The current study was conducted to elucidate the effect of genetic variations in 
one-carbon metabolism on the epigenetic regulation of major histocompatibility 
complex II transactivator (MHC2TA), reduced folate carrier 1 (RFC1/SLC19A1) and 
human leukocyte antigen (HLA)-DR in systemic lupus erythematosus (SLE). 
PCR-RFLP/AFLP, bisulfite-sequencing and real-time PCR approaches were used for 
genetic, epigenetic and expression analysis respectively. SLE cases exhibited 
elevated plasma homocysteine levels compared to healthy controls (24.93 ± 1.3 
vs. 11.67 ± 0.48 μmol/l), while plasma folate levels showed no association (7.10 
± 2.49 vs. 7.64 ± 2.09 ng/ml). The RFC1 80G>A polymorphism showed 1.32-fold risk 
(95% CI: 1.02-1.72) for SLE, while glutamate carboxypeptidase II (GCPII) 1561C>T 
showed reduced risk (OR: 0.47, 95% CI: 0.24-0.90). The expression of RFC1 (0.37 
± 0.09 vs. 0.60 ± 0.17) and HLA-DR (0.68 ± 0.17 vs. 0.98 ± 0.02) was down 
regulated in the SLE cases. The hypermethylation of RFC1 as observed in the 
current study may contribute for its down regulation. Plasma folate and 
thymidylate synthase (TYMS) 5'-UTR 28 bp tandem repeat showed an inverse 
association with methylation of RFC1 and MHC2TA. SLE cases with 
hypocomplementemia showed hypermethylation of RFC1, hypomethylation/up 
regulation of MHC2TA and down regulation of HLA-DR. The hypermethylation of 
MHC2TA and down regulation of RFC1, MHC2TA and HLA-DR were observed in 
anti-cardiolipin antibody positive SLE cases. The up regulation of RFC1 and 
HLA-DR was observed in anti-dsDNA antibody positive SLE cases. The 
hypomethylation/upregulation of RFC1 and MHC2TA was observed in anti-RNP 
antibody positive cases. To conclude, one-carbon genetic variants influence 
epigenetic of MHC2TA and RFC1, thus contributing to phenotypic heterogeneity of 
SLE.