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      Genome-wide DNA methylation analysis of extreme phenotypes in the identification of novel epigenetic modifications in diabetic retinopathy

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          Abstract

          Background

          Aberrant epigenetic modifications such as DNA methylation may contribute to the pathogenesis of DR. We aimed at elucidating the role of novel DNA methylation modifications in diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM) using an extreme phenotypic design.

          Methods/results

          Two consecutive studies were conducted. A cross-sectional study using an extreme phenotypic design was conducted to identify rare methylation modifications that might contribute to DR pathogenesis. A 2-year longitudinal nested case–control study was conducted to validate the results and assess whether these novel methylation modifications could be used as biomarkers for predicting DR onset. A large number of differentially methylated CpG sites were identified in the cross-sectional study, and two (cg12869254 and cg04026387) corresponding to known genes were replicated in the longitudinal study. Higher methylation of cg12869254 significantly correlated with macular RNFL thinning in the superior and nasal subregions, and that of cg04026387 correlated with reduced deep capillary plexus VD in the superior and inferior subregions after adjusting for covariates.

          Conclusions

          Cg12869254 and cg04026387 hypermethylation may complement the known risk factors that contribute to the pathogenesis of DR and as novel biomarkers for disease prediction.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13148-022-01354-z.

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          Most cited references43

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          Prediction of Creatinine Clearance from Serum Creatinine

          A formula has been developed to predict creatinine clearance (C cr ) from serum creatinine (S cr ) in adult males: Ccr = (140 – age) (wt kg)/72 × S cr (mg/100ml) (15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18–92. Values for C cr were predicted by this formula and four other methods and the results compared with the means of two 24-hour C cr’s measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr·s of 0.83; on average, the difference between predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
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            Global aetiology and epidemiology of type 2 diabetes mellitus and its complications

            Globally, the number of people with diabetes mellitus has quadrupled in the past three decades, and diabetes mellitus is the ninth major cause of death. About 1 in 11 adults worldwide now have diabetes mellitus, 90% of whom have type 2 diabetes mellitus (T2DM). Asia is a major area of the rapidly emerging T2DM global epidemic, with China and India the top two epicentres. Although genetic predisposition partly determines individual susceptibility to T2DM, an unhealthy diet and a sedentary lifestyle are important drivers of the current global epidemic; early developmental factors (such as intrauterine exposures) also have a role in susceptibility to T2DM later in life. Many cases of T2DM could be prevented with lifestyle changes, including maintaining a healthy body weight, consuming a healthy diet, staying physically active, not smoking and drinking alcohol in moderation. Most patients with T2DM have at least one complication, and cardiovascular complications are the leading cause of morbidity and mortality in these patients. This Review provides an updated view of the global epidemiology of T2DM, as well as dietary, lifestyle and other risk factors for T2DM and its complications.
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              Biochemistry and molecular cell biology of diabetic complications.

              Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.
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                Author and article information

                Contributors
                wangwei@gzzoc.com
                Journal
                Clin Epigenetics
                Clin Epigenetics
                Clinical Epigenetics
                BioMed Central (London )
                1868-7075
                1868-7083
                31 October 2022
                31 October 2022
                2022
                : 14
                : 137
                Affiliations
                [1 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, ; Guangzhou, China
                [2 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, , University of Melbourne, ; Level 7, 32 Gisborne Street, East Melbourne, VIC 3002 Australia
                [3 ]GRID grid.410556.3, ISNI 0000 0001 0440 1440, John Radcliffe Hospital, , Oxford University Hospitals NHS Foundation Trust, ; Oxford, UK
                Author information
                http://orcid.org/0000-0002-5273-3332
                Article
                1354
                10.1186/s13148-022-01354-z
                9623976
                36316758
                4dd0eed9-d8b5-4e10-befe-aec305e87add
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 21 August 2022
                : 11 October 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82000901
                Award Recipient :
                Funded by: Guangzhou Science & Technology Plan of Guangdong Pearl River Talents Program
                Award ID: 202102010162
                Award Recipient :
                Funded by: Fundamental Research Funds of the State Key Laboratory of Ophthalmology
                Award ID: 303060202400362
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2022

                Genetics
                diabetic retinopathy,type 2 diabetes mellitus,dna methylation,extreme phenotypes,biomarkers

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