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Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes
Ishant Khurana, … , Per-Henrik Groop, Assam El-Osta
Ishant Khurana, … , Per-Henrik Groop, Assam El-Osta
Published January 12, 2023
Citation Information: J Clin Invest. 2023;133(4):e160959. https://doi.org/10.1172/JCI160959.
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Research Article Metabolism Nephrology Article has an altmetric score of 68

Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes

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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 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.

Authors

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

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Figure 6

Prospective data analysis of FinnDiane replication and PROFIL validation cohorts.

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Prospective data analysis of FinnDiane replication and PROFIL validation...
(A) Schema of prospective data analysis in FinnDiane and PROFIL cohorts — data were obtained prospectively to evaluate disease progression by also including follow-up eGFR from 527 individuals with T1D. (B) Reduced DNA methylation is a feature of albuminuria progression. DNA methylation analysis of genes associated with the DDNs, including MTOR, RPTOR, IRS2, COL1A2, TXNRD1, LCAT, and SMPD3. Samples from these T1D cohorts were classified as nonprogressors and progressors based on change in albuminuria stages (Normo to Micro; Micro to Macro; Macro to ESRD). Changes in DNA methylation for the different groups are presented as bar graphs (combined core genes for each sample in different groups). Error bars represent SEM, and the statistical significance was calculated by comparing nonprogressors and progressors using the Mann-Whitney U test. (C) Reduced DNA methylation is a feature of eGFR decline. DNA methylation analysis of the core genes in the FinnDiane and PROFIL cohorts based on eGFR decline in slope. eGFR decline is defined as the calculated estimated glomerular filtration slope by comparing the difference in the first (with matching DNA methylation readout) and last eGFR measurements as an index of follow-up time in years. No decline is defined as an eGFR slope of –1 mL/min/1.73 m2 or greater. Slow decline is defined by an eGFR slope of greater than –3 and less than –1 mL/min/1.73 m2. Steep decline is defined by an eGFR slope of less than –3 mL/min/1.73 m2. Error bars represent SEM and the significance was calculated by comparing no decline with slow and steep decline groups using the Mann-Whitney U test. Reduced DNA methylation associates with steep eGFR decline (P = 0.006). (D) DNA methylation index improves prediction of eGFR decline. ROC plot shows the AUC score for combined clinical factors (DM duration, HbA1c, UACR, smoking, and systolic blood pressure) 0.65, P = 4.08 × 10–7 (green). The inclusion of DNA methylation index improves the AUC score of combined clinical factors from 0.65 to 0.75 (P = 7.75 × 10–7) in predicting eGFR decline in the FinnDiane and PROFIL cohorts (Δ AUC 0.10; P = 0.008). The model for (A) combined core gene methylation and (B) clinical factors reports the combined result of gene methylation with individual covariates and shown in Table 1. P values were processed using bootstrap in R.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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