Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study
Abstract Background Type 2 diabetes (T2D) has been linked to changes in DNA methylation levels, which can, in turn, alter transcriptional activity. However, most studies for epigenome-wide associations between T2D and DNA methylation comes from cross-sectional design. Few large-scale investigations...
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BMC
2025-01-01
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| Series: | Cardiovascular Diabetology |
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| Online Access: | https://doi.org/10.1186/s12933-024-02558-8 |
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| author | Liye Lai Dave Laurence Juntilla Monica Del Monica Del C Gomez-Alonso Harald Grallert Barbara Thorand Aiman Farzeen Wolfgang Rathmann Juliane Winkelmann Holger Prokisch Christian Gieger Christian Herder Annette Peters Melanie Waldenberger |
| author_facet | Liye Lai Dave Laurence Juntilla Monica Del Monica Del C Gomez-Alonso Harald Grallert Barbara Thorand Aiman Farzeen Wolfgang Rathmann Juliane Winkelmann Holger Prokisch Christian Gieger Christian Herder Annette Peters Melanie Waldenberger |
| author_sort | Liye Lai |
| collection | DOAJ |
| description | Abstract Background Type 2 diabetes (T2D) has been linked to changes in DNA methylation levels, which can, in turn, alter transcriptional activity. However, most studies for epigenome-wide associations between T2D and DNA methylation comes from cross-sectional design. Few large-scale investigations have explored these associations longitudinally over multiple time-points. Methods In this longitudinal study, we examined data from the Cooperative Health Research in the Region of Augsburg (KORA) F4 and FF4 studies, conducted approximately seven years apart. Leucocyte DNA methylation was assessed using the Illumina EPIC and 450K arrays. Linear mixed-effects models were employed to identify significant associations between methylation sites and diabetes status, as well as with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homoeostasis model assessment of beta cell function (HOMA-B), and homoeostasis model assessment of insulin resistance (HOMA-IR). Interaction effects between diabetes status and follow-up time were also examined. Additionally, we explored CpG sites associated with persistent prediabetes or T2D, as well as the progression from normal glucose tolerance (NGT) to prediabetes or T2D. Finally, we assessed the associations between the identified CpG sites and their corresponding gene expression levels. Results A total of 3,501 observations from 2,556 participants, with methylation measured at least once across two visits, were included in the analyses. We identified 64 sites associated with T2D including 15 novel sites as well as known associations like those with the thioredoxin-interacting protein (TXNIP) and ATP-binding cassette sub-family G member 1 (ABCG1) genes. Of these, eight CpG sites exhibited different rates of annual methylation change between the NGT and T2D groups, and seven CpG sites were linked to the progression from NGT to prediabetes or T2D, including those annotated to mannosidase alpha class 2a member 2 (MAN2A2) and carnitine palmitoyl transferase 1 A (CPT1A). Longitudinal analysis revealed significant associations between methylation and FPG at 128 sites, HbA1c at 41 sites, and HOMA-IR at 57 sites. Additionally, we identified 104 CpG-transcript pairs in whole blood, comprising 40 unique CpG sites and 96 unique gene transcripts. Conclusions Our study identified novel differentially methylated loci linked to T2D as well as to changes in diabetes status through a longitudinal approach. We report CpG sites with different rates of annual methylation change and demonstrate that DNA methylation associated with T2D is linked to following transcriptional differences. These findings provide new insights into the molecular mechanisms of diabetes development. Graphical abstract |
| format | Article |
| id | doaj-art-8b525027daa34619a39bf19bc69da5a0 |
| institution | Kabale University |
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| publishDate | 2025-01-01 |
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| series | Cardiovascular Diabetology |
| spelling | doaj-art-8b525027daa34619a39bf19bc69da5a02025-01-19T12:09:10ZengBMCCardiovascular Diabetology1475-28402025-01-0124111510.1186/s12933-024-02558-8Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 studyLiye Lai0Dave Laurence Juntilla1Monica Del2Monica Del C Gomez-Alonso3Harald Grallert4Barbara Thorand5Aiman Farzeen6Wolfgang Rathmann7Juliane Winkelmann8Holger Prokisch9Christian Gieger10Christian Herder11Annette Peters12Melanie Waldenberger13Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University DüsseldorfInstitute of Human Genetics, School of Medicine, Technical University MunichInstitute of Human Genetics, School of Medicine, Technical University MunichResearch Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)German Center for Diabetes Research (DZD)Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Abstract Background Type 2 diabetes (T2D) has been linked to changes in DNA methylation levels, which can, in turn, alter transcriptional activity. However, most studies for epigenome-wide associations between T2D and DNA methylation comes from cross-sectional design. Few large-scale investigations have explored these associations longitudinally over multiple time-points. Methods In this longitudinal study, we examined data from the Cooperative Health Research in the Region of Augsburg (KORA) F4 and FF4 studies, conducted approximately seven years apart. Leucocyte DNA methylation was assessed using the Illumina EPIC and 450K arrays. Linear mixed-effects models were employed to identify significant associations between methylation sites and diabetes status, as well as with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homoeostasis model assessment of beta cell function (HOMA-B), and homoeostasis model assessment of insulin resistance (HOMA-IR). Interaction effects between diabetes status and follow-up time were also examined. Additionally, we explored CpG sites associated with persistent prediabetes or T2D, as well as the progression from normal glucose tolerance (NGT) to prediabetes or T2D. Finally, we assessed the associations between the identified CpG sites and their corresponding gene expression levels. Results A total of 3,501 observations from 2,556 participants, with methylation measured at least once across two visits, were included in the analyses. We identified 64 sites associated with T2D including 15 novel sites as well as known associations like those with the thioredoxin-interacting protein (TXNIP) and ATP-binding cassette sub-family G member 1 (ABCG1) genes. Of these, eight CpG sites exhibited different rates of annual methylation change between the NGT and T2D groups, and seven CpG sites were linked to the progression from NGT to prediabetes or T2D, including those annotated to mannosidase alpha class 2a member 2 (MAN2A2) and carnitine palmitoyl transferase 1 A (CPT1A). Longitudinal analysis revealed significant associations between methylation and FPG at 128 sites, HbA1c at 41 sites, and HOMA-IR at 57 sites. Additionally, we identified 104 CpG-transcript pairs in whole blood, comprising 40 unique CpG sites and 96 unique gene transcripts. Conclusions Our study identified novel differentially methylated loci linked to T2D as well as to changes in diabetes status through a longitudinal approach. We report CpG sites with different rates of annual methylation change and demonstrate that DNA methylation associated with T2D is linked to following transcriptional differences. These findings provide new insights into the molecular mechanisms of diabetes development. Graphical abstracthttps://doi.org/10.1186/s12933-024-02558-8DNA methylationType 2 diabetesGlycemic traitsDiabetes progressionGene expression |
| spellingShingle | Liye Lai Dave Laurence Juntilla Monica Del Monica Del C Gomez-Alonso Harald Grallert Barbara Thorand Aiman Farzeen Wolfgang Rathmann Juliane Winkelmann Holger Prokisch Christian Gieger Christian Herder Annette Peters Melanie Waldenberger Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study Cardiovascular Diabetology DNA methylation Type 2 diabetes Glycemic traits Diabetes progression Gene expression |
| title | Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study |
| title_full | Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study |
| title_fullStr | Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study |
| title_full_unstemmed | Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study |
| title_short | Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study |
| title_sort | longitudinal association between dna methylation and type 2 diabetes findings from the kora f4 ff4 study |
| topic | DNA methylation Type 2 diabetes Glycemic traits Diabetes progression Gene expression |
| url | https://doi.org/10.1186/s12933-024-02558-8 |
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