Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease

Laura J Smyth; Emma H Dahlström; Anna Syreeni; Katie Kerr; Jill Kilner; Ross Doyle; Eoin Brennan; Viji Nair; Damian Fermin; Robert G Nelson; Helen C Looker; Christopher Wooster; Darrell Andrews; Kerry Anderson; Gareth J McKay; Joanne B Cole; Rany M Salem; Peter J Conlon; Matthias Kretzler; Joel N Hirschhorn; Denise Sadlier; Catherine Godson; Jose C Florez; GENIE consortium; Carol Forsblom; Alexander P Maxwell; Per-Henrik Groop; Niina Sandholm; Amy Jayne McKnight

doi:10.1038/s41467-022-34963-6

Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease

Nat Commun. 2022 Dec 22;13(1):7891. doi: 10.1038/s41467-022-34963-6.

Authors

Laura J Smyth^#¹, Emma H Dahlström^#^{2

3

4}, Anna Syreeni^{2

3

4}, Katie Kerr¹, Jill Kilner¹, Ross Doyle⁵, Eoin Brennan⁵, Viji Nair⁶, Damian Fermin⁷, Robert G Nelson⁸, Helen C Looker⁸, Christopher Wooster¹, Darrell Andrews⁵, Kerry Anderson¹, Gareth J McKay¹, Joanne B Cole^{9

10}, Rany M Salem¹¹, Peter J Conlon¹², Matthias Kretzler¹³, Joel N Hirschhorn^{9

14

15}, Denise Sadlier¹⁶, Catherine Godson⁵, Jose C Florez^{9

10

17}; GENIE consortium; Carol Forsblom^{2

3

4}, Alexander P Maxwell^{1

18}, Per-Henrik Groop^{2

3

4

19}, Niina Sandholm^{20

21

22}, Amy Jayne McKnight²³

Affiliations

¹ Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK.
² Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
³ Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁴ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland.
⁵ Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.
⁶ Department of Medicine-Nephrology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
⁷ Department of Pediatrics-Nephrology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
⁸ Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA.
⁹ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
¹⁰ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
¹² Department of Nephrology and Transplantation, Beaumont Hospital and Department of Medicine Royal College of Surgeons in Ireland, Dublin 9, Ireland.
¹³ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
¹⁴ Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
¹⁵ Department of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.
¹⁶ Mater Misericordiae Hospital, D07 K201, Dublin, Ireland.
¹⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁸ Regional Nephrology Unit, Belfast City Hospital, Belfast, Northern Ireland, UK.
¹⁹ Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
²⁰ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland. [email protected].
²¹ Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. [email protected].
²² Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland. [email protected].
²³ Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK. [email protected].

^# Contributed equally.

Abstract

Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
CpG Islands
DNA
DNA Methylation / genetics
Diabetes Mellitus, Type 1* / complications
Diabetes Mellitus, Type 1* / genetics
Diabetic Nephropathies* / genetics
Epigenesis, Genetic
Epigenome
Genome-Wide Association Study
Humans

Substances

Biomarkers
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding