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ResearchIn-Press PreviewMetabolismNephrology Open Access | 10.1172/JCI160959

Reduced methylation corresponds with diabetic nephropathy risk in type 1 diabetes

Ishant Khurana,1 Harikrishnan Kaipananickal,1 Scott Maxwell,1 Sørine Birkelund,1 Anna Syreeni,2 Carol Forsblom,2 Jun Okabe,1 Mark Ziemann,3 Antony Kaspi,4 Haloom Rafehi,4 Anne Jørgensen,1 Keith Al-Hasani,1 Merlin C. Thomas,1 Guozhi Jiang,5 Andrea O.Y. Luk,5 Heung Man Lee,5 Yu Huang,6 Yotsapon Thewjitcharoen,7 Soontaree Nakasatien,7 Thep Himathongkam,7 Christopher Fogarty,2 Rachel Njeim,8 Assaad Eid,9 Tine Willum Hansen,10 Nete Tofte,10 Evy Connie Ottesen,10 Ronald C.W. Ma,5 Juliana C.N. Chan,11 Mark Emmanuel Cooper,1 Peter Rossing,10 Per-Henrik Groop,2 and Assam El-Osta12

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Khurana, I. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Kaipananickal, H. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Maxwell, S. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Birkelund, S. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Syreeni, A. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Forsblom, C. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Okabe, J. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Ziemann, M. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Kaspi, A. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Rafehi, H. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Jørgensen, A. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Al-Hasani, K. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Thomas, M. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Jiang, G. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Luk, A. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Lee, H. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Huang, Y. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Thewjitcharoen, Y. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Nakasatien, S. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Himathongkam, T. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Fogarty, C. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Njeim, R. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Eid, A. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Hansen, T. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Tofte, N. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Ottesen, E. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Ma, R. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Chan, J. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Cooper, M. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Rossing, P. in: JCI | PubMed | Google Scholar |

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

Find articles by Groop, P. in: JCI | PubMed | Google Scholar

1Department of Diabetes, Monash University, Melbourne, Australia

2Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

3School of Life and Environmental Sciences, Monash University, Melbourne, Australia

4Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

6School of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong

7Diabetes, Theptarin Hospital, Bangkok, Thailand

8Department of Anatomy, American University of Beirut, Beirut, Lebanon

9American University of Beirut, Beirut, Lebanon

10Complications Research, Steno Diabetes Center, Copenhagen, Denmark

11The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong

12Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, Australia

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Published January 12, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI160959.
Copyright © 2023, Khurana et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 12, 2023 - Version history
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Abstract

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome wide methylation patterns are poorly defined. While methylation is known to alter gene expression the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n=39) that was subsequently replicated in a larger validation cohort (n=296). Gene body related regions made up >60% of the methylation differences and emphasised the importance of methylation sequencing. We observe differentially methylated genes associated with DN (DDN) in three independent T1D registries originating from Denmark (n=445), Hong Kong (n=107) and Thailand (n=130). Reduced DNA methylation at CTCF and Pol2B sites were tightly connected with DN pathways that include insulin signalling, lipid metabolism and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubules. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding and the activation of insulin signalling phosphoproteins in hyperglycaemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophage and vascular endothelial cells.

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