Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes
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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 more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, 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 tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.
Originalsprog | Engelsk |
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Artikelnummer | e160959 |
Tidsskrift | Journal of Clinical Investigation |
Vol/bind | 133 |
Udgave nummer | 4 |
ISSN | 0021-9738 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We dedicate this article in memoriam to our friend and colleague, Dr. Carol Forsblom. AEO is a National Health and Medical Research Council (NHMRC) Senior Research Fellow (grant 1154650) and acknowledges grant support from NHMRC Clinical Trials and Cohort Studies (grant 2014763). MEC is an NHM-RC level 3 Investigator (grant 1175760). The authors acknowledge support from the National Natural Science Foundation of China–NHMRC Joint Research Scheme (grant 81561128017), NHMRC project grants (1113188 and 1082572), the Juvenile Diabetes Research Foundation (JDRF 5-2009-467), the Centre of Research Excellence (CRE 1078609) of the JDRF/NHMRC, Diabetes Australia, Research Trust (DART Millennium Award), and the Hong Kong Research Grants Council Research Impact Fund (R4012-18) and Senior Research Fellowship (SRFS2021-4S04). PR acknowledges funding for PROFIL from SYSKID, an EU FP7 research project (SysKid HEALTH-F2-2009-241544), and Novo Nordisk Foundation grants NNF14OC0013659 PROTON - PeRsOnalising Treatment Of Diabetic Nephropathy and NNF19OC0058900 PRIMETIME. This work was also supported by a research grant from the Danish Diabetes Academy to AEO, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406.
Publisher Copyright:
Copyright: © 2023, Khurana et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
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