DNA Methylation of TXNIP Independently Associated with Inflammation and Diabetes Mellitus in Twins

Abstract

AbstractThioredoxin-interacting protein (TXNIP) plays a key role in diabetes development and prognosis through its role in pancreatic β-cell dysfunction and death as well as in upregulating the inflammatory response in hyperglycemia. DNA methylation (DNAm) of TXNIP (TXNIP-cg19693031) is associated with the prevalence and incidence of type 2 diabetes (T2D); however, its role in inflammation and its relationship with T2D remain unclear. We aimed to investigate the epigenetic associations of TXNIP-cg19693031 with a panel of inflammatory biomarkers and to examine whether these inflammatory biomarkers modify the association between TXNIP-cg19693031 methylation and diabetes in 218 middle-aged male twins from the Emory Twin Study. We confirmed the association of TXNIP-cg19693031 DNAm with T2D, as well as with HbA1c, insulin and fasting glucose. We found that hypomethylation at TXNIP-cg19693031 is strongly associated with both type 2 diabetes and higher levels of inflammatory biomarkers (VCAM-1, ICAM-1, MMP-2, sRAGE and P-selectin); however, the relationship between TXNIP-cg19693031 and T2D is independent of the levels of these inflammatory biomarkers. Our results suggest that DNA methylation of TXNIP is linked with multiple biological processes, through which the TXNIP may have broad influence on chronic disease risk.