Chen Xi Yang1, Emma Schon2, Ma'en Obeidat1,3, Michael S Kobor4, Lisa McEwen4, Julie MacIsaac4, David Lin4, Richard M Novak5, Fleur Hudson6, Hartwig Klinker7, Nila Dharan8, Steve Horvath9, Jean Bourbeau10, Wan Tan1,3, Don D Sin1,3, S F Paul Man1,3, Ken Kunisaki11,12, Janice M Leung1,3. 1. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada. 2. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 3. Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 4. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada. 5. Section of Infectious Diseases, University of Illinois at Chicago, Chicago, Illinois, USA. 6. MRC Clinical Trials Unit, University College London, London, United Kingdom. 7. University of Würzburg Medical Center, Department of Internal Medicine II, Division of Infectious Diseases, Würzburg, Germany. 8. Kirby Institute, Sydney, Australia. 9. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. 10. Respiratory Epidemiology and Clinical Research Unit, McGill University, Montreal, Quebec, Canada. 11. Minneapolis Veterans Affairs Health Care System, Section of Pulmonary, Critical Care and Sleep Medicine, Minneapolis, Minnesota, USA. 12. Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Abstract
BACKGROUND: Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART). METHODS: A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. RESULTS: There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration. CONCLUSIONS: PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.
BACKGROUND: Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART). METHODS: A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. RESULTS: There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration. CONCLUSIONS: PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.
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