Association of hyperhomocysteinemia with genetic variants in key enzymes of homocysteine metabolism and methotrexate toxicity in rheumatoid arthritis patients

Chaabane, Souhir; Messedi, Meriam; Akrout, R.; Hamad, Mariem Ben; Turki, Mouna; Marzouk, S.; Keskes, Leila; Bahloul, Z.; Rebai, Ahmed; Ayedi, Fatma; Maalej, Aref

doi:10.1007/s00011-018-1161-8

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…The difference between ACCP groups and MTX level status was statistically significant, similarly, same difference was noted between groups of ACCP, CRP, and of Hcys, and MTX level status (P <0.05). Similar to our study, Chaabane et al, observed the significant association between MTX toxicity and elevated level of Hcys in RA patients p <0.05 [42]. Lima et al, showed that positive ACPA could use as potential predictive factor for not-responding to MTX drug [16].…”

Section: Relation Between Mtx and Biochemical Characteristicssupporting

confidence: 91%

MTHFR Gene Polymorphisms in Iraqi Kurdish Rheumatoid Arthritis Patients: Relation to Methotrexate Response and Toxicity

Younis

Issa²,

Sulaiman³

2022

Iraqi Journal of Science

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Methotrexate (MTX) is still one of the gold standard treatments for rheumatoid arthritis (RA). It shows diverse outcomes in blood level and clinical response, this was demonstrated by its relation to the genetic polymorphism in the pharmacogenetic study. This study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in relation to MTX efficacy and toxicity in Iraqi Kurdish RA patients. Sixty-four RA patients were involved in this study with an average age of 47.78 ±14.08 and female to male ratio of (8.1). Diagnosis and disease activity were confirmed. Blood analyses, including those of laboratory markers of disease activity, were done. The 28 joint disease activity score (DAS28-CRP) was calculated. MTHFR gene polymorphisms were analyzed by real-time polymerase chain reaction. The most frequent genotypes which were identified in RA patients were the CT genotype of the C677T single nucleotide polymorphism (SNP) (51.6%) and the AC genotype of the A1298C SNP (48.4%). Patients with non-response to treatment had high frequencies of genotypes CT and TT (58.0% and 12.0%) of the C677T SNP respectively, as compared to those in the responder group; 28.6% and 0.0%); T-allele was associated with drug non-responding OR=4.17, P value=.0.009, meanwhile; genotypes AC and CC of the A1298C SNP were seen in (54.0% and 16.0%) in non-responder group. Patients with active RA had increased frequencies of CT and TT genotypes of the C677T SNP (60.0% and16.0%) respectively as compared to those who were in remission (26.6% and 0.0%); T-allele was associated with high disease activity; OR = 5.11. No association was found between C677T SNP and A1298C SNP, and MTX level status (P> 0.05). However, the variant alleles (T and C) were associated with the MTX toxic level (OR: 2.05, 95% CI [0.97 – 4.32]) and (OR: 1.99, 95% CI [0.96 – 4.18]) respectively. This study suggests that genetic polymorphisms of MTHFR SNP (C677T and A1298C) are associated with MTX efficacy but not toxicity in RA patients. This may assist the physicians in personalizing RA treatment in Iraqi patients.

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Section: Relation Between Mtx and Biochemical Characteristicssupporting

confidence: 91%

MTHFR Gene Polymorphisms in Iraqi Kurdish Rheumatoid Arthritis Patients: Relation to Methotrexate Response and Toxicity

Younis

Issa²,

Sulaiman³

2022

Iraqi Journal of Science

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“…Methylenetetrahydrofolate reductase (MTHFR) is also a key enzyme in the de novo synthesis pathway ( Song et al, 2014 ). TYMS competes with MTHFR for one of its substrates: 5,10-MTHF ( Chaabane et al, 2018 ). MTXPGs can inhibit aminoimidazole carboxamide ribonucleotide transformylase (ATIC), causing the intracellular accumulation of aminoimidazole carboxamide ribonucleotide, which in turn inhibits adenosine-metabolizing enzymes.…”

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms of TYMS, MTHFR, ATIC, MTR, and MTRR Are Related to the Outcome of Methotrexate Therapy for Rheumatoid Arthritis in a Chinese Population

Liu

Fan²,

et al. 2018

Front. Pharmacol.

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Objective: Analysis of the relationship between single nucleotide polymorphisms (SNPs) and outcomes of methotrexate (MTX) therapy for rheumatoid arthritis (RA) in China.Materials and Methods: TYMS 28 bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) enzyme proteins may be related to the outcomes of MTX therapy, according to our previous meta-analysis. A total of 162 patients with RA were included in our study. SNPs were evaluated using polymerase chain reaction (PCR). Disease Activity Score 28 (DAS28) was used to evaluate the clinical response, and adverse drug reactions (ADRs) were collected after physical examinations of the patients.Results: The MTHFR 677C>T gene showed a relationship with the ADRs of MTX in the Recessive model [TT vs. (CC+CT)] (p = 0.04, OR = 2.20, 95% CI: 1.01, 4.77). In the Codominant model [CT vs. (CC+TT)], the MTHFR 677C>T gene also showed a trend of association with ADRs (p = 0.08, OR = 0.52, 95% CI: 0.25, 1.08). No significant difference was found between TYMS, MTHFR, ATIC, MTR, and MTRR gene polymorphisms and the RA response or ADRs related to MTX in our study.Conclusion: Our results showed that the MTHFR [677C>T (rs1801133)] TT genotype is associated with ADRs to MTX in Chinese RA patients. Other SNPs, including TYMS 28bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) gene polymorphisms, were not associated with MTX treatment outcomes. Further studies are required to validate these findings.

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“…According to Koh et al [58], a dose of both 5 and 30 mg of FA, within a week has the same protective effect against the occurrence of toxic symptoms caused by methotrexate therapy. A high level of HCY in the blood may, according to the opinion of Chaabane et al [59], be a useful marker of the toxic effects of this drug.…”

Section: Methotrexate and Folic Acidmentioning

confidence: 97%

The importance of homocysteine in the development of cardiovascular complications in patients with rheumatoid arthritis

et al. 2020

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Rheumatoid arthritis (RA) not only leads to disability due to joint changes, but also significantly shortens the life expectancy of patients, mainly due to more frequent occurrence of heart attacks and strokes. Accelerated atherosclerosis in these patients is caused, among other factors, by high homocysteine (HCY) concentration in blood. Numerous studies have shown that treatment with vitamin B significantly reduces the concentration of HCY in blood, but does not reduce the risk of heart diseases. Recent studies have shown, however, that folic acid (FA) administration reduces the risk of stroke by 10–20%. Due to the fact that in patients with RA strokes are more frequent than in the general population and hyperhomocysteinemia (HHCY) is often found, determination of HCY concentration in blood is advisable, and in persons with HHCY it is recommended to use FA in primary and secondary stroke prevention.

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Association of hyperhomocysteinemia with genetic variants in key enzymes of homocysteine metabolism and methotrexate toxicity in rheumatoid arthritis patients

Abstract: The MTHFR 677TT genotype is an independent risk factor for HHC in Tunisians RA patients. HHC could be a useful marker of MTX toxicity in RA patients.

Cited by 11 publications

References 36 publications

MTHFR Gene Polymorphisms in Iraqi Kurdish Rheumatoid Arthritis Patients: Relation to Methotrexate Response and Toxicity

MTHFR Gene Polymorphisms in Iraqi Kurdish Rheumatoid Arthritis Patients: Relation to Methotrexate Response and Toxicity

Genetic Polymorphisms of TYMS, MTHFR, ATIC, MTR, and MTRR Are Related to the Outcome of Methotrexate Therapy for Rheumatoid Arthritis in a Chinese Population

The importance of homocysteine in the development of cardiovascular complications in patients with rheumatoid arthritis

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