Articles de revues : « Dhfr polymorphism »

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DURAISINGH, M. T., L. VON SEIDLEIN, A. JEPSON, P. JONES, I. SAMBOU, M. PINDER et D. C. WARHURST. « Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum ». Parasitology 121, n^o 1 (juillet 2000) : 1–7. http://dx.doi.org/10.1017/s0031182099006022.

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Chloroquine-resistance in Plasmodium falciparum is associated with polymorphisms in a locus on or near the cg2 gene on chromosome 7, and in the pfmdr1 gene on chromosome 5. In this study we typed P. falciparum DNA from uncomplicated malaria cases in The Gambia in 1990, 1995 and 1996 for size polymorphism in the omega repeat of cg2, for sequence polymorphisms in pfmdr1 at codons 86 and 184, in dhfr at codon 108 and in the msp2 gene. Chloroquine sensitivity tests were conducted in vitro. A significant but incomplete association was found between the presence of the cg2 Dd2-like omega repeat size polymorphism and in vitro resistance, and between the tyr-86 allele of pfmdr1 and in vitro resistance. Furthermore there was strong linkage disequilibrium between the pfmdr1 asn-86 allele and the cg2 not Dd2-like omega repeat allele located on different chromosomes. In contrast, no linkage disequilibrium was found between these alleles and either the dhfr ser-108 allele or the msp2 IC sequence polymorphism. No significant linkage was measured between pfmdr1 asn-86 and phe-184 although these loci are separated only by 296 base pairs. Our results suggest that genetic elements linked to the cg2 and the pfmdr1 genes are important determinants of chloroquine resistance. It can be concluded that the observed linkage disequilibrium is maintained epistatically through selection by chloroquine.

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Mendes, Cristiani Cortez, Joice Matos Biselli, Bruna Lancia Zampieri, Eny Maria Goloni-Bertollo, Marcos Nogueira Eberlin, Renato Haddad, Maria Francesca Riccio, Hélio Vannucchi, Valdemir Melechco Carvalho et Érika Cristina Pavarino-Bertelli. « 19-base pair deletion polymorphism of the dihydrofolate reductase (DHFR) gene : maternal risk of Down syndrome and folate metabolism ». Sao Paulo Medical Journal 128, n^o 4 (juillet 2010) : 215–18. http://dx.doi.org/10.1590/s1516-31802010000400008.

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CONTEXT AND OBJECTIVE: Polymorphisms in genes involved in folate metabolism may modulate the maternal risk of Down syndrome (DS). This study evaluated the influence of a 19-base pair (bp) deletion polymorphism in intron-1 of the dihydrofolate reductase (DHFR) gene on the maternal risk of DS, and investigated the association between this polymorphism and variations in the concentrations of serum folate and plasma homocysteine (Hcy) and plasma methylmalonic acid (MMA). DESIGN AND SETTING: Analytical cross-sectional study carried out at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS: 105 mothers of individuals with free trisomy of chromosome 21, and 184 control mothers were evaluated. Molecular analysis on the polymorphism was performed using the polymerase chain reaction (PCR) through differences in the sizes of fragments. Folate was quantified by means of chemiluminescence, and Hcy and MMA by means of liquid chromatography and sequential mass spectrometry. RESULTS: There was no difference between the groups in relation to allele and genotype frequencies (P = 0.44; P = 0.69, respectively). The folate, Hcy and MMA concentrations did not differ significantly between the groups, in relation to genotypes (P > 0.05). CONCLUSIONS: The 19-bp deletion polymorphism of DHFR gene was not a maternal risk factor for DS and was not related to variations in the concentrations of serum folate and plasma Hcy and MMA in the study population.

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Mishra, Prasunkumar J., Giuseppe S. A. Longo, Lata G. Menon, Emine Abali, Debabrata Banerjee et Joseph Bertino. « A 3′ UTR Single Nucleotide Polymorphism 829C→T in Dihydrofolate Reductase Gene Results in an Increase in DHFR Protein Level and MTX Resistance. » Blood 104, n^o 11 (16 novembre 2004) : 2084. http://dx.doi.org/10.1182/blood.v104.11.2084.2084.

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Abstract Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF) required for the synthesis of thymidylate and purines. Methotrexate (MTX) acts as a tight-binding inhibitor of DHFR and remains an important chemotherapeutic agent for treatment of leukemias and lymphomas. Increased DHFR confers resistance to antifolates in target cells. A previously reported single nucleotide polymorphism (SNP) 829C/C→829T/T (829C→T) found in the 3′- untranslated region of DHFR gene transcript (between the first and second polyadenylation site) was associated with higher expression of the DHFR transcript. The SNP was identified in 5.4% of the cases and 6.0% in the controls of Japanese patients with childhood leukemia/lymphomas (Goto et al. 2001, Clinical Cancer Research, Vol. 7, 1952-1956). The objective of the present study was to determine the role of the 3′ UTR SNP 829C→T in DHFR gene expression, DHFR protein level and resistance to MTX. The mutation 829C→T in the 3′ UTR of wild type DHFR was introduced by site directed mutagenesis and the mutant cDNA expressed in DHFR deficient CHO cells (DG-44), wild type DHFR and vector alone constructs were also transfected into DG44 as controls. After two weeks of selection in G418 containing media, several well-isolated surviving colonies were picked and expanded as cell lines in media containing G418. Real-time quantitative PCR was used to compare mRNA and genomic DNA level of the clones while Western blotting was used to compare the protein levels. MTX cytotoxicity assay was carried out in media lacking thymidine. Clones expressing the mutant 829C→T showed greater than two fold enhanced expression of DHFR transcripts as compared to wild type clones. Corresponding to the high mRNA levels, an increase in DHFR protein level was observed in the mutant clones without an increase in DHFR gene copy number. Cytotoxicity studies showed that cell lines with increased levels of DHFR were significantly more resistant to MTX than cells with wild type 3′ UTR. Of interest clonogenic efficiency of the mutants in medium lacking thymidine was greater than wild type and was directly proportional to the level of DHFR expressed in the clones. This study demonstrates that when SNP 829C→T is introduced in the 3′ UTR of wild type DHFR, the expression of the DHFR mRNA is enhanced with a corresponding increase in the protein level. The presence of a SNP 829C→T in patients with ALL may contribute to treatment failure, as MTX is a key drug in curative regimen for this disease. Future studies are directed toward determining the abundance of this SNP in other populations, and the correlation between this SNP and clinical methotrexate resistance and or decreased MTX toxicity.

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Detera-Wadleigh, S. D., D. Coffman et T. Shimada. « A frequent DHFR polymorphism detected by an intron fragment ». Nucleic Acids Research 17, n^o 15 (1989) : 6432. http://dx.doi.org/10.1093/nar/17.15.6432.

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Costa-Lima, Marcelo Aguiar, Hazel Nunes Barboza, Joissy Aprigio, Cláudia de Melo Moura, Thereza Fonseca Quirico-Santos, Márcia Gonçalves Ribeiro et Márcia Rodrigues Amorim. « Dihydrofolate Reductase (DHFR) del19bp Polymorphism and Down Syndrome Offspring ». Journal of Molecular Neuroscience 70, n^o 9 (22 mai 2020) : 1410–14. http://dx.doi.org/10.1007/s12031-020-01561-4.

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Tisato, Veronica, Paola Muggeo, Tracy Lupiano, Giovanna Longo, Maria Luisa Serino, Massimo Grassi, Ermanno Arcamone et al. « Maternal Haplotypes in DHFR Promoter and MTHFR Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency : Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS) ». Genes 10, n^o 9 (22 août 2019) : 634. http://dx.doi.org/10.3390/genes10090634.

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Childhood acute lymphoblastic leukemia (ALL) peaks around age 2–4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated DHFR and MTHFR gene variants in 235 ALL children and their mothers to disclose their role in determining ALL onset age and survival. Pyrosequence of DHFR 19bp ins/del (rs70991108; W/D), MTHFR C677T (rs1801133; C>T), and MTHFR A1298C (rs1801131; A>C) was assessed in children and in 72% of mothers for dyad-analysis comparison. DHFR DD-children had delayed ALL onset compared to WW-children (7.5 ± 4.8 vs. 5.2 ± 3.7 years; P = 0.002) as well as MTHFR 1298 CC-children compared to AA-children (8.03 ± 4.8 vs. 5.78 ± 4.1 years; P = 0.006), and according to the strong linkage disequilibrium between MTHFR 677 T-allele and 1298C-allele, MTHFR TT-children showed early mean age of onset though not significant. Offspring of MTHFR 677 TT-mothers had earlier ALL onset compared to offspring of 677 CC-mothers (5.4 ± 3.3 vs. 7 ± 5.3 years; P = 0.017). DHFR/MTHFR 677 polymorphism combination influenced onset age by comparing DD/CC vs. WW/TT children (8.1 ± 5.7 vs. 4.7 ± 2.1 years; P = 0.017). Moreover, mother-child genotype combination gave 5.5-years delayed onset age in favor of DD-offspring of 677 CC-mothers vs. WW-offspring of 677 TT-mothers, and it was further confirmed including any D-carrier children and any 677 T-carrier mothers (P = 0.00052). Correction for multiple comparisons maintained statistical significance for DHFR ins/del and MTHFR A1298C polymorphisms. Unexpectedly, among the very-early onset group (<2.89 years; 25th), DD-genotype inversely clustered in children and mothers (4.8% vs. 23.8% respectively), and accordingly ALL offspring of homozygous DD-mothers had increased risk to have early-onset (adjusted OR (odds ratio) = 3.08; 1.1–8.6; P = 0.03). The opposite effect DHFR promoter variant has in tuning ALL onset-time depending on who is the carrier (i.e., mother or child) might suggest a parent-origin-effect of the D-allele or a two-faced epigenetic role driven by unbalanced folate isoform availability during the in-utero leukemogenesis responsible for the wide postnatal childhood ALL latency.

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Flower, Michael, Vilija Lomeikaite, Marc Ciosi, Sarah Cumming, Fernando Morales, Kitty Lo, Davina Hensman Moss et al. « MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1 ». Brain 142, n^o 7 (19 juin 2019) : 1876–86. http://dx.doi.org/10.1093/brain/awz115.

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Abstract The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

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Imwong, Mallika, Sasithon Pukrittakayamee, Sornchai Looareesuwan, Geoffrey Pasvol, Jean Poirreiz, Nicholas J. White et Georges Snounou. « Association of Genetic Mutations inPlasmodium vivax dhfr with Resistance to Sulfadoxine-Pyrimethamine : Geographical and Clinical Correlates ». Antimicrobial Agents and Chemotherapy 45, n^o 11 (1 novembre 2001) : 3122–27. http://dx.doi.org/10.1128/aac.45.11.3122-3127.2001.

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ABSTRACT Mutations in the Plasmodium falciparum gene (dhfr) encoding dihydrofolate reductase are associated with resistance to antifols. Plasmodium vivax, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the dhfrgene of P. vivax (pvdhfr) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (n = 100), India (n = 16), and Madagascar and the Comoros Islands (n = 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of P. vivax dhfr(pvdhfr), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (P < 0.0001). The dhfr PCR products of P. vivax from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (P = 0.01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax. These mutations presumably arose from selection pressure.

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Wu, Yuanyuan, A. David Smith, Nasser E. Bastani, Helga Refsum et Timothy Kwok. « The dihydrofolate reductase 19-bp deletion modifies the beneficial effect of B-vitamin therapy in mild cognitive impairment : pooled study of two randomized placebo-controlled trials ». Human Molecular Genetics 31, n^o 7 (12 novembre 2021) : 1151–58. http://dx.doi.org/10.1093/hmg/ddab246.

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Abstract Background: Higher serum homocysteine is associated with cognitive decline in older people. But homocysteine-lowering trials including folic acid (FA) show inconsistent results on cognitive decline. The reduction of FA to dihydrofolate by dihydrofolate reductase (DHFR) is slow in humans. Objective: We examined the effects of the DHFR 19-bp deletion/insertion (del/ins) polymorphism on FA-containing treatment on cognitive decline and brain atrophy in older people with mild cognitive impairment (MCI). Methods: This study used pooled data from two randomized B-vitamin trials on 545 MCI subjects who received either FA-containing B vitamins or placebo for 24 months. Subjects were typed for the DHFR genotype. Primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). Secondary outcomes were CDR-sum of boxes score (CDR-SOB), memory and executive Z-scores and whole brain atrophy rate by serial MRI. Results: The proportions of subjects with del/del, del/ins and ins/ins genotype were 29.5, 44.3 and 26.1%, respectively. DHFR genotypes modified the effects of B vitamins on CDR-global, CDR-SOB and executive function Z-score (Pinteraction = 0.017, 0.014 and 0.052, respectively), with significant benefits being observed only in those with ins/ins genotype (Beta = −1.367, −0.614 and 0.315, P = 0.004, 0.014 and 0.012, respectively). The interaction was not significant for memory Z-score and whole brain atrophy rate. Notably, the supplements only slowed brain atrophy in members of the ‘ins/ins’ group who were not using aspirin. Conclusions: Our data indicate that the beneficial effects of B vitamins including FA on cognitive function are only apparent in those with ins/ins genotype, i.e. relatively better preserved DHFR activity.

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Park, Jeong A., Hyoung Jin Kang, Ho Joon Im, Hee Young Shin et Hyo Seop Ahn. « Association of genetic polymorphisms in the folate pathway with efficacy and toxicity of methotrexate in pediatric osteosarcoma. » Journal of Clinical Oncology 31, n^o 15_suppl (20 mai 2013) : 10051. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10051.

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10051 Background: Osteosarcoma is the most common childhood malignant bone tumor. Methotrexate (MTX), one of the main drugs used for osteosarcoma, is a representative folic acid antagonist. Genetic polymorphisms in folate pathway genes are expected to influence the response and toxicity of high-dose MTX therapy. However, there are scarce data available regarding associations between genetic polymorphisms and pediatric osteosarcoma. This study evaluated the effect of common genetic polymorphisms in the folate metabolic pathway on overall survival, event-free survival and histological response to neoadjuvant chemotherapy including high-dose MTX. In addition, whether these genetic polymorphisms affect the concentrations of MTX and toxicity after high-dose MTX therapy for osteosarcoma was investigated. Methods: Blood and tissue samples from 48 osteosarcoma patients who had completed chemotherapy were obtained, and the following polymorphisms were analyzed; RFC1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, AMPD1 34C>T, ATIC 347C>G, and ITPA 94C>A. Associations between candidate polymorphisms and survival, histological response (tumor necrosis rate) and MTX level and toxicity after high-dose MTX therapy were analyzed. Results: Event-free survival significantly decreased in DHFR 829 CC homozygote (P=0.045). Variant carriers of MTHFR 677C>T had tendency towards poor histological response (P=0.078). MTX concentration was significantly associated with RFC1 80G>A polymorphism (P=0.027). Liver toxicity after high-dose MTX was associated with ATIC 347C>G (P=0.043) and tended to increase in carriers of MTHFR 677C>T (P=0.069). Severe stomatitis was associated with RFC1 80G>A (P=0.012). Conclusions: This study has demonstrated that several genetic polymorphisms in folate pathway can significantly influence therapeutic response, clinical outcome and MTX level and toxicity after high-dose MTX therapy in osteosarcoma patients. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of patients with osteosarcoma, aiding the development of tailored therapeutic approaches.

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Yang, Honghao, et Peter W. Melera. « A genetic polymorphism within the third poly(A) signal of the DHFR gene alters the polyadenylation pattern of DHFR transcripts in CHL cells ». Nucleic Acids Research 22, n^o 13 (1994) : 2694–702. http://dx.doi.org/10.1093/nar/22.13.2694.

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Kiara, Steven M., John Okombo, Victor Masseno, Leah Mwai, Isabella Ochola, Steffen Borrmann et Alexis Nzila. « In Vitro Activity of Antifolate and Polymorphism in Dihydrofolate Reductase of Plasmodium falciparum Isolates from the Kenyan Coast : Emergence of Parasites with Ile-164-Leu Mutation ». Antimicrobial Agents and Chemotherapy 53, n^o 9 (15 juin 2009) : 3793–98. http://dx.doi.org/10.1128/aac.00308-09.

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ABSTRACT We have analyzed the activities of the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), WR99210, trimethoprim (TMP), methotrexate (MTX), and trimetrexate (TMX) against Kenyan Plasmodium falciparum isolates adapted in vitro for long-term culture. We have also assessed the relationship between these drug activities and mutations in dihydrofolate reductase (dhfr), a domain of the gene associated with antifolate resistance. As expected, WR99210 was the most potent drug, with a median 50% inhibitory concentration (IC50) of <0.075 nM, followed by TMX, with a median IC50 of 30 nM. The median IC50 of CCG was 37.80 nM, and that of MTX was 83.60 nM. PM and TMP were the least active drugs, with median IC50s of 733.26 nM and 29,656.04 nM, respectively. We analyzed parasite dhfr genotypes by the PCR-enzyme restriction technique. No wild-type dhfr parasite was found. Twenty-four of 33 parasites were triple mutants (mutations at codons 108, 51, and 59), and only 8/33 were double mutants (mutations at codons 108 and 51 or at codons 108 and 59). IC50s were 2.1-fold (PM) and 3.6-fold (TMP) higher in triple than in double mutants, though these differences were not statistically significant. Interestingly, we have identified a parasite harboring a mutation at codon 164 (Ile-164-Leu) in addition to mutations at codons 108, 51, and 59. This quadruple mutant parasite had the highest TMP IC50 and was in the upper 10th percentile against PM and CCG. We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa.

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Thomas, Bolaji N., Carlyn R. Petrella, Stephanie R. Crespo, Tanya J. Thakur, Joann M. Moulds et Dapa A. Diallo. « Genetic Polymorphism of Plasmodium falciparum Merozoite Surface Protein-1 and -2 and Diversity of Drug Resistance Genes in Blood Donors from Bamako, Mali ». Infectious Diseases : Research and Treatment 5 (janvier 2012) : IDRT.S10094. http://dx.doi.org/10.4137/idrt.s10094.

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We examined malaria infection in asymptomatic blood donors from Mali, analyzing allelic diversity of Plasmodium falciparum (Pf) merozoite surface proteins (msp) -1 and -2 as well as the distribution of sulphadoxine-pyrimethamine (SP) resistance genes. A total of 140 genomic DNA samples were screened. Allele-specific nested polymerase chain reaction (PCR) analysis of Pfmsp-1 and Pfmsp-2 was performed, plus fragment analysis of the polymorphic regions to identify allelic diversity of the parasite population. We found parasite positivity due to Pf alone in 20.7% of these donors. Diverse allelic polymorphism of Pfmsp-1 and Pfmsp-2 was identified, with a high rate of multiplicity of infection (1.84 and 1.82 for Pfmsp-1 and Pfmsp-2, respectively). In addition, we found a high degree of SP resistance, with mutations at several dhfr and dhps codons. We conclude that there is an extensive diversity of Pfmsp-1 and Pfmsp-2 allelic types and SP drug resistance in Pf-infected donors from Mali.

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Valiev, Timur T., Vera V. Semenova, Anna Yu Ikonnikova, Alisa A. Petrova, Tatiana S. Belysheva et Tatiana V. Nasedkina. « Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors : A review ». Journal of Modern Oncology 23, n^o 4 (15 décembre 2021) : 622–27. http://dx.doi.org/10.26442/18151434.2021.4.201127.

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Methotrexate (MTX) is one of the main chemotherapeutic agents that has determined the high effectiveness of protocols for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphomas. The reverse side of the high anti-tumor activity of MTX is the adverse reactions, which require accompanying preventive therapy. But even modern accompanying therapy in some cases does not avoid severe toxicity from the skin and mucous membranes, nervous system, kidneys, liver. MTX pharmacokinetics exhibits significant individual variability, which may be a reflection of genetic variability. Numerous pharmacogenetic studies have evaluated the effect of polymorphism of various genes involved in MTX metabolism on MTX pharmacokinetics and the development of toxic manifestations in order to improve patient outcomes and decrease drug toxicity. This review presents impact of key metabolic MTX genes (ATIC, DHFR, GGH, FPGS, MTHFR, MTR, MTRR, TYMS) and transporter proteins genes (ABCB1, ABCG2, ABCC2, ABCC4, SLC19A1, SLCO1B1) in the development of MTX side effects. Polymorphic markers in SLCO1B1 gene have the most influence with MTX pharmacokinetic.

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GILES, M., D. C. WARHURST, K. A. WEBSTER, D. M. WEST et J. A. MARSHALL. « A multiplex allele specific polymerase chain reaction (MAS-PCR) on the dihydrofolate reductase gene for the detection of Cryptosporidium parvum genotypes 1 and 2 ». Parasitology 125, n^o 1 (juillet 2002) : 35–44. http://dx.doi.org/10.1017/s0031182002001786.

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A multiplex allele specific polymerase chain reaction (MAS-PCR) based on the Cryptosporidium parvum dihydrofolate reductase (dhfr) gene sequence differentiates genotype 1 (‘Human’) from 2 (‘Cattle’) in a 1-step reaction. The MAS-PCR was validated on a panel of 34 microscopically positive C. parvum faecal samples of human and animal origin in comparison with 2 published PCR-restriction fragment length polymorphism (RFLP) methods targeting dhfr and the oocyst wall protein (cowp) genes. A validation panel of 37 negative faecal samples of human and animal origin was also tested in comparison with the cowp PCR-RFLP. MAS-PCR was found to be as sensitive for species detection as the most sensitive of the other tests, and detected more mixed genotype infections than the two other tests combined. In addition the MAS-PCR showed equivalent detection sensitivity in comparison with a published nested RFLP targeting the SSU rRNA gene, on a panel of prepared mixed genotype samples. The 1-step reaction is simpler and less expensive to perform than the RFLP methods, while the C. parvum specific amplicons and those for genotypes 1 and 2 (575, 357 and 190 bp respectively) can be easily distinguished on agarose gel.

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Dagnogo, Oléfongo, Aristide Berenger Ako, Kouakou Brice Bla, Dougba Noel Dago, N'golo David Coulibaly, Baba Coulibaly, Offianan André Touré et Allico Joseph Djaman. « Assessing the polymorphism of DHFR gene from Plasmodium falciparum in the south of Cte dIvoire ». African Journal of Microbiology Research 14, n^o 5 (31 mai 2020) : 158–65. http://dx.doi.org/10.5897/ajmr2020.9309.

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Peyron, François, Nathalie Eudes, Frédérique de Monbrison, Martine Wallon et Stéphane Picot. « Fitness of Toxoplasma gondii is not related to DHFR single-nucleotide polymorphism during congenital toxoplasmosis ». International Journal for Parasitology 34, n^o 10 (septembre 2004) : 1169–75. http://dx.doi.org/10.1016/j.ijpara.2004.05.009.

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Adams, Michelle, Mark Lucock, John Stuart, Sean Fardell, Kerrie Baker et Xiaowei Ng. « Preliminary evidence for involvement of the folate gene polymorphism 19bp deletion-DHFR in occurrence of autism ». Neuroscience Letters 422, n^o 1 (juillet 2007) : 24–29. http://dx.doi.org/10.1016/j.neulet.2007.05.025.

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Tulstrup, Morten, Takaya Moriyama, Chuang Jiang, Marie Grosjean, Jacob Nersting, Jonas Abrahamsson, Kathrine Grell et al. « Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia ». Blood 136, n^o 10 (3 septembre 2020) : 1161–68. http://dx.doi.org/10.1182/blood.2020005064.

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Abstract Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10−8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10−9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.

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SUMMERS, CAROLYN M., ANDREW J. CUCCHIARA, ELENI NACKOS, ANDREA L. HAMMONS, ELISABETH MOHR, ALEXANDER S. WHITEHEAD et JOAN M. VON FELDT. « Functional Polymorphisms of Folate-Metabolizing Enzymes in Relation to Homocysteine Concentrations in Systemic Lupus Erythematosus ». Journal of Rheumatology 35, n^o 11 (novembre 2008) : 2179–86. http://dx.doi.org/10.3899/jrheum.080071.

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ObjectiveTo determine if functional polymorphisms of folate/homocysteine pathway enzymes are associated with homocysteine concentrations and/or coronary artery calcification (CAC) scores in patients with systemic lupus erythematosus (SLE) and controls.MethodsWe investigated 163 SLE patients and 160 controls. Functional polymorphisms in 6 genes in the folate/homocysteine pathway were genotyped: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, cystathionine β-synthase (CBS) 844ins68, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, thymidylate synthase (TYMS) 1494del6, and dihydrofolate reductase (DHFR) c.86+60_78.ResultsHomocysteine levels were higher in African American SLE patients than Caucasian patients and African American controls. Genotype distributions were significantly different in African American and Caucasian controls for 6 of the 7 polymorphisms. Genotype distributions for each polymorphism did not differ significantly between SLE patients and controls even after stratification by race. Glomerular filtration rate was strongly negatively correlated to homocysteine levels, and was therefore adjusted for as a covariate in the models of the effects of the polymorphisms on homocysteine levels. In SLE patients none of the 7 polymorphisms was associated with homocysteine concentrations. In Caucasian controls only MTHFR 677C>T and 1298A>C showed effects on homocysteine similar to what would be expected from the literature. There were no genotypic associations with median CAC scores in SLE patients or controls with and without stratification by race.ConclusionPolymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE.

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Orjuela, Manuela A., Lourdes Cabrera-Muñoz, Ligi Paul, Marco A. Ramirez-Ortiz, Xinhua Liu, Jia Chen, Fabiola Mejia-Rodriguez et al. « Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake ». Cancer 118, n^o 23 (30 mai 2012) : 5912–19. http://dx.doi.org/10.1002/cncr.27621.

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Xu, Xinran, Marilie D. Gammon, James G. Wetmur, Manlong Rao, Mia M. Gaudet, Susan L. Teitelbaum, Julie A. Britton, Alfred I. Neugut, Regina M. Santella et Jia Chen. « A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users ». American Journal of Clinical Nutrition 85, n^o 4 (1 avril 2007) : 1098–102. http://dx.doi.org/10.1093/ajcn/85.4.1098.

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Ndiaye, Daouda, Baba Dieye, Yaye D. Ndiaye, Daria Van Tyne, Rachel Daniels, Amy K. Bei, Aminata Mbaye et al. « Polymorphism in dhfr/dhps genes, parasite density and ex vivo response to pyrimethamine in Plasmodium falciparum malaria parasites in Thies, Senegal ». International Journal for Parasitology : Drugs and Drug Resistance 3 (décembre 2013) : 135–42. http://dx.doi.org/10.1016/j.ijpddr.2013.07.001.

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Dahlström, Sabina, M. Isabel Veiga, Andreas Mårtensson, Anders Björkman et J. Pedro Gil. « Polymorphism in PfMRP1 (Plasmodium falciparum Multidrug Resistance Protein 1) Amino Acid 1466 Associated with Resistance to Sulfadoxine-Pyrimethamine Treatment ». Antimicrobial Agents and Chemotherapy 53, n^o 6 (13 avril 2009) : 2553–56. http://dx.doi.org/10.1128/aac.00091-09.

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ABSTRACT Sulfadoxine-pyrimethamine (SP) remains widely recommended for intermittent preventive treatment against Plasmodium falciparum malaria for pregnant women and infants in Africa. Resistance to SP is increasing and associated primarily with mutations in the P. falciparum dhfr (Pfdhfr) and Pfdhps genes. This study aimed to explore the hypothetical association of genetic alterations in the P. falciparum multidrug resistance protein gene (Pfmrp1) with the in vivo response to SP by detecting the selection of single nucleotide polymorphisms (SNPs) following standard single-dose treatment administered to children with acute uncomplicated P. falciparum malaria in Tanzania. We detected significant selection of parasites carrying the Pfmrp1 1466K allele in samples from children with recrudescent infections, with 12 (100%) of 12 such samples being positive for this allele, compared to 52 (67.5%) of 77 baseline samples (P = 0.017), in parallel with the selection of the Pfdhfr Pfdhps quintuple mutant haplotype in cases of recrudescence (P = 0.001). There was no association between the 1466K SNP and the Pfdhfr Pfdhps quintuple mutation, indicating independent selections. Our data point for the first time to a role for a P. falciparum multidrug resistance protein homologue in the antimalarial activity of SP. Moreover, they add to the growing evidence of the potential importance of Pfmrp1 in antimalarial drug resistance.

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Stanisławska-Sachadyn, Anna, Karen S. Brown, Laura E. Mitchell, Jayne V. Woodside, Ian S. Young, John M. Scott, Liam Murray et al. « An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women ». Human Genetics 123, n^o 3 (5 février 2008) : 289–95. http://dx.doi.org/10.1007/s00439-008-0475-y.

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RAFIGHDOOST, Firoozeh, Amir RAFIGHDOOST, Houshang RAFIGHDOOST, Mohammad-Ayoob RIGI-LADEZ, Mohammad HASHEMI et Ebrahim ESKANDARI-NASAB. « The 19-bp deletion polymorphism of dihydrofolate reductase (DHFR) and nonsyndromic cleft lip with or without cleft palate : evidence for a protective role ». Journal of Applied Oral Science 23, n^o 3 (juin 2015) : 272–78. http://dx.doi.org/10.1590/1678-775720140473.

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Gemmati, Donato, Monica De Mattei, Linda Catozzi, Matteo Della Porta, Maria L. Serino, Cristina Ambrosio, Antonio Cuneo et al. « DHFR 19-bp insertion/deletion polymorphism and MTHFR C677T in adult acute lymphoblastic leukaemia : Is the risk reduction due to intracellular folate unbalancing ? » American Journal of Hematology 84, n^o 8 (août 2009) : 526–29. http://dx.doi.org/10.1002/ajh.21451.

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Johnson, William G., Edward S. Stenroos, John R. Spychala, Sansnee Chatkupt, Sue X. Ming et Steven Buyske. « New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) : A risk factor for spina bifida acting in mothers during pregnancy ? » American Journal of Medical Genetics 124A, n^o 4 (2004) : 339–45. http://dx.doi.org/10.1002/ajmg.a.20505.

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Kononova, I. N., E. N. Kareva et Yu E. Dobrokhotova. « Fourth-generation folic acid active metabolite Quatrefolic® and micronized, microencapsulated iron Lipofer® : innovative approaches for iron and folic acid deficiencies in women (a review) ». Russian Journal of Woman and Child Health 5, n^o 1 (2022) : 18–27. http://dx.doi.org/10.32364/2618-8430-2022-5-1-18-27.

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To review up-to-date management algorithms for iron and folic acid deficiency in women of reproductive age, we selected relevant publications in the PubMed and Google Scholar databases (2012–2022). Current limitations of using peroral iron salts (malabsorption, poor adherence to treatment due to gastrointestinal adverse reactions, risks of oxidative stress, and ferroptosis resulting from iron overload) were prerequisites for developing innovative technology, Lipofer®. Lipofer® is a micronized and microencapsulated iron in a phospholipid coat which provides better absorption independent of hepcidin status and targeted iron delivery in tissues with minimization of adverse reaction risks. Limitations of using folic acid include low bioavailability in polymorphisms of folate cycle enzymes (dihydrofolate reductase/DHFR and methylenetetrahydrofolate reductase/MTHFR) which results in potential toxic effects of unmetabolized folic acid and abnormal homocysteine clearance (risk factors for vascular disorders and B12-deficiency anemia masking). These entities were prerequisites for the development of Quatrefolic®. Quatrefolic® is the glucosamine salt of (6S)-5-methyltetrahydrofolate, an active metabolite of folic acid with high solubility and bioavailability ready to enter the folate cycle without involving reductases. Quatrefolic® is safe and has no risks of overdosing or effects on B12-deficiency anemia diagnosis. A combination of two high-tech molecules is an innovative therapeutic tool for essential microelement requirements in women with high risks of iron and folic acid deficiencies. KEYWORDS: iron-deficiency anemia, ferric pyrophosphate, microencapsulated iron, liposomal form, Lipofer, neural tube defect, folic acid, polymorphism, Quatrefolic, glucosamine salt. FOR CITATION: Kononova I.N., Kareva E.N. Fourth-generation folic acid active metabolite Quatrefolic® and micronized, microencapsulated iron Lipofer®: innovative approaches for iron and folic acid deficiencies in women (a review). Russian Journal of Woman and Child Health. 2022;5(1):18–27 (in Russ.). DOI: 10.32364/2618-8430-2022-5-1-18-27.

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Parle-McDermott, Anne, Faith Pangilinan, James L. Mills, Peadar N. Kirke, Eileen R. Gibney, James Troendle, Valerie B. O'Leary et al. « The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk for spina bifida in the Irish population ». American Journal of Medical Genetics Part A 143A, n^o 11 (1 juin 2007) : 1174–80. http://dx.doi.org/10.1002/ajmg.a.31725.

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Escudero Contreras, A., R. Ortega Castro, J. Calvo Gutierrez, N. Mena-Vázquez, R. Cáliz Cáliz, E. Collantes Estevez, A. Fernandez-Nebro et al. « AB0338 EVALUATION OF THE ASSOCIATION OF ALLELES OF INTOLERANCE RISK TO METOTREXATE IN RHEUMATOID ARTHRITIS PATIENTS UNDER TREATMENT WITH BIOLOGIC THERAPIES ». Annals of the Rheumatic Diseases 79, Suppl 1 (juin 2020) : 1467.2–1468. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3258.

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Background:Metotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA) both in monotherapy and in combination with biologic disease-modifying antirheumatic drugs (bDMARDs), it usually well tolerated but AEs may appear that causing toxicity that requires suspension of the treatmentObjectives:Determine the prevalence of certain polymorphisms among patients that receive bDMARD in monotherapy or in combination with MTX to confirm its relevance as biomarkers of intolerance. Evaluate the influence of certain polymorphisms in the effectiveness of monotherapy or combined treatment in patients, through“Disease Activity Score 28”(DAS28), SDAI Simple disease activity index (SDAI), Clinical disease activity index (CDAI) and each one of its componentsMethods:Retrospective observational multicentric study (University Hospital Complex, Granada, Carlos de Haya Hospital, Malaga and University Hospital Reina Sofia, Cordoba), of cases-control of 227 patients with RA (criteria ACR/EULAR), of which 120 received MTX and bDMARD combined therapy (cases) and other with only bDMARD (controls). All of them had been or were currently treated with MTX, remained with stable doses of bDMARD, and had a DNA sample stored before the inclusion in the studyDNA was isolated from total peripheral blood and by fluorescent probe HybProbe and/ or Taqman, 10 polymorphisms of 10 protein coding genes were determined involved in the metabolism and toxicity of MTX according to current evidenceBesides the type of polymorphism, data on the activity of the disease were analysed (DAS28VSG, DAS28PCR, SDAI, CDAI, at the start of the MTX income, of the BT, and in the inclusion visitA descriptive and comparative study was carried out on all that and afterwards an assessment was made through a multiple logistic regression analysis (MLR) on the risk of intolerance to MTXResults:An analysis was carried out on 227 patients (120 cases and 107 controls) with an average age of 60 (12,1) being women 78,4%, with a time of evolution since diagnosis of 14,84 (7,78) years48,9% registered adverse events (AE) MTX related, mainly gastrointestinal, hepatobiliary and skin-subcutaneous tissue. The percentage of AE appearance was superior in the monotherapy group than in the group with combined therapyThe most prevalent polymorphism (84,6% (IC95%: 84,09%-85,11%) and in cases (86,0% (IC95%: 79,43%-92,57%) washomozygous CC (ITPase-c94a); in controlshomozygous GG (GGH-T401C) (87,5% (IC95%:81,58%-93,42%)There were no significant differences in the parameters of activity between groups, in both, patients were best basally controlled than at the start of the MTX income and/or bDMARDBeinghomozygous-AA for the DHFR genewas significantly associated (p<0.05) with the appearance of AE (none of the 4 homozygous AA patients for that gene had AE)In MLR,homozygous GG(ref. heterozygous AG) in polymorphismGGH-T401C,beinghomozygous CC(ref. heterozygous TC) in polymorphismABCC2-C24TandPCR (mg/dL) at the start of bDMARDresulted independent predictive factors of MTX intoleranceConclusion:Polymorphisms T401C for the GGH gene and C24T for the ABCC2 gene and PCR at the start of the bDMARD resulted independent predictive factors of MTX intolerance. Polymorphismhomozygous AAforDHFR genewas related to significant protection against appearance of AEDisclosure of Interests:Alejandro Escudero Contreras: None declared, Rafaela Ortega Castro: None declared, Jerusalem Calvo Gutierrez: None declared, Natalia Mena-Vázquez: None declared, Rafael Cáliz Cáliz: None declared, Eduardo Collantes Estevez Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene, Antonio Fernandez-Nebro: None declared, Maria del Carmen Abalos-Aguilera: None declared, Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer., Mª Teresa Ruiz Jimenez Employee of: Roche Farma, SPAIN, Font Ugalde Pilar: None declared

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Dulucq, Stéphanie, Geneviève St-Onge, Vincent Gagné, Marc Ansari, Daniel Sinnett, Damian Labuda, Albert Moghrabi et Maja Krajinovic. « DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL ». Blood 111, n^o 7 (1 avril 2008) : 3692–700. http://dx.doi.org/10.1182/blood-2007-09-110593.

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Abstract Dihydrofolate reductase (DHFR) is the major target of methotrexate (MTX), a key component in childhood acute lymphoblastic leukemia (ALL) treatment. A total of 15 polymorphisms in DHFR promoter were analyzed, and 3 sites (C−1610G/T, C−680A, and A−317G) were identified as sufficient to define observed haplotypes (tag single nucleotide polymorphisms [tagSNPs]). These polymorphisms were investigated for association with treatment response in 277 children with ALL. Lower event-free survival (EFS) was associated with homozygosity for the allele A−317 and C−1610 (P = .03 and .02), and with the haplotype *1, defined by both C−1610 and A−317 alleles (P = .03). The haplotype *1 conferred higher transcriptional activity (P < .01 compared with haplotypes generating minimal luciferase expression). Quantitative mRNA analysis showed higher DHFR levels for particular haplotype *1 carriers (P < .01). The analysis combining haplotype *1 with thymidylate synthase (TS) and cyclin D1 (CCND1) genotypes previously shown to affect ALL outcome showed that the number of event-predisposing genotypes was associated with increasingly lower EFS (P < .001). In conclusion, DHFR promoter polymorphisms are associated with worse ALL outcome, likely due to a higher DHFR expression. Combined effects among genes of the folate cycle can further accentuate differences in the response to the treatment.

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Shiao, S., James Grayson et Chong Yu. « Gene-Metabolite Interaction in the One Carbon Metabolism Pathway : Predictors of Colorectal Cancer in Multi-Ethnic Families ». Journal of Personalized Medicine 8, n^o 3 (6 août 2018) : 26. http://dx.doi.org/10.3390/jpm8030026.

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For personalized healthcare, the purpose of this study was to examine the key genes and metabolites in the one-carbon metabolism (OCM) pathway and their interactions as predictors of colorectal cancer (CRC) in multi-ethnic families. In this proof-of-concept study, we included a total of 30 participants, 15 CRC cases and 15 matched family/friends representing major ethnic groups in southern California. Analytics based on supervised machine learning were applied, with the target variable being specified as cancer, including the ensemble method and generalized regression (GR) prediction. Elastic Net with Akaike’s Information Criterion with correction (AICc) and Leave-One-Out cross validation GR methods were used to validate the results for enhanced optimality, prediction, and reproducibility. The results revealed that despite some family members sharing genetic heritage, the CRC group had greater combined gene polymorphism-mutations than the family controls (p < 0.1) for five genes including MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, and DHFR 19bp. Blood metabolites including homocysteine (7 µmol/L), methyl-folate (40 nmol/L) with total gene mutations (≥4); age (51 years) and vegetable intake (2 cups), and interactions of gene mutations and methylmalonic acid (MMA) (400 nmol/L) were significant predictors (all p < 0.0001) using the AICc. The results were validated by a 3% misclassification rate, AICc of 26, and >99% area under the receiver operating characteristic curve. These results point to the important roles of blood metabolites as potential markers in the prevention of CRC. Future intervention studies can be designed to target the ways to mitigate the enzyme-metabolite deficiencies in the OCM pathway to prevent cancer.

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Singh, Yogita, Bijay Ranjan Mirdha, Randeep Guleria, Shehla Khalil, Ashutosh Panda, Rama Chaudhry, Anant Mohan, Sushil Kumar Kabra, Lalit Kumar et Sanjay Kumar Agarwal. « Molecular detection of DHFR gene polymorphisms in Pneumocystis jirovecii isolates from Indian patients ». Journal of Infection in Developing Countries 9, n^o 11 (30 novembre 2015) : 1250–56. http://dx.doi.org/10.3855/jidc.6810.

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Introduction: Pneumocystis pneumonia (PCP) is an opportunistic life-threatening infection, especially for immunocompromised individuals. A trimethoprim-sulfamethoxazole (TMP-SMX) combination is commonly used for the treatment of PCP, targeting both dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) enzymes. Several studies have already shown that polymorphisms in the DHPS gene are associated with drug resistance. The present study analyzed DHFR gene polymorphisms in Pneumocystis jirovecii recovered from clinical samples from patients admitted to a tertiary care health center in New Delhi, India. Methodology: Detection of P. jirovecii was performed using Gomori methenamine silver staining (GMS) and nested polymerase chain reaction (PCR) assay targeting the mitochondrial large subunit ribosomal RNA (mt LSU rRNA) gene. The DHFR gene was amplified using nested PCR protocol and was sequenced for detection of polymorphisms. Results: Of 180 clinical samples, only 4% (7/180) were positive by GMS staining, and 10% (18/180) were positive by mt LSU rRNA PCR assay. Of these 18 positive samples, only 77% (14/18) were amplified by the DHFR gene PCR assay. A total of 16 nucleotide substitutions were observed in 42% (6/14) samples targeted for the DHFR gene, of which 8 nucleotide substitutions were synonymous and the rest were non-synonymous. Conclusions: The DHFR gene mutations found in this study may possibly indicate an association of process likely to contribute to therapeutic failure or an evolutionary process, and warrant continuous monitoring.

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Reynolds, Mary G., Jung Oh et David S. Roos. « In Vitro Generation of Novel Pyrimethamine Resistance Mutations in the Toxoplasma gondiiDihydrofolate Reductase ». Antimicrobial Agents and Chemotherapy 45, n^o 4 (1 avril 2001) : 1271–77. http://dx.doi.org/10.1128/aac.45.4.1271-1277.2001.

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ABSTRACT Pyrimethamine is a potent inhibitor of dihydrofolate reductase and is widely used in the treatment of opportunistic infections caused by the protozoan parasite Toxoplasma gondii. In order to assess the potential role of dhfr sequence polymorphisms in drug treatment failures, we examined the dhfr-ts genes of representative isolates for T. gondii virulence types I, II, and III. These strains exhibit differences in their sensitivities to pyrimethamine but no differences in predicted dhfr-tsprotein sequences. To assess the potential for pyrimethamine-resistantdhfr mutants to emerge, three drug-sensitive variants of the T. gondii dhfr-ts gene (the wild-type T. gondii sequence and two mutants engineered to reflect polymorphisms observed in drug-sensitive Plasmodium falciparum) were subjected to random mutagenesis and transfected into either wild-type T. gondii parasites ordhfr-deficient Saccharomyces cerevisiae under pyrimethamine selection. Three resistance mutations were identified, at amino acid residues 25 (Trp→Arg), 98 (Leu→Ser), and 134 (Leu→His).

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Biswajit, Dubashi, Sunitha Kodidela, Suresh Chandra Pradhan, Debdatta Basu, Ravi Prasad et Umamaheswaran Gurusamy. « Influence of Dihydrofolate Reducatse (DHFR) Gene Polymorphisms on Outcome of Methotrexate Maintenance Therapy in Patients with Acute Lymphoblastic Leukemia ». Blood 124, n^o 21 (6 décembre 2014) : 3661. http://dx.doi.org/10.1182/blood.v124.21.3661.3661.

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Abstract Objectives: 1)To determine the influence of DHFR gene polymorphisms on outcome of methotrexate-based maintenance therapy in patients with acute lymphoblastic leukemia (ALL) 2)To compare the relapse free survival between DHFR genotype 3)To establish the normal allele and genotype frequencies of the DHFR polymorphisms in the South Indian population Methods: A total of thirty one patients with ALL were included for the study. A total of 85 healthy volunteers from the South India were recruited to establish the allelic frequencies of the A-317G & C-680A variants of DHFR gene. DNA was extracted by phenol chloroform method and genotyping was done by allelic discrimination method. Patients were followed up for two years for the outcome. Results: Homozygous mutant genotype carriers (GG) were at two-fold increased risk of relapse when compared to the other genotypes (AA & AG) [Relative risk= 2.6; 95% CI, 1.260 to 5.365, P<0.05]. Relapse-free survival rate was lower in GG genotype carriers when compared to wild and hetero genotypes [Log-rank test, p<0.05]. The genotype frequencies of A-317G variant in healthy volunteers were- AA=51.76%, AG=37.64%, GG=10.58% and C-608A variant genotype frequency were-CC=0%, AC=20.98%, AA=79.01%. Conclusion: GG variant of DHFR A-317G is associated with increased relapse and lower relapse-free survival in ALL patients. Disclosures No relevant conflicts of interest to declare.

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Nahimana, Aimable, Meja Rabodonirina, Jacques Bille, Patrick Francioli et Philippe M. Hauser. « Mutations of Pneumocystis jirovecii Dihydrofolate Reductase Associated with Failure of Prophylaxis ». Antimicrobial Agents and Chemotherapy 48, n^o 11 (novembre 2004) : 4301–5. http://dx.doi.org/10.1128/aac.48.11.4301-4305.2004.

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ABSTRACT Most drugs used for prevention and treatment of Pneumocystis jirovecii pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of P. jirovecii drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in P. jirovecii DHFR from 33 patients diagnosed with P. jirovecii pneumonia who were receiving prophylaxis with a DHFR inhibitor (n = 15), prophylaxis without a DHFR inhibitor (n = 11), or no prophylaxis (n = 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18; P = 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance.

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Alker, Alisa P., Victor Mwapasa et Steven R. Meshnick. « Rapid Real-Time PCR Genotyping of Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in Plasmodium falciparum ». Antimicrobial Agents and Chemotherapy 48, n^o 8 (août 2004) : 2924–29. http://dx.doi.org/10.1128/aac.48.8.2924-2929.2004.

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ABSTRACT The resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) is an emerging public health threat. Resistance to these drugs is associated with point mutations in the genes encoding dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). We describe here an assay using real-time PCR and sequence-specific probes that detects these mutations. Using DNA from plasmids, cultured strains, and clinical samples, real-time PCR could distinguish four DHPS polymorphisms (codons 437, 540, 581, and 613) and three DHFR polymorphisms (codons 51, 59, and 108). This assay is rapid and sensitive, with a detection limit of 10 copies in most cases. This assay is amenable to large-scale studies of drug resistance.

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CHANDRAN, VINOD, FOTIOS SIANNIS, PROTON RAHMAN, FAWNDA J. PELLETT, VERNON T. FAREWELL et DAFNA D. GLADMAN. « Folate Pathway Enzyme Gene Polymorphisms and the Efficacy and Toxicity of Methotrexate in Psoriatic Arthritis ». Journal of Rheumatology 37, n^o 7 (15 mai 2010) : 1508–12. http://dx.doi.org/10.3899/jrheum.091311.

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Objective.To determine the association between folate pathway gene polymorphisms and the effectiveness, toxicity, and drug survival of methotrexate (MTX) in psoriatic arthritis (PsA).Methods.Data were obtained from a longitudinal cohort of PsA patients evaluated according to a standard protocol. Data on duration of drug therapy, dose, side effects, and reasons for discontinuation are systematically recorded. Patients treated with MTX after clinic admission who had ≥ 3 swollen joints prior to initiating MTX therapy were selected for evaluation of effectiveness. Response to MTX treatment was assessed at 6 months. Data from all patients treated in the clinic with MTX were used in evaluation of toxicity and drug survival. The following single-nucleotide polymorphisms (SNP) were measured using the Sequenom platform: MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), DHFR −473T>C (rs1650697), DHFR 35289A>G (rs1232027), and RFC 80G>A (rs1051266). Fisher’s exact test, logistic regression, and Cox proportional hazard analyses were used to determine association.Results.Two hundred eighty-one patients were identified from the database. All patients were included in the analysis for side effects and drug survival, and 119 patients were included in the effectiveness analysis. The minor A allele of DHFR gene at +35289 was the only SNP demonstrating association with response to MTX therapy (OR 2.99, p = 0.02). Patients homozygous for the minor allele of MTHFR 677C/T (677TT) had more liver toxicity (Fisher exact test, p = 0.04).Conclusion.Polymorphisms of the DHFR gene may be associated with MTX efficacy. MTHFR 677TT may have a relationship with MTX-induced liver toxicity in PsA.

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Eroğlu, Aydan, Yonca Eğin et Nejat Akar. « The effects of tamoxifen on homocysteine levels in breast cancer patients ». Open Medicine 4, n^o 4 (1 décembre 2009) : 450–53. http://dx.doi.org/10.2478/s11536-009-0020-y.

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AbstractTamoxifen is widely used in the treatment of breast cancer and associated with an increased risk of thromboembolism (TE). An elevated homocysteine is one of the risk factors for TE. The aim of the study was to assess the effect of tamoxifen on serum homocysteine levels in breast cancer patients. We performed a case-control study in 20 female subjects to evaluate the relationship between homocysteine levels, and 5,10-methylenetetrahyrofolate reductase (MTHFR) C677T and dihydrofolate reductase (DHFR) 19-bp intron-1 deletion polymorphisms in breast cancer patients and in control subjects. It was observed that homocysteine levels were decreased during tamoxifen therapy, but this finding was not statistically significant. There was also no statistically significant difference in homocysteine levels between the two groups (p> 0.05). MTHFR C677T and DHFR 19-bp deletion polymorphisms were not associated with serum homocysteine value in either group.

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Mita, Toshihiro, Kazuyuki Tanabe, Nobuyuki Takahashi, Takahiro Tsukahara, Hideaki Eto, Lek Dysoley, Hiroshi Ohmae et al. « Independent Evolution of Pyrimethamine Resistance in Plasmodium falciparum Isolates in Melanesia ». Antimicrobial Agents and Chemotherapy 51, n^o 3 (8 janvier 2007) : 1071–77. http://dx.doi.org/10.1128/aac.01186-06.

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ABSTRACT Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CN RN I [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (C IRN I) or quadruple (C IRNL ) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.

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Cario, Holger, Desiree E. C. Smith, Henk J. Blom, Harald Bode, Nenad Blau, Karlheinz Holzmann, Ulrich Pannicke et al. « Dihydrofolate Reductase Deficiency Is Caused by a Homozygous DHFR Mutation and Leads to Congenital Megaloblastic Anemia and Cerebral Folate Deficiency ». Blood 116, n^o 21 (19 novembre 2010) : 1006. http://dx.doi.org/10.1182/blood.v116.21.1006.1006.

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Abstract Abstract 1006 Folate deficiency can be associated with megaloblastic anemia, neurological and mental disorders, cardiovascular disease, embryonic defects, in particular neural tube defects, and, possibly, malignancies. The importance of an intact intracellular folate metabolite cycle is illustrated by the severity of symptoms in rare inborn disorders of folate metabolism. Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) and at a lower rate of folic acid (FA) to DHF. DHFR plays a key role in maintaining intracellular folate homeostasis. A distinct genetic defect associated with DHFR deficiency has not been described. We examined three children of healthy distantly related parents presenting with megaloblastic anemia and neurological symptoms of varying severity. Total serum folate and cobalamin, homocysteine, urinary excretion of methylmalonic acid, orotic acid, formiminoglutamic acid, and cobalamin binding capacity were normal. Red blood cell (RBC) folate was below the normal range in all patients. Cerebrospinal fluid (CSF) analysis revealed very low 5-methyl-tetrahydrofolate (5MTHF) in one and the absence of detectable CSF 5MTHF in two siblings. Treatment with folinic acid (5-formyl-tetrahydrofolate; 5FTHF) increased RBC folate in all patients associated with a normalization of RBC indices and bone marrow morphology and led to CSF 5MTHF normalization. According to a recessive inheritance model, we conducted a screen for homozygous chromosomal regions using genome-wide analysis of single nucleotide polymorphisms. This analysis revealed a short overlap on the long arm of chromosome 2 and a second common region on the long arm of chromosome 5. This region included the DHFR gene locus. Genomic sequence analysis of DHFR exons and neighboring nucleotides revealed a homozygous mutation DHFR c.458A>T in exon 5 (RefSeq NM_000791) leading to the amino acid change DHFR p.Asp153Val (p.D153V) in all siblings. Assuming DHFR deficiency we analyzed folate metabolites in RBCs and plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS). The folate profile in RBCs and plasma was compatible with DHFR deficiency. To examine DHFR function we studied the formation of THF out of DHF in EBV-immortalized lymphoblastoid cells from patients, their heterozygous mother and healthy control individuals. DHFR activity was severely reduced in all patient cells (12, 88, 51 pmol THF per hour and mg protein, respectively) as compared to controls (median 3741, range 1441–6828 pmol/h*mg) whereas cells of the heterozygous mother exhibited DHFR activity close to the lower limit of the control range (1156 pmol/h*mg). A fluorescent Methotrexate (MTX) binding assay showed a markedly reduced MTX binding capacity in EBV-immortalized lymphoblastoid cells of all three patients. Cells of the heterozygous mother presented an intermediate binding capacity. To assess whether the reduced DHFR activity was caused by an altered mRNA and protein expression due to the DHFR p.Asp153Val mutation we performed RT-PCR and western blot analyses. RT-PCR revealed a single ∼450bp cDNA fragment without significant quantitative differences between DHFR wildtype, DHFR p.Asp153Val heterozygous, or homozygous cells. In contrast, DHFR protein expression was reduced in EBV-immortalized lymphoblastoid cells carrying the DHFR mutation as compared to wildtype cells. Semiquantitative assessment revealed a reduction of the amount of intact DHFR protein in heterozygous lymphoblastoid cells to about 70 percent, in homozygous cells from one patient to 50 percent and from the other patients to 20–30 percent as compared to wildtype cells. In conclusion, the homozygous mutation DHFR p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease which can successfully be treated with 5FTHF. Disclosures: No relevant conflicts of interest to declare.

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Tanomsing, Naowarat, Mallika Imwong, Sasithon Pukrittayakamee, Kesinee Chotivanich, Sornchai Looareesuwan, Mayfong Mayxay, Christiane Dolecek et al. « Genetic Analysis of the Dihydrofolate Reductase-Thymidylate Synthase Gene from Geographically Diverse Isolates of Plasmodium malariae ». Antimicrobial Agents and Chemotherapy 51, n^o 10 (6 août 2007) : 3523–30. http://dx.doi.org/10.1128/aac.00234-07.

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ABSTRACT Plasmodium malariae, the parasite responsible for quartan malaria, is transmitted in most areas of malaria endemicity and is associated with significant morbidity. The sequence of the gene coding for the enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) was obtained from field isolates of P. malariae and from the closely related simian parasite Plasmodium brasilianum. The two sequences were nearly 100% homologous, adding weight to the notion that they represent genetically distinct lines of the same species. A survey of polymorphisms of the dhfr sequences in 35 isolates of P. malariae collected from five countries in Asia and Africa revealed a low number of nonsynonymous mutations in five codons. In five of the isolates collected from southeast Asia, a nonsynonymous mutation was found at one of the three positions known to be associated with antifolate resistance in other Plasmodium species. Five isolates with the wild-type DHFR could be assayed for drug susceptibility in vitro and were found to be sensitive to pyrimethamine (mean 50% inhibitory concentration, 2.24 ng/ml [95% confidence interval, 0.4 to 3.1]).

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Xue, Ting, Wei-Qin Du, Wen-Juan Dai, Yi-Shan Li, Shu-Feng Wang, Jun-Ling Wang et Xin-Ri Zhang. « Genetic Polymorphisms of Pneumocystis jirovecii in HIV-Positive and HIV-Negative Patients in Northern China ». Polish Journal of Microbiology 71, n^o 1 (23 février 2022) : 27–34. http://dx.doi.org/10.33073/pjm-2022-002.

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Abstract Pneumocystis jirovecii is an opportunistic fungus that can cause severe and potentially fatal Pneumocystis pneumonia (PCP) in immunodeficient patients. In this study, we investigated the genetic polymorphisms of P. jirovecii at eight different loci, including six nuclear genes (ITS, 26S rRNA, sod, dhps, dhfr and β-Tub) and two mitochondrial genes (mtLSU-rRNA and cyb) in three PCP cases, including two patients with HIV infection and one without HIV infection in Shanxi Province, P.R. China. The gene targets were amplified by PCR followed by sequencing of plasmid clones. The HIV-negative patient showed a coinfection with two genotypes of P. jirovecii at six of the eight loci sequenced. Of the two HIV-positive patients, one showed a coinfection with two genotypes of P. jirovecii at the same two of the six loci as in the HIV-negative patient, while the other showed a single infection at all eight loci sequenced. None of the three drug target genes (dhfr, dhps and cyb) showed mutations known to be potentially associated with drug resistance. This is the first report of genetic polymorphisms of P. jirovecii in PCP patients in Shanxi Province, China. Our findings expand our understanding of the genetic diversity of P. jirovecii in China.

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Salazar, J., J. Gordillo Abalos, A. Fernández, M. Esteve, J. Pérez Gisbert, D. Busquets, A. Lucendo et al. « P671 Effect of genetic polymorphisms in the folate pathway on the efficacy and safety of methotrexate in Crohn’s disease ». Journal of Crohn's and Colitis 15, Supplement_1 (1 mai 2021) : S593. http://dx.doi.org/10.1093/ecco-jcc/jjab076.791.

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Abstract Background Methotrexate (MTX) is currently used in steroid-dependent patients with moderate-to-severe Crohn’s disease (CD) when thiopurines have failed or are contraindicated. Although its efficacy has been proved for both induction and maintenance of remission, its use is limited due to the rate of associated adverse events. Polymorphisms in the folate pathway might predict the efficacy and toxicity of MTX. Our aims were to evaluate the predictive value of these polymorphisms of MTX efficacy and safety in CD. Methods Patients from ENEIDA registry of GETECCU who were treated with MTX on monotherapy and of whom genomic DNA was available, were identified. Clinical efficacy and MTX-related toxicity were collected, and 10 variants from ATIC, DHFR, MTHFR, RFC1, ABCB1 and ABCC3 genes were genotyped with TaqMan assays. Results One hundred and twenty nine patients were included, 55% were female and 31% active smokers. MTX was used as first and second-line therapy in 10% and 60% of patients, respectively, at a mean dose of 22 mg and for a median time of 14 months. Thirty-seven per cent of patients achieved clinical remission, whereas 34% were non-responders (MTX failure). Forty patients (30%) developed MTX-related toxicity, with nausea and vomiting, myelotoxicity and hepatotoxicity as the most frequent adverse events (37%, 15% and 15%, respectively). MTX was discontineud in 19% of the patients due to toxicity. In the multivariable analysis, patients with the AA genotype for the rs408626 DHFR variant was predictive of a higher efficacy as compared to the G allele carriers (RR 0.372, p=0.026), and smoking was associated with a higher risk of MTX therapy failure (RR 2.676, p=0.015). Moreover, the CC genotype for the rs1476413 MTHFR variant and the TT genotype for the rs4793665 ABCC3 variant were independently associated with a higher risk of MTX toxicity (RR 2.357, p=0.038 and RR 2.368, p=0.044, respectively). Conclusion Genetic polymorphisms related to the folate pathway (mainly the variant rs408626 of DHFR, rs1476413 of MTHFR and rs4793665 of ABCC3) seem to impact on MTX efficacy and toxicity in CD. Smoking could also influence MTX efficacy.

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Wang, Feng, Paras Jain, Gulcin Gulten, Zhen Liu, Yicheng Feng, Krishna Ganesula, Alifiya S. Motiwala et al. « Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid ». Antimicrobial Agents and Chemotherapy 54, n^o 9 (21 juin 2010) : 3776–82. http://dx.doi.org/10.1128/aac.00453-10.

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ABSTRACT Mycobacterium tuberculosis enoyl-acyl-ACP reductase (InhA) has been demonstrated to be the primary target of isoniazid (INH). Recently, it was postulated that M. tuberculosis dihydrofolate reductase (DHFR) is also a target of INH, based on the findings that a 4R-INH-NADP adduct synthesized from INH by a nonenzymatic approach showed strong inhibition of DHFR in vitro, and overexpression of M. tuberculosis dfrA in M. smegmatis conferred a 2-fold increase of resistance to INH. In the present study, a plasmid expressing M. tuberculosis dfrA was transformed into M. smegmatis and M. tuberculosis strains, respectively. The transformant strains were tested for their resistance to INH. Compared to the wild-type strains, overexpression of dfrA in M. smegmatis and M. tuberculosis did not confer any resistance to INH based on the MIC values. Similar negative results were obtained with 14 other overexpressed proteins that have been proposed to bind some form of INH-NAD(P) adduct. An Escherichia coli cell-based system was designed that allowed coexpression of both M. tuberculosis katG and dfrA genes in the presence of INH. The DHFR protein isolated from the experimental sample was not found bound with any INH-NADP adduct by enzyme inhibition assay and mass spectroscopic analysis. We also used whole-genome sequencing to determine whether polymorphisms in dfrA could be detected in six INH-resistant clinical isolates known to lack mutations in inhA and katG, but no such mutations were found. The dfrA overexpression experiments, together with the biochemical and sequencing studies, conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH.

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Reeve, Stephanie M., Pablo Gainza, Kathleen M. Frey, Ivelin Georgiev, Bruce R. Donald et Amy C. Anderson. « Protein design algorithms predict viable resistance to an experimental antifolate ». Proceedings of the National Academy of Sciences 112, n^o 3 (31 décembre 2014) : 749–54. http://dx.doi.org/10.1073/pnas.1411548112.

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Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydrofolate reductase (DHFR) from Staphylococcus aureus. Four of the top-ranked mutations in DHFR were found to be catalytically competent and resistant to the inhibitor. Selection of resistant bacteria in vitro reveals that two of the predicted mutations arise in the background of a compensatory mutation. Using enzyme kinetics, microbiology, and crystal structures of the complexes, we determined the fitness of the mutant enzymes and strains, the structural basis of resistance, and the compensatory relationship of the mutations. To our knowledge, this work illustrates the first application of protein design algorithms to prospectively predict viable resistance mutations that arise in bacteria under antibiotic pressure.

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Mixson-Hayden, Tonya, Vidhan Jain, Andrea M. McCollum, Amanda Poe, Avinash C. Nagpal, Aditya P. Dash, Jonathan K. Stiles, Venkatachalam Udhayakumar et Neeru Singh. « Evidence of Selective Sweeps in Genes Conferring Resistance to Chloroquine and Pyrimethamine in Plasmodium falciparum Isolates in India ». Antimicrobial Agents and Chemotherapy 54, n^o 3 (28 décembre 2009) : 997–1006. http://dx.doi.org/10.1128/aac.00846-09.

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ABSTRACT Treatment of Plasmodium falciparum is complicated by the emergence and spread of parasite resistance to many of the first-line drugs used to treat malaria. Antimalarial drug resistance has been associated with specific point mutations in several genes, suggesting that these single nucleotide polymorphisms can be useful in tracking the emergence of drug resistance. In India, P. falciparum infection can manifest itself as asymptomatic, mild, or severe malaria, with or without cerebral involvement. We tested whether chloroquine- and antifolate drug-resistant genotypes would be more commonly associated with cases of cerebral malaria than with cases of mild malaria in the province of Jabalpur, India, by genotyping the dhps, dhfr, pfmdr-1, and pfcrt genes using pyrosequencing, direct sequencing, and real-time PCR. Further, we used microsatellites surrounding the genes to determine the origins and spread of the drug-resistant genotypes in this area. Resistance to chloroquine was essentially fixed, with 95% of the isolates harboring the pfcrt K76T mutation. Resistant genotypes of dhfr, dhps, and pfmdr-1 were found in 94%, 17%, and 77% of the isolates, respectively. Drug-resistant genotypes were equally likely to be associated with cerebral malaria as with mild malaria. We found evidence of a selective sweep in pfcrt and, to a lesser degree, in dhfr, indicating high levels of resistance to chloroquine and evolving resistance to pyrimethamine. Microsatellites surrounding pfcrt indicate that the resistant genotypes (SVMNT) were most similar to those found in Papua New Guinea.

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Domingo, Pere, M. Carmen Cabeza, Alain Pruvost, Ferran Torres, Juliana Salazar, M. del Mar Gutierrez, M. Gracia Mateo et al. « Association of Thymidylate Synthase Gene Polymorphisms with Stavudine Triphosphate Intracellular Levels and Lipodystrophy ». Antimicrobial Agents and Chemotherapy 55, n^o 4 (31 janvier 2011) : 1428–35. http://dx.doi.org/10.1128/aac.01589-10.

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ABSTRACTThe antiviral activity and toxicity of stavudine (d4T) depend on its triphosphate metabolite, stavudine triphosphate (d4T-TP). Therefore, modifications in intracellular levels of d4T-TP may change the toxicity profile of stavudine. d4T-TP intracellular levels in peripheral blood mononuclear cells were determined with a prominence liquid chromatograph connected to a triple-quadruple mass spectrometer. Polymorphisms in the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), reduced folate carrier 1 (RFC1; SLC19A1), and cyclin D1 (CCND1) genes were determined by direct sequencing using an ABI Prism 3100 genetic analyzer or Fluidigm's Biomark system. The Mann-Whitney test, rank analysis of variance (with Bonferroni's adjustedpost hoccomparisons), and logistic regression were used for the inferential analyses. Thirty-three stavudine-treated patients were enrolled in this cross-sectional study. d4T-TP intracellular levels were 11.50 fmol/106cells (interquartile range [IQR] = 8.12 to 13.87 fmol/106cells) in patients with a high-expression TS genotype (2/3G, 3C/3G, and 3G/3G), whereas in those with a low-expression TS genotype (2/2, 2/3C, and 3C/3C), they were 21.40 fmol/106cells (IQR = 18.90 to 27.0 fmol/106cells) (P< 0.0001). Polymorphisms in the MTHFR, DHFR, RFC1, and CCND1 genes did not influence the intracellular concentration of d4T-TP. d4T-TP levels were independently associated with the TS genotype (low versus high expression; odds ratio [OR] = 86.22; 95% confidence interval [CI] = 8.48 to nonestimable;P= 0.0023). The low-expression TS genotype was associated with the development of HIV/highly active antiretroviral therapy-associated lypodystrophy syndrome (HALS) (OR = 14.0; 95% CI = 2.09 to 108.0;P= 0.0032). Our preliminary data show that polymorphisms in the thymidylate synthase gene are strongly associated with d4T-TP intracellular levels and with development of HALS.

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Ludovini, V., L. Crinò, L. Pistola, I. Floriani, M. Meacci, R. Chiari, D. Garavaglia et al. « Effect of genetic polymorphisms on toxicity and survival in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with carboplatin (CBDCA) and pemetrexed disodium regimen ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : e19028-e19028. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19028.

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e19028 Background: Identification of genetic polymorphisms which influence chemotherapy outcome may help towards individually optimized therapy. We investigated the influence of ten single nucleotide polymorphisms (SNPs) of 7 genes (P53 Arg72Pro (G/C); XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); ERCC1 Asn118Asn (C/T); GARFT C/G, GARFT C/T, DHFR C/G, DHFR A/G, TS 5’UTR, TS 3’UTR involved with metabolism of CBDCA and Alimta regimen in pts with advanced NSCLC. Methods: Genomic DNA was extracted from whole blood samples using the QIAamp DNA estraction kit on Biorobot EZ1 (Qiagen). Polymorphisms were detected with TaqMan-probe based assays using the 7300 Real-Time PCR system (Applied Biosystems, Foster City, CA) or PCR followed by RFLP. The results of SNPs were assessed by Cox model for survival/PFS & logistics regression for response/toxicity. Results: We performed a retrospective analysis in 57 advanced pretreated (2nd or 3th line) NSCLC pts treated with CBDCA(AUC=5) + Alimta (500 mg/m2). Median age was 59 years (range 26–79), M/F:63/37%; Adeno/Squa/other Ca:65/20/15%; ECOG PS:0–1/2–3:96/4%. Overall response rate was 38.6%, stable disease 38.6% and disease progression 21.1%. At median follow-up of 7.9 months, 10 pts (17.5%) died, 47 pts (82.5%) are alive. The median progression free survival (PFS) was 7.4 months, the median survival time not reached. P53 Pro72Pro was significantly associated with shorter survival (HR 5.5, 95%CI 1.01–30.5, p=0.04) when compared to P53 Arg72Arg. None of the analyzed polymorphisms was related to response to therapy. No associations were found between the analyzed polymorphisms and toxicity considered either as the maximum observed grade, or as sum of each toxicity pattern grade, probably due to low number of events observed for toxicity within this data set. Conclusions: P53 Pro72Pro may be associated with shorter survival in pts with advanced NSCLC. Further studies are warranted to validate this finding. Genotype-related differences in common toxicities and in response to therapy were not observed. The small sample size limits interpretation of these data. No significant financial relationships to disclose.

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