GLO1 cg26053840 Methylation Associates with Kidney Injury and Inflammatory Markers in Hospitalized Older Adults.

Abstract

The glyoxalase pathway detoxifies reactive dicarbonyls generated during hyperglycemia, but the role of its epigenetic regulation in renal dysfunction and inflammatory dysregulation in older adults remains unclear. We investigated CpG-specific DNA methylation within the glyoxal detoxification pathway, focusing on the GLO1 gene, and examined associations with glycemic status, renal function, and systemic inflammation in hospitalized older adults. We identified a single CpG site within the GLO1 gene (cg26053840) significantly associated with fasting glycemia, suggesting that methylation levels at this locus reflects metabolic stress. Higher methylation at cg26053840 was also associated with impaired renal function, including increased serum creatinine and reduced estimated glomerular filtration rate. Additionally, GLO1 methylation correlated with multiple inflammatory indices, including C-reactive protein, erythrocyte sedimentation rate, neutrophil-to-lymphocyte ratio, and the CRP-to-albumin ratio. Associations with circulating cytokines and immune activation markers such as IL-6, IL-17A, GDF-15, CXCL9, CD163, and soluble RAGE further indicated broader immune-metabolic dysregulation. In silico analyses revealed a significant inverse correlation between cg26053840 methylation and GLO1 mRNA expression in the Broad Institute GDAC Firehose dataset. Genomic annotation further identified putative CEBPD and MYF6 transcription factor binding sites in proximity to the CpG site, suggesting a potential regulatory context. These findings support a model in which glycemic dysregulation increases methylglyoxal production, while reduced renal clearance enhances dicarbonyl stress, potentially driving epigenetic modulation of GLO1. These findings suggest the presence of a metabolic-epigenetic-inflammatory axis, although longitudinal and mechanistic studies are required to determine whether it contributes to organ dysfunction and vulnerability in hospitalized older adults.