Galactosyltransferase core-1 beta3-galactosyltransferase-1 (C1GALT1) and core 1 3-galactosyltransferase-specific molecular chaperone (COSMC) are required for the O-glycosylation of the IgA1 hinge region. IgA nephropathy (IgAN) patients have high serum levels of galactose-deficient immunoglobulin A1 (GdIgA1). We aimed to demonstrate that hypermethylation of the COSMC gene promoter region is associated with GdIgA1 levels in IgAN patients.
Thirty-nine IgAN patients, 11 relative healthy controls, and 20 normal controls were recruited. Peripheral B lymphocytes were treated with Interleukin- 4 (IL-4) or 5-Aza-2'-deoksisitidin (AZA), after which COSMC mRNA levels and the DNA methylation profile of the COSMC gene promoter region were measured by real-time RT-PCR. The GdIgA1 levels were measured using ELISA in cell culture supernatant and patient serum.
The levels of DNA methylation were positive correlated with the level of serum or supernatant Gd-IgA1in the IgAN patients (respectively: r=0.28, p=0.02, r=0.30, p=0.009). COSMC mRNA levels were found to be negatively correlated with serum GdIgA1 (r=-0.38, p=0.001). GdIgA1 levels were significantly higher in IgAN patients compared to healthy controls (serum: p<0.001, supernatant: p=0.004). Supernatant or serum GdIgA1 levels correlated with clinical parameters such as eGFR (r=-0.34, p=0.03; r=-0.32, p=0.05, respectively) and serum Creatinine (respectively; r=0.44, p=0.005; r=0.39, p=0,01), but not with proteinuria and the MEST-C scores.
High levels of GdIgA1 have a high positive predictive value for diagnostic purposes; however, it is not informative about disease progression or severity. The epigenetic silencing of the COSMC gene by hypermethylation of its promoter can be one of the mechanisms responsible for high GdIgA1 levels in IgAN patients.