You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients.
Abstract 1:
OBJECTIVE To study the possible relationship between the C677 T mutation in the methylenetetrahydrofolate reductase ( MTHFR ) gene and the toxicity and efficacy of treatment with  methotrexate ( MTX ) in patients with rheumatoid arthritis ( RA ) . METHODS Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with ( n = 157 ) or without ( n = 79 ) folic or folinic acid supplementation .  Outcomes were parameters of efficacy of MTX treatment , patient withdrawal due to adverse events , discontinuation of MTX treatment because of elevated liver enzyme levels , and the total occurrence of elevated liver enzyme levels during the study . Multivariate logistic regression analysis was used to study the relationship between the presence of the MTHFR C677 T mutation and toxicity outcomes of MTX treatment . RESULTS Forty-eight percent of the patients showed the homozygous ( T/T ) or heterozygous ( T/C ) mutation . The presence of the C677CT or C677TT genotypes was associated with an increased risk of discontinuing MTX treatment because of adverse events ( relative risk 2.01 ; 95 % confidence interval 1.09 , 3.70 ) , mainly due to an increased risk of elevated liver enzyme levels ( relative risk 2.38 ; 95 % confidence interval 1.06 , 5.34 ) . Efficacy parameters were not significantly different between the patients with and those without the mutation . CONCLUSION The C677 T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patients with RA . We postulate that the incidence of clinical ly important elevation of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism . Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation


Title 2:
Impact of Thrombophilic Gene Mutations and Graft-versus-Host Disease on Thromboembolic Complications after Allogeneic Hematopoietic Stem-Cell Transplantation
Abstract 2:
Background . Hemostatic events in patients undergoing allogeneic hematopoietic stem-cell transplantation ( HSCT )  increase the morbidity and mortality in this cohort . Little is known about the impact of graft-versus-host disease ( GvHD ) or of thrombophilic gene mutations/polymorphisms on these complications . Study Design . Eighty-nine allogeneic stem-cell recipients and their donors were evaluated prospect ively for the presence of the factor V G1691A mutation , the prothrombin G20210A mutation , the 5,10-methylenetetrahydrofolate-reductase ( MTHFR ) C677 T mutation , the glycoprotein IIIa PIa1/a2 polymorphism , the fibrinogen-β-chain 455G/A polymorphism , the plasminogen activator inhibitor-1 −675 4G/5 G polymorphism , and the angiotensin-converting enzyme intron 16 I/D polymorphism . These mutations/polymorphisms and GvHD parameters were correlated to hemostatic and toxic complications after transplantation . The data were compared with those of 128 healthy controls . Results . The PAI-1 4G/4 G polymorphism increases the risk for catheter thrombosis after HSCT 5.7-fold ( 32.2 % vs. 71.4 % , P<0.05 ) . In patients with hepatic veno-occlusive disease , the frequency of the PAI-1 4 G allele is also increased ( 83.3 % vs. 55.1 % , NS ) . Thrombophilic mutations/polymorphisms in donors do not influence complications in the corresponding recipients . The MTHFR TT genotype does not modify severity and duration of mucositis and aplasia in patients receiving methotrexate prophylaxis . Patients with chronic GvHD have a higher risk of thromboembolism ( 12.9 % vs. 1.7 % , P<0.05 ) . Conclusion . Thrombophilic gene mutations have only a moderate influence on hemostatic complications in patients undergoing HSCT . This may be because of the overwhelming immunologic impact of GvHD on hemostasis in the allogeneic transplantation setting


Title 3:
Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis.
Abstract 3:
BACKGROUND The anti-folate drug methotrexate ( MTX ) is commonly used to treat rheumatoid arthritis . OBJECTIVE To determine the allele frequencies of five common coding single-nucleotide polymorphisms ( SNPs ) in the methylenetetrahydrofolate reductase ( MTHFR ) gene in African-Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX . METHODS Allele frequencies in the 677 , 1298 and 3 additional SNPs in the MTHFR coding region in 223 ( 193 Caucasians and 30 African-Americans ) patients with rheumatoid arthritis who previously participated in one of two prospect i ve clinical trials were characterised , and genotypes were correlated with the efficacy and toxicity of MTX .  Another 308 subjects with rheumatoid arthritis who participated in observational studies , one group predominantly Caucasian and the other African-American , as well as 103 normal controls ( 53 African-Americans and 50 Caucasians ) were used to characterise allele frequencies of these SNPs and their associated haplotypes . RESULTS Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African-Americans . Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group . Frequencies of the rs4846051C , 677 T and 1298C alleles were 0.33 , 0.11 and 0.13 , respectively , among African-Americans with rheumatoid arthritis . Among Caucasians with rheumatoid arthritis , these allele frequencies were 0.08 ( p<0.001 compared with African-Americans with rheumatoid arthritis ) , 0.30 ( p = 0.002 ) and 0.34 ( p<0.001 ) , respectively . There was no association between SNP alleles or haplotypes and response to MTX  as measured by the mean change in the 28-joint Disease Activity Score from baseline values . In Caucasians , the 1298 A ( major ) allele was associated with a significant increase in MTX-related adverse events characteristic of a recessive genetic effect ( odds ratio 15.86 , 95 % confidence interval 1.51 to 167.01 ; p = 0.021 ) , confirming previous reports . There was an association between scores of MTX toxicity and the rs4846051 C allele , and haplotypes containing this allele , in African-Americans , but not in Caucasians . CONCLUSIONS : These results , although preliminary , highlight racial or ethnic differences in frequencies of common MTHFR SNPs . The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX-related adverse events in Caucasians and African-Americans , respectively , but these findings should be replicated in larger studies . The rs4846051 SNP , which is far more common in African-Americans than in Caucasians , can also be proved to be a useful ancestry informative marker in future studies on genetic admixture


Title 4:
MTHFR 677 (C→T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95
Abstract 4:
We analyzed the relationship of genetic variation within the methylenetetrahydrofolate reductase gene ( MTHFR 677 C→T ) with clinical characteristics , outcome , and therapy-related toxicity in pediatric non-Hodgkin ’s lymphoma ( NHL ) in our multicenter trial NHL-BFM 95 . In this trial , high-dose methotrexate ( MTX ) infusion regimens were r and omized ( 4- vs 24-h infusion ) in patients with B-cell lymphoma ;  MTX was applied as 24-h infusion in all patients with lymphoblastic lymphoma and anaplastic large cell lymphoma .  Toxicity data were collected per patient and therapy course according to National Cancer Institute Common Toxicity Criteria ( NCI-CTC ) . The genotypes in 484 pediatric patients were distributed as follows : MTHFR 677 CC , 206 patients ( 42.6 % ) ; MTHFR 677 CT , 214 patients ( 44.2 % ) ; and MTHFR 677 TT , 64 patients ( 13.2 % ) . Lymphoblastic lymphoma was significantly associated with homozygosity for the MTHFR 677 T allele . No association of MTHFR 677 genotype with clinical characteristics ( sex , age , and tumor stage ) , outcome , or therapy-related toxicity could be detected . Therefore , we conclude that the MTHFR 677 C→T polymorphism does not appear to influence outcome or therapy-associated toxicity in pediatric patients with NHL treated on BFM protocol
RESULTS The analysis highlighted a significant association of C677 T polymorphism with overall MTX toxicity , hepatotoxicity , hematological toxicity , and neurotoxicity .
It also revealed an association with MTX toxicity  in patients with rheumatoid arthritis .
In contrast , a protective effect of C677 T MTHFR polymorphism on acute graft-versus-host disease and on patients treated with hematopoietic cell transplantation was found .
As for the A1298C polymorphism , a statistically significant association with overall MTX toxicity and a protective role of the polymorphism in rheumatoid arthritis patients was detected .
These results indicate the association of MTHFR polymorphisms with MTX toxicity .