@article{10.1172/jci.insight.136579, author = {Daniel Neiman AND David Gillis AND Sheina Piyanzin AND Daniel Cohen AND Ori Fridlich AND Joshua Moss AND Aviad Zick AND Tal Oron AND Frida Sundberg AND Gun Forsander AND Oskar Skog AND Olle Korsgren AND Floris Levy-Khademi AND Dan Arbel AND Saar Hashavya AND A.M. James Shapiro AND Cate Speake AND Carla Greenbaum AND Jennifer Hosford AND Amanda Posgai AND Mark A. Atkinson AND Benjamin Glaser AND Desmond A. Schatz AND Ruth Shemer AND Yuval Dor}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Multiplexing DNA methylation markers to detect circulating cell-free DNA derived from human pancreatic β cells}, year = {2020}, month = {7}, volume = {5}, url = {https://insight.jci.org/articles/view/136579}, abstract = {It has been proposed that unmethylated insulin promoter fragments in plasma derive exclusively from β cells, reflect their recent demise, and can be used to assess β cell damage in type 1 diabetes. Herein we describe an ultrasensitive assay for detection of a β cell–specific DNA methylation signature, by simultaneous assessment of 6 DNA methylation markers, that identifies β cell DNA in mixtures containing as little as 0.03% β cell DNA (less than 1 β cell genome equivalent). Based on this assay, plasma from nondiabetic individuals (N = 218, aged 4–78 years) contained on average only 1 β cell genome equivalent/mL. As expected, cell-free DNA (cfDNA) from β cells was significantly elevated in islet transplant recipients shortly after transplantation. We also detected β cell cfDNA in a patient with KATP congenital hyperinsulinism, in which substantial β cell turnover is thought to occur. Strikingly, in contrast to previous reports, we observed no elevation of β cell–derived cfDNA in autoantibody-positive subjects at risk for type 1 diabetes (N = 32), individuals with recent-onset type 1 diabetes (<4 months, N = 92), or those with long-standing disease (>4 months, N = 38). We discuss the utility of sensitive β cell cfDNA analysis and potential explanations for the lack of a β cell cfDNA signal in type 1 diabetes.}, number = {14}, doi = {10.1172/jci.insight.136579}, url = {https://doi.org/10.1172/jci.insight.136579}, }