Folyl polyglutamate synthethase (FPGS) gene polymorphisms may influence methotrexate adverse events in South Indian Tamil Rheumatoid Arthritis patients

Muralidharan, Niveditha; Sundaram, Rajan; Kodidela, Sunitha; Chengappa, K G; Mariaselvam, Christina Mary; Misra, Durga Prasanna; Negi, Vir Singh

doi:10.1038/s41397-019-0097-x

Cited by 9 publications

(11 citation statements)

References 38 publications

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“…In the present report, we considered only severe hematological toxicity as a phenotype for association in ALL patients receiving other combination medications that result in myelosupression, primarily 6-MP. The heterozygosity observed in our study (56%) is comparable to that reported by Muralidharan et al, [ 42 ]. The FPGS rs1544105 ‘T’ variant leads to decreased transcription and hence reduced function of FPGS.…”

Section: Discussionsupporting

confidence: 91%

“…In a recent study conducted in patients with rheumatoid arthritis, it was shown that rs1544105 ‘CT’ genotype carriers of the FPGS gene, but not ‘TT’ carriers, had an increased risk of MTX-induced toxicity. The authors of that report included multiple types of toxicities, including hepatic, hematological, and gastrointestinal, without grading their severity [ 42 ]. In the present report, we considered only severe hematological toxicity as a phenotype for association in ALL patients receiving other combination medications that result in myelosupression, primarily 6-MP.…”

Section: Discussionmentioning

confidence: 99%

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Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

Kumar

Dorababu

Thakkar

et al. 2020

Genes

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Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

Kumar

Dorababu

Thakkar

et al. 2020

Genes

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“…Previous studies have reported higher GGH expression levels in urothelial, invasive breast, ERG-negative prostate, gallbladder, and gastric cancers compared to corresponding control tissues ( Pollard et al, 2009 ; Silva et al, 2013 ; Wang et al, 2014 ; Zali et al, 2019 ; Muralidharan et al, 2020 ), which is consistent with our pancancer analysis of TCGA data showing higher GGH expression in numerous cancers including other gynecologic cancers. This elevated expression was observed at both protein and mRNA levels in UCEC patients.…”

Section: Discussionsupporting

confidence: 92%

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma

et al. 2022

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Uterine corpus endometrial carcinoma (UCEC) is a common malignant tumor of the female reproductive system with poor prognosis in advanced, recurrent, and metastatic cases. Identification of reliable molecular markers will help in the development of clinical strategies for early detection, diagnosis, and intervention. Gamma-glutamyl hydrolase (GGH) is a key enzyme in folate metabolism pathway. High expression of GGH is associated with severe clinicopathological features and poor prognosis of several cancers. High GGH expression is also related to cell resistance to antifolate drugs such as methotrexate. In this study we focused on the prognostic value of immunohistochemical GGH expression level in UCEC tissue and RNA-seq data from The Cancer Genome Atlas to establish associations with clinical features and outcomes. Further, we conducted comprehensive bioinformatics analyses to identify and functionally annotate differentially expressed genes (DEGs) associated with UCEC upregulation and assessed the effects of upregulation on immune infiltration. Both GGH mRNA and protein expression levels were elevated in tumor tissues, and higher expression was significantly associated with advanced clinicopathological features and poor prognosis by univariate analysis. Further multivariate analysis identified elevated GGH expression as an independent risk factor for poor outcome. Nomograms including GGH expression yielded a c-index for disease-specific survival prediction of 0.884 (95% confidence interval: 0.861–0.907). A total of 520 DEGs (111 upregulated and 409 downregulated) were identified between high and low GGH expression groups. Analysis using Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Gene set enrichment analysis, and protein‒protein interaction indicated significant associations of altered GGH expression with cell proliferation, immune response, and the occurrence and development of UCEC tumors. Finally, GGH expression level was associated with high Th2 cell and low natural killer CD56bright cell infiltration. Collectively, these findings indicate that GGH drives UCEC progression and could be a useful biomarker for survival prediction as well as a therapeutic target.

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“…To the best of our knowledge, there is no evidence of association between FPGS rs4451422 or rs10106 SNPs and the risk of orofacial clefts or any other structural birth defects. Nevertheless, both variants have been associated with the pharmacokinetics of methotrexate, a drug used for the treatment of rheumatoid arthritis [35,36]. In addition, among the spectrum of embryopathies related to using this drug, one can find orofacial clefts in humans and in animal models [37].…”

Section: Discussionmentioning

confidence: 99%

Maternal genotypes of folate/one‐carbon metabolism gene variants and nonsyndromic cleft lip with or without cleft palate risk in Chile

Inostroza

Salamanca

Recabarren

et al. 2021

European J Oral Sciences

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The aim of this study was to evaluate, in a case-control design, the association between maternal genotypes for variants in 23 genes involved in folate/one-carbon metabolism and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a Chilean population. After applying several filters to an Illumina array, we extracted 175 single nucleotide polymorphisms (SNPs) from 150 mothers of NSCL/P cases and 150 control women. Association was evaluated using computed odds ratio (OR) with a 95% confidence interval (95% CI) in additive, recessive, and dominant models. After multiple comparison correction, only SNP rs4451422 (A>C), located 237 bp downstream of the gene encoding the human folylpolyglutamate synthetase (FPGS), maintained a significant association with NSCL/P in the offspring (OR 3.03; 95% CI 1.69-5.26). The variant rs4451422 is associated with a decrease in FPGS expression according to database annotation. Our results lead to a new hypothesis that a lower activity of FPGS enzyme reduces intracellular folate levels and increases the risk of an offspring having NSCL/P.

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Folyl polyglutamate synthethase (FPGS) gene polymorphisms may influence methotrexate adverse events in South Indian Tamil Rheumatoid Arthritis patients

Cited by 9 publications

References 38 publications

Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma

Maternal genotypes of folate/one‐carbon metabolism gene variants and nonsyndromic cleft lip with or without cleft palate risk in Chile

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