addition to the conventional risk factors, such as diabetes duration, glycaemic control and blood pressure, familial factors, age at onset of type 1 diabetes and glycaemic profile may explain a significant proportion of the risk of severe forms of diabetic retinopathy.Tausta Diabeteksen aiheuttama silmänpohjasairaus eli diabeettinen retinopatia on tärkein hoidettavissa oleva näkövammaisuuden syy kaikissa länsimaissa. Diabeettisen retinopatian riskitekijöitä ovat diabeteksen huono hoitotasapaino, korkea verenpaine, diabeteksen pitkä kesto, sekä rasva-aineenvaihdunnan häiriöt. Kuitenkin, nämä tekijät ovat monimuuttujamalleissa selittäneet vain alle puolet vaikea-asteisen retinopatian riskistä. Tavoite Tutkimuksen tavoitteena oli selvittää mitä muita mahdollisia riskitekijöitä diabeettiselle retinopatialle olisi löydettävissä, jotka selittäisivät vaikea-asteisten retinopatian muotojen ilmaantumista. Potilaat ja menetelmät Väitöskirja tehtin FinnDiane-tutkimuksen osatutkimuksena. FinnDiane-tutkimus on monikeskustutkimus, joka on aloitettu vuonna 1997 ja siihen on kerätty kattavat kliiniset tiedot kaikkiaan 4800 suomalaisesta tyypin 1 diabetesta sairastavasta potilaasta. FinnDiane-tutkimuksen tarkoituksena on tunnistaa diabeteksen liitännäissairauksille altistavia geneettisiä- ja ympäristötekijöitä. Väitöskirjatutkimusta varten potilaiden tarkka silmänpohjatilanne määriteltiin silmänpohjakuvista ja silmätautialan sairauskertomuksista. Tulokset Kaikkiaan 188 perheessä oli vähintään kahdella sisaruksella tyypin 1 diabetes. Proliferatiivinen retinopatia vanhimmalla sisaruksella lisäsi selvästi proliferatiivisen retinopatian riskiä myöhemmin sairastuneella sisaruksella OR 2.76 (95% CI 1.25 - 6.11, P=0.01) muiden riskitekijöiden suhteen korjattuna. Variassikomponenttimallilla laskettuna suvuttainen alttius selitti 52% (SE 0.31, P<0.05) proliferatiivisen retinopatian riskistä. Samassa sisaruspariaineistossa myöhemmin diabetekseen sairastuneella sisaruksella oli hieman korkeampi riski saada proliferatiivinen retinopatia verrattuna ensimmäisenä sairastuneeseen HR 1.76 ( 95%CI 1.13-2.75, P=0.01). Sairastumisikä vaikutti proliferatiivisen retinopatian riskiin siten, että 5-14 ikäisenä sairastuneilla oli korkeampi riski HR 1.90 (95% CI 1.45 2.48, p<0.001) kuin yli 15-vuotiaina sairastuneilla. Keskeisen silmänpohjaturvotuksen riski oli korkein yli 15-vuotiaina sairastuneilla HR 3.72 (95% CI 2.35 5.89, p<0.0001) verrattuna alle 5-vuotiaina sairastuneisiin. HbA1c-tason laaja vaihtelu lisäsi laserhoidon tarvetta HR 1.6 (95%CI 1.1-2.5, P=0.02) ja proliferatiivisen retinopatian riskiä HR 1.7 (95% CI 1.3, 2.2, P<0.001) Päätelmä Suvuttainen alttius, sairastumisikä diabetekseen ja laaja HbA1c-tason vaihtelu voivat vaikuttaa merkittävästi diabeettisen retinopatian vaikea-asteisten muotojen riskiin

Uncertainty-aware deep learning methods for robust diabetic retinopathy classification

Automatic classification of diabetic retinopathy from retinal images has been increasingly studied using deep neural networks with impressive results. However, there is clinical need for estimating uncertainty in the classifications, a shortcoming of modern neural networks. Recently, approximate Bayesian neural networks (BNNs) have been proposed for this task, but previous studies have only considered the binary referable/non-referable diabetic retinopathy classification applied to benchmark datasets. We present novel results for 9 BNNs by systematically investigating a clinical dataset and 5-class classification scheme, together with benchmark datasets and binary classification scheme. Moreover, we derive a connection between entropy-based uncertainty measure and classifier risk, from which we develop a novel uncertainty measure. We observe that the previously proposed entropy-based uncertainty measure improves performance on the clinical dataset for the binary classification scheme, but not to such an extent as on the benchmark datasets. It improves performance in the clinical 5-class classification scheme for the benchmark datasets, but not for the clinical dataset. Our novel uncertainty measure generalizes to the clinical dataset and to one benchmark dataset. Our findings suggest that BNNs can be utilized for uncertainty estimation in classifying diabetic retinopathy on clinical data, though proper uncertainty measures are needed to optimize the desired performance measure. In addition, methods developed for benchmark datasets might not generalize to clinical datasets

Frequent physical activity is associated with reduced risk of severe diabetic retinopathy in type 1 diabetes

The aim of this study was to investigate whether leisure-time physical activity (LTPA) is associated with the development of severe diabetic retinopathy in individuals with type 1 diabetes.Peer reviewe

Arterial stiffness and vascular complications in patients with type 1 diabetes: The finnish diabetic nephropathy (FinnDiane) study

While patients with type 1 diabetes (T1D) are known to suffer from early cardiovascular disease (CVD), we examined associations between arterial stiffness and diabetic complications in a large patient group with T1D.This study included 807 subjects (622 T1D and 185 healthy volunteers (age 40.6 ± 0.7 versus 41.6 ± 1.2 years; P = NS)). Arterial stiffness was measured by pulse wave analysis from each participant. Furthermore, information on diabetic retinopathy, nephropathy, and CVD was collected. The renal status was verified from at least two out of three urine collections.Patients with T1D without signs of diabetic nephropathy had stiffer arteries measured as the augmentation index (AIx) than age-matched control subjects (17.3% ± 0.6% versus 10.0% ± 1.2%; P0.001). Moreover, AIx (OR 1.08; 95% CI 1.03-1.13; P = 0.002) was associated with diabetic laser-treated retinopathy in patients with normoalbuminuria in a multivariate logistic regression analysis. The same was true for AIx and diabetic nephropathy (1.04 (1.01-1.08); P = 0.004) as well as AIx and CVD (1.06 (1.00-1.12); P = 0.01) in patients with T1D.Arterial stiffness was associated with microvascular and macrovascular complications in patients with T1D

Frequent physical activity is associated with reduced risk of severe diabetic retinopathy in type 1 diabetes

AimsThe aim of this study was to investigate whether leisure-time physical activity (LTPA) is associated with the development of severe diabetic retinopathy in individuals with type 1 diabetes.MethodsProspective observational analysis as part of the Finnish diabetic nephropathy (FinnDiane) Study with a mean follow-up time of 10.7 years was performed. A total of 1612 individuals with type 1 diabetes were recruited, and LTPA was assessed at baseline using a validated self-report questionnaire. Severe diabetic retinopathy was defined as the initiation of laser treatment due to severe nonproliferative, proliferative retinopathy or diabetic maculopathy (identified from the Care Register for Health Care).ResultsA total of 261 patients received laser treatment during the follow-up. Higher frequency of LTPA was associated with a lower incidence of severe diabetic retinopathy (p = 0.024), a finding that remained significant after adjustment for gender, duration, age at onset of diabetes, kidney function, BMI, triglycerides and systolic blood pressure. However, when HbA1c and smoking were added to the Cox regression model the association was no more significant.ConclusionsFrequent LTPA is associated with a lower incidence of severe diabetic retinopathy during the follow-up. The total amount or the other components of LTPA (intensity or duration of a single session) were not associated with severe diabetic retinopathy.</p

CACNB2 Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and P value of 8.6 x 10(-4) for rs11014284. Sequencing of CACNB2 revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the beta 2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.Peer reviewe

Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms