TY - JOUR
T1 - Alterations of 5-hydroxymethylcytosines in circulating cell-free DNA reflect retinopathy in type 2 diabetes
AU - Han, Liyuan
AU - Chen, Chang
AU - Lu, Xingyu
AU - Song, Yanqun
AU - Zhang, Zhou
AU - Zeng, Chang
AU - Chiu, Rudyard
AU - Li, Li
AU - Xu, Miao
AU - He, Chuan
AU - Zhang, Wei
AU - Duan, Shiwei
N1 - Funding Information:
This study was supported by grants from the National Key R&D Program of China (2017YFC1310902, 2018YFC1315305), Ningbo Health Branding Subject Fund (PPXK2018-02), Natural Science Foundation of Zhejiang Province (LY17H260002), Sanming Project of Medicine in Shenzhen (SZSM201803080), and the K.C. Wong Magna Fund of Ningbo University. The raw and processed 5hmC-Seal data have been deposited into the NCBI Gene Expression Omnibus depository (GSE140842). The 5hmC-Seal technology was invented by CH and was licensed by Shanghai Epican Genetech Co. Ltd. for clinical applications in human diseases from the University of Chicago. XL and YS are employees and shareholders Shanghai Epican Genetech Co. Ltd. CH and WZ are shareholders of Shanghai Epican Genetech Co. Ltd. CH is a scientific founder of Accent Therapeutics, Inc. and a member of its scientific advisory board. All other authors reported no potential conflicts of interest.
Funding Information:
This study was supported by grants from the National Key R&D Program of China (2017YFC1310902, 2018YFC1315305), Ningbo Health Branding Subject Fund (PPXK2018-02), Natural Science Foundation of Zhejiang Province (LY17H260002), Sanming Project of Medicine in Shenzhen (SZSM201803080), and the K.C. Wong Magna Fund of Ningbo University .
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1
Y1 - 2021/1
N2 - Diabetic retinopathy (DR) is a common microvascular complication that may cause severe visual impairment and blindness in patients with type 2 diabetes mellitus (T2DM). Early detection of DR will expand the range of potential treatment options and enable better control of disease progression. Epigenetic dysregulation has been implicated in the pathogenesis of microvascular complications in patients with T2DM. We sought to explore the diagnostic value of 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA) for DR, taking advantage of a highly sensitive technique, the 5hmC-Seal. The genome-wide 5hmC profiles in cfDNA samples from 35 patients diagnosed with DR and 35 age-, gender-, diabetic duration-matched T2DM controls were obtained using the 5hmC-Seal, followed by a case-control analysis and external validation. The genomic distribution of 5hmC in cfDNA from patients with DR reflected potential gene regulatory relevance, showing co-localization with histone modification marks for active expression (e.g., H3K4me1). A three-gene signature (MESP1, LY6G6D, LINC01556) associated with DR was detected using the elastic net regularization on the multivariable logistic regression model, showing high accuracy to distinguish patients with DR from T2DM controls (AUC [area under curve] = 91.4%; 95% CI [confidence interval], 84.3– 98.5%), achieving a sensitivity of 88.6% and a specificity of 91.4%. In an external testing set, the 5hmC model detected 5 out of 6 DR patients and predicted 7 out of 8 non-DR patients with other microvascular complications. Circulating cfDNA from patients with DR contained 5hmC information that could be exploited for DR detection. As a novel non-invasive approach, the 5hmC-Seal holds the promise to be an integrated part of patient care and surveillance tool for T2DM patients.
AB - Diabetic retinopathy (DR) is a common microvascular complication that may cause severe visual impairment and blindness in patients with type 2 diabetes mellitus (T2DM). Early detection of DR will expand the range of potential treatment options and enable better control of disease progression. Epigenetic dysregulation has been implicated in the pathogenesis of microvascular complications in patients with T2DM. We sought to explore the diagnostic value of 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA) for DR, taking advantage of a highly sensitive technique, the 5hmC-Seal. The genome-wide 5hmC profiles in cfDNA samples from 35 patients diagnosed with DR and 35 age-, gender-, diabetic duration-matched T2DM controls were obtained using the 5hmC-Seal, followed by a case-control analysis and external validation. The genomic distribution of 5hmC in cfDNA from patients with DR reflected potential gene regulatory relevance, showing co-localization with histone modification marks for active expression (e.g., H3K4me1). A three-gene signature (MESP1, LY6G6D, LINC01556) associated with DR was detected using the elastic net regularization on the multivariable logistic regression model, showing high accuracy to distinguish patients with DR from T2DM controls (AUC [area under curve] = 91.4%; 95% CI [confidence interval], 84.3– 98.5%), achieving a sensitivity of 88.6% and a specificity of 91.4%. In an external testing set, the 5hmC model detected 5 out of 6 DR patients and predicted 7 out of 8 non-DR patients with other microvascular complications. Circulating cfDNA from patients with DR contained 5hmC information that could be exploited for DR detection. As a novel non-invasive approach, the 5hmC-Seal holds the promise to be an integrated part of patient care and surveillance tool for T2DM patients.
KW - 5-hydroxymethylcytosine
KW - Biomarker
KW - Diabetes
KW - Liquid biopsy
KW - Retinopathy
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U2 - 10.1016/j.ygeno.2020.11.014
DO - 10.1016/j.ygeno.2020.11.014
M3 - Article
C2 - 33221518
AN - SCOPUS:85097225872
VL - 113
SP - 79
EP - 87
JO - Genomics
JF - Genomics
SN - 0888-7543
IS - 1
ER -