Lung Allograft Epithelium DNA Methylation Age Is Associated With Graft Chronologic Age and Primary Graft Dysfunction

作者：Daniel T. Dugger, Daniel R. Calabrese, Ying Gao, Fred Deiter, Tasha Tsao, J. Maheshwari, Steven R. Hays, Lorriana E. Leard, Mary Ellen Kleinhenz, Rupal Shah, Jeffrey A. Golden, Jasleen Kukreja, Erin Gordon, Jonathan P. Singer, John R. Greenland · 发表于：Frontiers in Immunology · 年份：2021 · DOI：10.3389/fimmu.2021.704172 · 被引用次数：21 · 研究领域：Epigenetics and DNA Methylation、Transplantation: Methods and Outcomes、Neonatal Respiratory Health Research

Advanced donor age is a risk factor for poor survival following lung transplantation. However, recent work identifying epigenetic determinants of aging has shown that biologic age may not always reflect chronologic age and that stressors can accelerate biologic aging. We hypothesized that lung allografts that experienced primary graft dysfunction (PGD), characterized by poor oxygenation in the first three post-transplant days, would have increased biologic age. We cultured airway epithelial cells isolated by transbronchial brush at 1-year bronchoscopies from 13 subjects with severe PGD and 15 controls matched on age and transplant indication. We measured epigenetic age using the Horvath epigenetic clock. Linear models were used to determine the association of airway epigenetic age with chronologic ages and PGD status, adjusted for recipient PGD risk factors. Survival models assessed the association with chronic lung allograft dysfunction (CLAD) or death. Distributions of promoter methylation within pathways were compared between groups. DNA methyltransferase (DNMT) activity was quantified in airway epithelial cells under hypoxic or normoxic conditions. Airway epigenetic age appeared younger but was strongly associated with the age of the allograft (slope 0.38 per year, 95% CI 0.27-0.48). There was no correlation between epigenetic age and recipient age (P = 0.96). Epigenetic age was 6.5 years greater (95% CI 1.7-11.2) in subjects who had experienced PGD, and this effect remai...