Ying Yang1, Chang Zeng2,3, Xingyu Lu4, Yanqun Song4, Ji Nie5, Ruoxi Ran1, Zhou Zhang3, Chuan He6,7, Wei Zhang8, Song-Mei Liu9. 1. Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China. 2. Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL. 3. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. 4. Shanghai Epican Genetech Co. Ltd., Shanghai, China. 5. Department of Chemistry, The University of Chicago, Chicago, IL. 6. Department of Chemistry, The University of Chicago, Chicago, IL; chuanhe@uchicago.edu wei.zhang1@northwestern.edu smliu@whu.edu.cn. 7. Department of Biochemistry and Molecular Biology; Institute for Biophysical Dynamics; and The Howard Hughes Medical Institute, The University of Chicago, Chicago, IL. 8. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; chuanhe@uchicago.edu wei.zhang1@northwestern.edu smliu@whu.edu.cn. 9. Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China; chuanhe@uchicago.edu wei.zhang1@northwestern.edu smliu@whu.edu.cn.
Abstract
BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, noninvasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without [testing set: area under the curve (AUC) = 0.85; 95% CI, 0.73-0.96], outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84; 95% CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, noninvasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.
BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, noninvasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without [testing set: area under the curve (AUC) = 0.85; 95% CI, 0.73-0.96], outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84; 95% CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, noninvasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.
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