A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes
Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/11/8/542 |
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| author | Tim Vigers Lauren A. Vanderlinden Randi K. Johnson Patrick M. Carry Ivana Yang Brian C. DeFelice Alexander M. Kaizer Laura Pyle Marian Rewers Oliver Fiehn Jill M. Norris Katerina Kechris |
| author_facet | Tim Vigers Lauren A. Vanderlinden Randi K. Johnson Patrick M. Carry Ivana Yang Brian C. DeFelice Alexander M. Kaizer Laura Pyle Marian Rewers Oliver Fiehn Jill M. Norris Katerina Kechris |
| author_sort | Tim Vigers |
| collection | DOAJ |
| description | Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk. These pairs included five DNAm probes mediated by histidine (a metabolite known to affect T1D risk), one probe (cg01604946) mediated by phostidyl choline p-32:0 or o-32:1, and one probe (cg00390143) mediated by sphingomyelin d34:2. The top 100 DNAm probes were over-represented in six reactome pathways at the FDR <0.1 level (<i>q</i> = 0.071), including transport of small molecules and inositol phosphate metabolism. While the causal pathways in our mediation models require further investigation to better understand the biological mechanisms, we identified seven methylation sites that may improve our understanding of epigenetic protection against T1D as mediated by the metabolome. |
| first_indexed | 2024-03-10T08:36:11Z |
| format | Article |
| id | doaj.art-714dbdf695d241429a1a4ba14acd0040 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T08:36:11Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-714dbdf695d241429a1a4ba14acd00402023-11-22T08:39:49ZengMDPI AGMetabolites2218-19892021-08-0111854210.3390/metabo11080542A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 DiabetesTim Vigers0Lauren A. Vanderlinden1Randi K. Johnson2Patrick M. Carry3Ivana Yang4Brian C. DeFelice5Alexander M. Kaizer6Laura Pyle7Marian Rewers8Oliver Fiehn9Jill M. Norris10Katerina Kechris11Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 80045, USADepartment of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 80045, USADivision of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USABarbara Davis Center for Diabetes, University of Colorado, Aurora, CO 80045, USADivision of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USAWest Coast Metabolomics Center, University of California, Davis, CA 95616, USADepartment of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 80045, USADepartment of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 80045, USADepartment of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 80045, USAWest Coast Metabolomics Center, University of California, Davis, CA 95616, USABarbara Davis Center for Diabetes, University of Colorado, Aurora, CO 80045, USADepartment of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 80045, USAEnvironmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk. These pairs included five DNAm probes mediated by histidine (a metabolite known to affect T1D risk), one probe (cg01604946) mediated by phostidyl choline p-32:0 or o-32:1, and one probe (cg00390143) mediated by sphingomyelin d34:2. The top 100 DNAm probes were over-represented in six reactome pathways at the FDR <0.1 level (<i>q</i> = 0.071), including transport of small molecules and inositol phosphate metabolism. While the causal pathways in our mediation models require further investigation to better understand the biological mechanisms, we identified seven methylation sites that may improve our understanding of epigenetic protection against T1D as mediated by the metabolome.https://www.mdpi.com/2218-1989/11/8/542DNA methylationmetabolomicstype 1 diabetes |
| spellingShingle | Tim Vigers Lauren A. Vanderlinden Randi K. Johnson Patrick M. Carry Ivana Yang Brian C. DeFelice Alexander M. Kaizer Laura Pyle Marian Rewers Oliver Fiehn Jill M. Norris Katerina Kechris A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes Metabolites DNA methylation metabolomics type 1 diabetes |
| title | A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes |
| title_full | A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes |
| title_fullStr | A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes |
| title_full_unstemmed | A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes |
| title_short | A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes |
| title_sort | mediation approach to discovering causal relationships between the metabolome and dna methylation in type 1 diabetes |
| topic | DNA methylation metabolomics type 1 diabetes |
| url | https://www.mdpi.com/2218-1989/11/8/542 |
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