DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes
Metabolic memory, the persistent benefits of early glycaemic control on preventing and/or delaying the development of diabetic complications, has been observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but the underlying mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycaemic history, and with subsequent development of complications over an 18-yr period in the blood DNA of 499 randomly selected DCCT participants with type 1 diabetes who are also followed up in EDIC. We demonstrate the associations between DNAme near the closeout of DCCT and mean HbA1c during DCCT (mean-DCCT HbA1c) at 186 cytosine-guanine dinucleotides (CpGs) (FDR < 15%, including 43 at FDR < 5%), many of which were located in genes related to complications. Exploration studies into biological function reveal that these CpGs are enriched in binding sites for the C/EBP transcription factor, as well as enhancer/transcription regions in blood cells and haematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68-97% of the association of mean-DCCT HbA1c with the risk of complications during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycaemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:2 |
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| Enthalten in: |
Nature metabolism - 2(2020), 8 vom: 21. Aug., Seite 744-762 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Zhuo [VerfasserIn] |
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| Links: |
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| Themen: |
Chromatin |
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| Anmerkungen: |
Date Completed 31.12.2020 Date Revised 07.12.2022 published: Print-Electronic ClinicalTrials.gov: NCT00360815, NCT00360893 Citation Status MEDLINE |
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| doi: |
10.1038/s42255-020-0231-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM312710305 |
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| 245 | 1 | 0 | |a DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes |
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| 500 | |a Date Completed 31.12.2020 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT00360815, NCT00360893 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Metabolic memory, the persistent benefits of early glycaemic control on preventing and/or delaying the development of diabetic complications, has been observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but the underlying mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycaemic history, and with subsequent development of complications over an 18-yr period in the blood DNA of 499 randomly selected DCCT participants with type 1 diabetes who are also followed up in EDIC. We demonstrate the associations between DNAme near the closeout of DCCT and mean HbA1c during DCCT (mean-DCCT HbA1c) at 186 cytosine-guanine dinucleotides (CpGs) (FDR < 15%, including 43 at FDR < 5%), many of which were located in genes related to complications. Exploration studies into biological function reveal that these CpGs are enriched in binding sites for the C/EBP transcription factor, as well as enhancer/transcription regions in blood cells and haematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68-97% of the association of mean-DCCT HbA1c with the risk of complications during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycaemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Glycated Hemoglobin A |2 NLM | |
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| 700 | 1 | |a Miao, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Braffett, Barbara H |e verfasserin |4 aut | |
| 700 | 1 | |a Lachin, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lingxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Roshandel, Delnaz |e verfasserin |4 aut | |
| 700 | 1 | |a Carless, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xuejun Arthur |e verfasserin |4 aut | |
| 700 | 1 | |a Tompkins, Joshua D |e verfasserin |4 aut | |
| 700 | 1 | |a Kaddis, John S |e verfasserin |4 aut | |
| 700 | 1 | |a Riggs, Arthur D |e verfasserin |4 aut | |
| 700 | 1 | |a Paterson, Andrew D |e verfasserin |4 aut | |
| 700 | 0 | |a DCCT/EDIC Study Group |e verfasserin |4 aut | |
| 700 | 1 | |a Natarajan, Rama |e verfasserin |4 aut | |
| 700 | 1 | |a Braffet, Barbara H |e investigator |4 oth | |
| 700 | 1 | |a Lachin, John M |e investigator |4 oth | |
| 700 | 1 | |a Chen, Zhuo |e investigator |4 oth | |
| 700 | 1 | |a Miao, Feng |e investigator |4 oth | |
| 700 | 1 | |a Zhang, Lingxiao |e investigator |4 oth | |
| 700 | 1 | |a Natarajan, Rama |e investigator |4 oth | |
| 700 | 1 | |a Paterson, Andrew D |e investigator |4 oth | |
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