Osteoprotegerin and MTHFR gene variations in rheumatoid arthritis: association with disease susceptibility and markers of subclinical atherosclerosis

Abstract

We aimed to explore whether the rs2073618 variant (G1181C) of the osteoprotegerin (OPG) gene and the methylenetetrahydrofolate reductase (MTHFR) rs1801131 (A1298AC) and rs1801133 (C677T) gene polymorphisms contribute to rheumatoid arthritis (RA) susceptibility and RA related subclinical atherosclerosis. Overall 283 RA patients and 595 healthy controls (HC) were genotyped for common variants of the OPG and MTHFR genes using PCR based assays. Clinical and laboratory parameters were recorded following thorough chart review. Surrogate markers of subclinical atherosclerosis (Carotid/Femoral intima media thickness/plaque formation) along with traditional risk factors for atherosclerosis were assessed in all RA patients and 280HC. Increased prevalence of the CC genotype of the rs2073618 variant was detected in RA patients vs HC (42.4% vs. 33%, p-value: 0.04). RA patients with high serum titers of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) antibodies displayed increased prevalence of the CC genotype of the rs2073618 variant of the OPG gene compared to HC (48.6% and 47.5 vs 33.3%, p-values: 0.0029and 0.0077 respectively). Of interest, this genotype turned to be associated with higher carotid IMT scores (0.872 ± 0.264 vs 0.816 ± 0.284, p-value: 0.01) and marginally with higher rates of carotid plaque formation (66% vs 54.1%, p = 0.06). The MTHFR 1298CC genotype was more prevalent only in the anti-CCP positive group compared to HC, with no associations detected with markers of subclinical atherosclerosis, following adjustment for traditional cardiovascular (CVD) risk factors. Reduced rates of carotid/femoral plaque formation were detected among RA patients harboring the MTHFR TT genotype (52.4 vs 72.7, p-value: 0.009, respectively). This association remained significant following adjustment for classical CVD risk factors (OR [95% CI 0.364 [0.173–0.765], p-value: 0.008). Genetic variations of the osteoprotegerin and MTHFR genes seem to increase susceptibility for seropositive RA and potentially contribute to subclinical atherosclerosis linked to RA. Larger studies are needed to confirm these findings.

Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase

“…MTHFR dysfunction has been implicated in human diseased states 18 , 19 ranging from cancers 20 to psychiatric illnesses 21 . As such, providing a structural blueprint by which patient mutations in MTHFR can be understood has important implications for human health, and would allow for targeted drug discovery and therapy development.…”

Pharmacogenetic Sex-Specific Effects of Methotrexate Response in Patients with Rheumatoid Arthritis

“…For example, the interaction between MTX and the MTHFR (5,10-methylenetetrahydrofolate reductase) gene within the folate pathway is unclear. MTHFR is one of the most studied genes in this context, but its relationship with treatment response or toxicity is still not clear [ 7 , 13 , 14 , 15 ]. Other well-studied genes involved in the MTX pathways, such as those belonging to the ABC (multi-drug resistance protein) family pumps, RFC1 (replication factor C subunit 1), ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase), FPGS (folylpolyglutamate synthase), GGH (gamma-glutamyl hydrolase), and TYMS (thymidylate synthetase), have also shown conflicting results [ 6 , 7 , 16 ].…”

5-Formyltetrahydrofolate promotes conformational remodeling in a methylenetetrahydrofolate reductase active site and inhibits its activity

“…One carbon metabolism is a universal process that underpins most of life’s biochemistry and is central to essential and diverse cellular roles including the biosynthesis of the building blocks of life such as DNA, the generation and catabolism of amino acids, and has a master regulatory role via epigenetic modifications such as nucleic acid methylation. Indeed, there has been a rash of interest in enzymes critical to one carbon metabolism, given that their disfunction has been implicated in diseased states ( 1 , 2 ) ranging from cancers ( 3 ) to psychiatric illnesses ( 4 ). In humans, the folate and methionine cycles are (the) two key pathways in one carbon metabolism; here, one enzyme, methylenetetrahydrofolate reductase (MTHFR), bridges each cycle, allowing one-carbon units (such as methyl-, methylene-, and formyl-groups) carried by folate to be utilized to synthesize central to life metabolic feedstock compounds such as purine bases, thymidylate, and methionine.…”