scholarly journals Relationship Between Polymorphisms in Methotrexate Pathway Genes and Outcome of Methotrexate Treatment in a Cohort of 119 Patients with Juvenile Idiopathic Arthritis

2017 ◽  
Vol 44 (8) ◽  
pp. 1216-1223 ◽  
Author(s):  
Mojca Zajc Avramovič ◽  
Vita Dolžan ◽  
Nataša Toplak ◽  
Meta Accetto ◽  
Lara Lusa ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Disease Activity ◽  
Cox Regression ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Biologic Drugs ◽  
Single Nucleotide ◽  
Folate Pathway ◽  
Measure Disease Activity ◽  
Analyze Data

Objective.To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time.Methods.A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data.Results.Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient-years, and 10 patients (8.4%) discontinued MTX because of AE. AMPD1 rs17602729 and MTHFD1 rs2236225 were associated with gastrointestinal AE while the latter together with MTRR rs1801394 also demonstrated associations with developing hepatoxicity. MTHFR rs1801131, ABCG2 rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2 rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFR rs1801133, MTRR rs1801394, and ABCC2 rs2273697 were associated with switching to biologics.Conclusion.SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.

scholarly journals FRI0452 THE IMPACT OF SINGLE NUCLEOTIDE POLYMORPHISMS IN ADORA2A AND ADORA3 ON THE EARLY RESPONSE TO METHOTREXATE AND PRESENCE OF THERAPY SIDE EFFECTS IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 823.1-823
Author(s):  
J. Roszkiewicz ◽  
D. Michałek ◽  
A. Ryk ◽  
B. Szmyd ◽  
E. Smolewska
Keyword(s):  
Rheumatoid Arthritis ◽  
Juvenile Idiopathic Arthritis ◽  
Side Effects ◽  
Disease Activity ◽  
Global Assessment ◽  
Disease Activity Score ◽  
Clinical Parameters ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Active Arthritis

Background:Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease in children, with an estimated prevalence between 16 and 150 per 100 000 [1]. Methotrexate (MTX) administered at the dose 10-15mg/m2is currently recommended as the first-line treatment in most of JIA subtypes [2]. Despite its widespread use in rheumatology, the mechanism of MTX immunomodulatory action remains incompletely understood [3]. Free adenosine is one of the particles possibly associated with the action of MTX, acting via three types of adenosine receptor: ADORA2A, ADORA2B, and ADORA3 [4].Objectives:The aim of our study was to determine the association between single nucleotide polymorphisms inADORA2A(rs2236624, rs2298383) andADORA3(rs3393) receptors genes on the disease activity and presence of MTX therapy side effects in patients with JIA.Methods:One hundred children with JIA of all subtypes treated with MTX were recruited to the study. Demographic and clinical parameters were collected at the baseline of MTX therapy and on a control visit 4-6 months (median 5.09 months) after starting MTX. The clinical parameters included inflammatory markers values, number of joints with active arthritis, number of joints with restricted range of movement, physician’s global assessment of disease activity, parent/patient global assessment of overall well-being, functional ability (measured by the Childhood Health Assessment Questionnaire – CHAQ) and the value of Juvenile Idiopathic Arthritis Disease Activity Score 71 (JADAS 71). Presence of MTX side effects was evaluated on the control visit. SNP genotyping was performed using genomic DNA isolated from peripheral blood samples.Results:Both polymorphic variants ofADORA2A(rs2236624, rs2298383 - CC/CT) were significantly associated with 3.5 times higher odds of gastrointestinal side effects occurrence (OR: 3.52, 95%CI: 1.12-11.03, p=0.03 and OR: 3.49, 95%CI: 0.89-13.66 p=0.07) after adjustment to age, sex, dose and route of MTX administration. In addition, children with theADORA3rs3393 polymorphic variant (CT/CC) after six months of MTX treatment had significantly lower number of joints with active arthritis (0.0 vs 1.0, p=0.04), lower JADAS 71 score (3.0 vs 5.1, p=0.16) and lower value of CRP (0.6 vs 2.4, p=0.02).Conclusion:Although future studies are needed to verify our findings, polymorphisms inADORA2AandADORA3genes may become the determinants of MTX treatment efficacy and gastrointestinal toxicity in children with JIA.References:[1]Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001.J Rheumatol. 2004;31(2):390-392.[2]Ferrara G, Mastrangelo G, Barone P, et al. Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting.PediatrRheumatol Online J. 2018;16(1):46. Published 2018 Jul 11. doi:10.1186/s12969-018-0255-8.[3]Brown, P. M., Pratt, A. G., & Isaacs, J. D. (2016). Mechanism of action of methotrexate in rheumatoid arthritis and the search for biomarkers. Nature Reviews Rheumatology, 12(12), 731–742. doi:10.1038/nrrheum.2016.175.[4]Varani, K. et al. A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release. Arthritis Res. Ther. 13, R197 (2011).Disclosure of Interests:None declared

scholarly journals The Investigation of Associations between TP53 rs1042522, BBC3 rs2032809, CCND1 rs9344, EGFR rs2227983 Polymorphisms and Breast Cancer Phenotype and Prognosis

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1419
Author(s):  
Justina Bekampytė ◽  
Agnė Bartnykaitė ◽  
Aistė Savukaitytė ◽  
Rasa Ugenskienė ◽  
Erika Korobeinikova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regression Analysis ◽  
Cox Regression ◽  
Cancer Prognosis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Cox Regression Analysis ◽  
Pcr Rflp ◽  
Oncological Diseases ◽  
Cancer Phenotype

Breast cancer is one of the most common oncological diseases among women worldwide. Cell cycle and apoptosis—related genes TP53, BBC3, CCND1 and EGFR play an important role in the pathogenesis of breast cancer. However, the roles of single nucleotide polymorphisms (SNPs) in these genes have not been fully defined. Therefore, this study aimed to analyze the association between TP53 rs1042522, BBC3 rs2032809, CCND1 rs9344 and EGFR rs2227983 polymorphisms and breast cancer phenotype and prognosis. For the purpose of the analysis, 171 Lithuanian women were enrolled. Genomic DNA was extracted from peripheral blood; PCR-RFLP was used for SNPs analysis. The results showed that BBC3 rs2032809 was associated with age at the time of diagnosis, disease progression, metastasis and death. CCND1 rs9344 was associated with tumor size, however an association resulted in loss of significance after Bonferroni correction. In survival analysis, significant associations were observed between BBC3 rs2032809 and OS, PFS and MFS. EGFR rs2227983 also showed some associations with OS and PFS (univariate Cox regression analysis). However, the results were in loss of significance (multivariate Cox regression analysis). In conclusion, BBC3 rs2032809 polymorphism was associated with breast cancer phenotype and prognosis. Therefore, it could be applied as potential markers for breast cancer prognosis.

scholarly journals Significant Associations of lncRNA H19 Genotypes with Susceptibility to Childhood Leukemia in Taiwan

2021 ◽  
Vol 14 (3) ◽  
pp. 235
Author(s):  
Jen-Sheng Pei ◽  
Chao-Chun Chen ◽  
Wen-Shin Chang ◽  
Yun-Chi Wang ◽  
Jaw-Chyun Chen ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Childhood Leukemia ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Genotypic Distribution ◽  
Heterozygous Variant ◽  
Significant Difference ◽  
The Difference

The purpose of our study was to investigate whether genetic variations in lncRNA H19 were associated with susceptibility to childhood leukemia. Two hundred and sixty-six childhood leukemia patients and 266 healthy controls were enrolled in Taiwan, and two single nucleotide polymorphisms (SNPs), rs2839698 and rs217727, in H19 were genotyped and analyzed. There was a significant difference in the genotypic distribution of rs2839698 between patients and healthy controls (p = 0.0277). Compared to the wild-type CC genotype, the heterozygous variant CT and homozygous variant TT genotypes were associated with significantly increased risks of childhood leukemia with an adjusted odd ratio (OR) of 1.46 (95% confidence interval (CI), 1.08–2.14, p = 0.0429) and 1.94 (95%CI, 1.15–3.31, p = 0.0169), respectively (pfor tread = 0.0277). The difference in allelic frequencies between childhood leukemia patients and controls was also significant (T versus C, adjusted OR = 1.53, 95%CI, 1.13–1.79, p = 0.0077). There were no significant differences in the genotypic and allelic distributions of rs217727 between cases and controls. Interestingly, the average level of H19 rs2839698 was statistically significantly higher for patients with CT and TT genotypes than from those with the CC genotype (p < 0.0001). Our results indicate that H19 SNP rs2839698, but not rs217727, may serve as a novel susceptibility marker for childhood leukemia.

Associations between varied susceptibilities of PfATP4 inhibitors and genotypes in Ugandan Plasmodium falciparum isolates

2021 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Stephanie A. Rasmussen ◽  
Aarti A. Ramanathan ◽  
Patrick K. Tumwebaze ◽  
Oswald Byaruhanga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Ex Vivo ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Field Isolates ◽  
Frequent Mutations ◽  
Mixed Field ◽  
P Type

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda from 2016-2019. Median IC 50 s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many non-synonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%) and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92 and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.

scholarly journals Impacts of FcγRIIB and FcγRIIIA gene polymorphisms on systemic lupus erythematous disease activity index

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Mansoor Karimifar ◽  
Khosro Akbari ◽  
Reza ArefNezhad ◽  
Farshid Fathi ◽  
Mohammad Moosaeepour ◽  
...  
Keyword(s):  
Disease Activity ◽  
Activity Index ◽  
Clinical Manifestations ◽  
Disease Activity Index ◽  
Unknown Etiology ◽  
Systemic Lupus Erythematous ◽  
Nucleotide Polymorphisms ◽  
Systemic Lupus ◽  
Single Nucleotide ◽  
Chronic Autoimmune Disease

Abstract Objective Systemic lupus erythematous (SLE) disease is a chronic autoimmune disease with unknown etiology that can involve different organs. Polymorphisms in Fcγ receptors have been identified as genetic factors in susceptibility to SLE. This study was aimed to investigate effects of two single nucleotide polymorphisms (SNPs) within FcγRIIB and FcγRIIIA genes on systemic lupus erythematous disease activity index (SLEDAI) in an Iranian population. Results Our findings indicated TT and GG genotypes were the common genotypes of FcγRIIB and FcγRIIIA SNPs in SLE patients, respectively. There were no significant differences in genotype and allele frequencies of FcγRIIB and FcγRIIIA SNPs in SLE and healthy subjects. However, the frequencies of genotypes and alleles of FcγRIIB and FcγRIIIA SNPs were significantly associated with some clinical manifestations used to determine SLEDAI (P < 0.001–0.5).

scholarly journals Causal Role of Single Nucleotide Polymorphisms within themprFGene of Staphylococcus aureus in Daptomycin Resistance

2013 ◽  
Vol 57 (11) ◽  
pp. 5658-5664 ◽  
Author(s):  
Soo-Jin Yang ◽  
Nagendra N. Mishra ◽  
Aileen Rubio ◽  
Arnold S. Bayer
Keyword(s):  
Staphylococcus Aureus ◽  
Single Nucleotide Polymorphisms ◽  
Point Mutations ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Content Type ◽  
Reading Frame ◽  
A Charge

ABSTRACTSingle nucleotide polymorphisms (SNPs) within themprFopen reading frame (ORF) have been commonly observed in daptomycin-resistant (DAPr)Staphylococcus aureusstrains. Such SNPs are usually associated with a gain-in-function phenotype, in terms of either increased synthesis or enhanced translocation (flipping) of lysyl-phosphatidylglycerol (L-PG). However, it is unclear if suchmprFSNPs are causal in DAPrstrains or are merely a biomarker for this phenotype. In this study, we used an isogenic set ofS. aureusstrains: (i) Newman, (ii) its isogenic ΔmprFmutant, and (iii) several intransplasmid complementation constructs, expressing either a wild-type or point-mutated form of themprFORF cloned from two isogenic DAP-susceptible (DAPs)-DAPrstrain pairs (616-701 and MRSA11/11-REF2145). Complementation of the ΔmprFstrain with singly point-mutatedmprFgenes (mprFS295LormprFT345A) revealed that (i) individual and distinct point mutations within themprFORF can recapitulate phenotypes observed in donor strains (i.e., changes in DAP MICs, positive surface charge, and cell membrane phospholipid profiles) and (ii) these gain-in-function SNPs (i.e., enhanced L-PG synthesis) likely promote reduced DAP binding toS. aureusby a charge repulsion mechanism. Thus, for these two DAPrstrains, the definedmprFSNPs appear to be causally related to this phenotype.

Characterisation of the melanocortin-1 receptor gene in alpaca and identification of possible markers associated with phenotypic variations in colour

2009 ◽  
Vol 49 (8) ◽  
pp. 675 ◽  
Author(s):  
N. L. Feeley ◽  
K. A. Munyard
Keyword(s):  
Mus Musculus ◽  
Bos Taurus ◽  
Receptor Gene ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Melanocortin 1 Receptor ◽  
Mc1r Gene ◽  
Pcr Products ◽  
Phenotypic Variations

The aim of this study was to determine if any correlation exists between melanocortin-1 receptor (MC1R) polymorphisms and skin and fibre colour in alpacas. Primers capable of amplifying the entire alpaca MC1R gene were designed from a comparative alignment of Bos taurus and Mus musculus MC1R gene sequences. The complete MC1R gene of 41 alpacas exhibiting a range of fibre colours, and which were sourced from farms across Australia, was sequenced from PCR products. Twenty-one single nucleotide polymorphisms were identified within MC1R. Two of these polymorphisms (A82G and C901T) have the potential to reduce eumelanin production by disrupting the activity of MC1R. No agreement was observed between fibre colour alone and MC1R genotype in the 41 animals in this study. However, when the animals were assigned to groups based on the presence or absence of eumelanin in their fibre and skin, only animals that had at least one allele with the A82/C901 combination expressed eumelanin. We propose that A82/C901 is the wild-type dominant ‘E’ MC1R allele, while alpacas with either G82/T901 or G82/Y901 are homozygous for the recessive ‘e’ MC1R allele and are therefore unable to produce eumelanin.

Association of RETN and TNFRSF1B polymorphisms with TNF-α inhibitor response in rheumatoid arthritis patients

2020 ◽  
Author(s):  
Nga Thi Trinh ◽  
Hyun Jeong Kim ◽  
Woorim Kim ◽  
Sang Oh Kang ◽  
Kyung Hyun Min ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Multivariable Logistic Regression Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Final Model ◽  
Asian Populations ◽  
Tnf Α

Abstract Background: Despite the improvement from the introduction of tumor necrosis factor inhibitors (TNFi) in the rheumatoid arthritis (RA), TNFi therapy fails for more than 30% or results in a partial response. Thus, we aimed to explore treatment marker by examining the association of single nucleotide polymorphisms (SNPs) with response to TNFi therapy.Method: Genes associated with RA or RA treatment were reviewed and fourteen SNPs with minor allele frequency ≥ 20% in the East Asian populations were selected and analyzed. Data were collected from 105 RA patients. Our primary endpoint was the disease activity score using 28-joint count after six months of treatment (DAS28-6month). The secondary outcomes were the subcomponents of DAS28.Results: A total of 88 patients were included in the final analyses. Among the 14 SNPs analyzed, one SNP showed statistical significance in DAS28-6month: patients with the GG allele of RETN rs1862513 had a 4.7 times higher chance of low disease activity at 6-months than GC or CC-carriers (p = 0.033), as indicated by multivariable logistic regression analysis. Rs3397 was marginally significant in univariate analysis (p=0.059), but was significant in the multivariable model (p=0.041). The final model explained 24.5% (Nagelkerke R2) of the variance in DAS28-6month.Conclusion: Our results demonstrated that, among the genes related to RA, SNPs in RETN and TNFRSF1B were associated with the response of TNFi treatment.

scholarly journals Non-syndromic cleft palate: Association analysis on three gene polymorphisms of the folate pathway in Asian and Italian populations

2019 ◽  
Vol 33 ◽  
pp. 205873841985857 ◽  
Author(s):  
Francesco Carinci ◽  
Annalisa Palmieri ◽  
Luca Scapoli ◽  
Francesca Cura ◽  
Francesco Borelli ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Folic Acid Supplementation ◽  
Nucleotide Polymorphisms ◽  
Orofacial Clefts ◽  
Single Nucleotide ◽  
Candidate Gene Association ◽  
Folate Pathway ◽  
Family Based ◽  
Gene Association Study

Periconceptional folic acid supplementation can reduce the risk of inborn malformations, including orofacial clefts. Polymorphisms of MTHFR, TCN2, and CBS folate-related genes seem to modulate the risk of cleft lip with or without cleft palate (CL/P) in some populations. CL/P and cleft palate only (CPO) are different malformations that share several features and possibly etiological causes. In the present investigation, we conducted a family-based, candidate gene association study of non-syndromic CPO. Three single nucleotide polymorphisms, namely, rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were investigated in a sample that included 129 Italian and 65 Asian families. No evidence of association between the three genotyped polymorphisms and CPO was found in the Italian and Asian cases, indeed the transmission disequilibrium test did not detect any asymmetry of transmission of alleles. This investigation, although with some limitation, further supports that CL/P and CPO diverge in their genetic background.

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