Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes-Reference-Cited by-同舟云学术

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes

Published:2024-05-22 Issue:748 Volume:16 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Chen Zhuo¹^ORCID,Satake Eiichiro²³^ORCID,Pezzolesi Marcus G.⁴,Md Dom Zaipul I.²³^ORCID,Stucki Devorah⁴,Kobayashi Hiroki²³⁵^ORCID,Syreeni Anna⁶⁷⁸^ORCID,Johnson Adam T.⁴^ORCID,Wu Xiwei⁹¹⁰^ORCID,Dahlström Emma H.⁶⁷⁸,King Jaxon B.⁴^ORCID,Groop Per-Henrik⁶⁷⁸¹¹^ORCID,Rich Stephen S.¹²^ORCID,Sandholm Niina⁶⁷⁸^ORCID,Krolewski Andrzej S.²³^ORCID,Natarajan Rama¹^ORCID

Affiliation:

1. Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

2. Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.

3. Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.

4. Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

5. Division of Nephrology, Hypertension, and Endocrinology, Nihon University School of Medicine, Tokyo, Japan.

6. Folkhälsan Research Center, Helsinki, 00290, Finland.

7. Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland.

8. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland.

9. Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

10. Integrative Genomics Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

11. Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.

12. Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.

Abstract

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5′-cytosine-phosphate-guanine-3′ loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10 −14 . In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.adj3385

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