title: Epigenetic modulation of RFC1, MHC2TA and HLA-DR in systemic lupus erythematosus: association with serological markers and six functional polymorphisms of one-carbon metabolic pathway.
abstract: 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.
authors: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Hyderabad 500082, India.
authors: Yedluri
authors: Y
authors: Rupasree
authors: School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India.
authors: Shaik Mohammad
authors: SM
authors: Naushad
authors: Department of Rheumatology, Nizam's Institute of Medical Sciences (NIMS), Hyderabad 500082, India.
authors: Liza
authors: L
authors: Rajasekhar
authors: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Hyderabad 500082, India. Electronic address: vijaykutala@gmail.com.
authors: Vijay Kumar
authors: VK
authors: Kutala
mesh_terms: D015415:Biomarkers / Q000097:blood; D002244:Carbon / Q000378:metabolism; D016022:Case-Control Studies; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D056726:Genetic Association Studies; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D051818:Replication Protein C / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D015415:Biomarkers; D006684:HLA-DR Antigens; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C081632:RFC1 protein, human; D015534:Trans-Activators; D002244:Carbon; D051818:Replication Protein C
keywords: CI; DNA methylation; GCPII; HLA; HWE; Hardy–Weinberg equilibrium; MHC class II transactivator; MHC2TA; MTHFR; MTR; OR; One-carbon metabolism; RFC1; Reduced folate carrier 1; SLE; Systemic lupus erythematosus; TYMS; confidence interval; glutamate carboxypeptidase II; human leukocyte antigen; major histocompatibility complex II transactivator; methionine synthase; methylene tetrahydrofolate reductase; odds ratio; reduced folate carrier 1; systemic lupus erythematosus; thymidylate synthase