RESUMO
Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.
Assuntos
Doenças Inflamatórias Intestinais , Inibidores do Fator de Necrose Tumoral , Humanos , Criança , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/genética , Estudos Prospectivos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único , BiomarcadoresRESUMO
Vitamin D is an environmental factor related to multiple sclerosis that plays a significant role in immune regulation. TGF-ß is a superfamily of cytokines with an important dual effect on the immune system. TGF-ß inhibits the Th1 response while facilitating the preservation of regulatory T cells (FOXP3+) in an immunoregulatory capacity. However, when IL-6 is present, it stimulates the Th17 response. Our aim was to analyze the regulatory effect of vitamin D on the in vivo TGF-ß signaling pathway in patients with relapsing-remitting multiple sclerosis (RRMS). A total of 21 patients with vitamin D levels < 30 ng/mL were recruited and supplemented with oral vitamin D. All patients were receiving disease-modifying therapy, with the majority being on natalizumab. Expression of SMAD7, ERK1, ZMIZ1, BMP2, BMPRII, BMP4, and BMP5 was measured in CD4+ lymphocytes isolated from peripheral blood at baseline and one and six months after supplementation. SMAD7 was overexpressed at six months with respect to baseline and month one. ERK1 was overexpressed at six months with respect to month one of treatment. No significant differences in expression were observed for the remaining genes. No direct correlation was found with serum vitamin D levels. BMPRII expression changed differentially in non-natalizumab- versus natalizumab-treated patients. Changes were observed in the expression of ERK1, BMP2, and BMP5 based on disease activity measured using the Rio-Score, BMP2 in patients who had relapses, and BMP5 in those whose EDSS worsened. Our results suggest indirect regulation of vitamin D in TGF-ß pathway genes in patients with RRMS.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Vitamina D/metabolismo , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/genética , Natalizumab , Vitaminas/farmacologia , Vitaminas/uso terapêutico , Fator de Crescimento Transformador beta/genéticaRESUMO
The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.
Assuntos
Doenças Inflamatórias Intestinais , Inibidores do Fator de Necrose Tumoral , Adulto , Humanos , Criança , Adolescente , Infliximab/uso terapêutico , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único , DNA/uso terapêutico , Estudos RetrospectivosRESUMO
To assess the proposed associations of the c.742-227G>A (rs2612091) polymorphism within the Enolase Superfamily Member 1 gene (ENOSF1) and two variants in the adjacent Thymidylate Synthase gene (TYMS): the 5'VNTR 28bp-repeat (rs45445694) and 3'UTR 6bp-indel (rs11280056) with severe toxicity in fluoropyrimidine-treated cancer patients, we performed an individual patient data meta-analysis. Only studies investigating all three-abovementioned variants with fluoropyrimidine-related toxicities were considered for meta-analysis. Associations were tested individually for each study using multivariate regression. Meta-analysis was performed using a random-effects model. One-stage multivariate regressions including tests for independent SNP effects were applied to investigate individual effects of the variants. Multivariate haplotype regression analyses were performed on a pooled dataset to test multi-SNP effects. Of four studies including 2'067 patients, 1'912 were eligible for meta-analysis. All variants were exclusively associated with severe hand-foot-syndrome (HFS) (TYMS 2R: ORâ¯=â¯1.50, pâ¯=â¯0.0002; TYMS 6bp-ins: ORâ¯=â¯1.42 pâ¯=â¯0.0036; ENOSF1 c.742-227G: ORâ¯=â¯1.64 pâ¯<â¯0.0001, per allele). We observed independent effects for ENOSF1 c.742-227G>A and the TYMS 28bp-repeat: each toxicity-associated allele increased the risk for severe HFS (ORâ¯=â¯1.32 per allele, pâ¯<â¯0.0001). Patients homozygous for both variants were at the 3-fold higher risk for severe HFS compared to wild-type patients. Our results confirm an essential role for ENOSF1 c.742-227G and TYMS 2R-alleles in the development of fluoropyrimidine-related HFS. This suggests an important function of these genes in the development of severe HFS. Furthermore, these variants might help stratify patients in studies investigating measures of HFS prevention.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Fluoruracila/efeitos adversos , Síndrome Mão-Pé/genética , Hidroliases/genética , Neoplasias/tratamento farmacológico , Timidilato Sintase/genética , Humanos , Neoplasias/genéticaRESUMO
OBJECTIVES: Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS: An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS: After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P valueâ<â0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value â<â0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P valueâ<â0.05). CONCLUSIONS: Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Adulto , Criança , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Infliximab/uso terapêutico , Necrose , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/genéticaRESUMO
Around a 20-30% of inflammatory bowel disease (IBD) patients are diagnosed before they are 18 years old. Anti-TNF drugs can induce and maintain remission in IBD, however, up to 30% of patients do not respond. The aim of the work was to identify markers that would predict an early response to anti-TNF drugs in pediatric patients with IBD. The study population included 43 patients aged <18 years with IBD who started treatment with infliximab or adalimumab. Patients were classified into primary responders (n = 27) and non-responders to anti-TNF therapy (n = 6). Response to treatment could not be analyzed in 10 patients. Response was defined as a decrease in over 15 points in the disease activity indexes from week 0 to week 10 of infliximab treatment or from week 0 to week 26 of adalimumab treatment. The expression profiles of nine genes in total RNA isolated from the whole-blood of pediatric IBD patients taken before biologic administration and after 2 weeks were analyzed using qPCR and the 2-∆∆Ct method. Before initiation and after 2 weeks of treatment the expression of SMAD7 was decreased in patients who were considered as non-responders (p value < 0.05). Changes in expression were also observed for TLR2 at T0 and T2, although that did not reach the level of statistical significance. In addition, the expression of DEFA5 decreased 1.75-fold during the first 2 weeks of anti-TNF treatment in responders, whereas no changes were observed in non-responders. Expression of the SMAD7 gene is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD. TLR2 and DEFA5 need to be validated in larger studies.
Assuntos
Adalimumab/farmacologia , Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/farmacologia , Transcriptoma/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Adolescente , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/genética , Infliximab/uso terapêutico , Masculino , RNA Mensageiro/biossíntese , RNA Mensageiro/sangue , RNA Mensageiro/genética , Receptores Tipo II do Fator de Necrose Tumoral/biossíntese , Receptores Tipo II do Fator de Necrose Tumoral/genética , Proteína Smad7/biossíntese , Proteína Smad7/genética , Receptor 2 Toll-Like/biossíntese , Receptor 2 Toll-Like/genética , Resultado do Tratamento , Receptor Gatilho 1 Expresso em Células Mieloides/biossíntese , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , alfa-Defensinas/biossíntese , alfa-Defensinas/genéticaRESUMO
The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We aimed to identify biomarkers of MS in an accessible sample, such as blood, by quantifying the relative expression of 91 Th17-related genes in CD4+ T lymphocytes from patients with MS during a relapse or during a remitting phase. We also compared our findings with those of healthy controls. After confirmation in a validation cohort, expression of SMAD7 and S1PR1 mRNAs was decreased in remitting disease (-2.3-fold and -1.3-fold, respectively) and relapsing disease (-2.2-fold and -1.3-fold, respectively). No differential expression was observed for other SMAD7-related genes, namely, SMAD2, SMAD3, and SMAD4. Under-regulation of SMAD7 and S1PR1 was also observed in another autoimmune disease, Crohn's disease (CD) (-4.6-fold, -1.6-fold, respectively), suggesting the presence of common markers for autoimmune diseases. In addition, expression of TNF, SMAD2, SMAD3, and SMAD4 were also decreased in CD (-2.2-fold, -1.4-fold, -1.6-fold, and -1.6-fold, respectively). Our study suggests that expression of SMAD7 and S1PR1 mRNA in blood samples are markers for MS and CD, and TNF, SMAD2, SMAD3, and SMAD4 for CD. These genes could prove useful as markers of autoimmune diseases, thus obviating the need for invasive methods.
Assuntos
Biomarcadores/análise , Doença de Crohn/imunologia , Esclerose Múltipla/imunologia , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato/genética , Linfócitos T CD4-Positivos , Humanos , Proteína Smad2/genética , Proteína Smad3/genética , Proteína Smad4/genética , Proteína Smad7/genética , Células Th17/imunologia , Fator de Crescimento Transformador beta/genéticaRESUMO
INTRODUCTION: Several factors, such as trough serum anti-TNF levels, have been associated with response to therapy in Crohn's disease. However, this association is observed after initiation of treatment. Identifying DNA variants may prove useful for predicting long-term response or failure to these drugs before initiation of treatment. OBJECTIVE: To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn's disease. PATIENTS AND METHODS: An observational, longitudinal study was conducted. We analyzed blood samples from 132 infliximab-treated patients diagnosed with Crohn's disease from 2 hospitals. We genotyped 21 polymorphisms previously related to anti-TNF response in genes involved in the NFkB-mediated inflammatory response, TNFα-signaling and cytokines regulated by NFkB, using real-time PCR. Trough infliximab levels were measured using ELISA. The association between SNPs and time-to-failure (defined as the time from the initiation of induction therapy to the date of treatment withdrawal due to a primary or secondary failure) was analyzed using log-rank test. The association between SNPs and supra-(>7⯵g/mL) or infratherapeutic (<3⯵g/mL) infliximab trough levels was analyzed using a linear-by-linear association chi-squared test. RESULTS: Two SNPs in TLR2, rs1816702 and rs3804099, and 1 SNP in TNFRSF1B, rs1061624, were associated with long-term response (up to ten years follow-up) to infliximab (HR, 0.13 [95%CI, 0.02-1.00], pâ¯<â¯0.05; HR, 0.39 [95%CI, 0.18-0.88], pâ¯<â¯0.05; and HR, 0.04 [95%CI, 0.18-0.92] pâ¯>â¯0.05, respectively). In addition, IL6 rs10499563 C and IL10 rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10 rs3024505â¯T was associated with infratherapeutic levels (pâ¯<â¯0.05). CONCLUSION: Genotyping of the variants identified in the genes encoding TLR2, TNFRSF1B, IL6 and IL10 reported herein represent a promising tool for the identification and selection of those patients who will benefit most from infliximab.
Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Criança , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Feminino , Humanos , Interleucina-10/genética , Interleucina-6/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptor 2 Toll-Like/genética , Resultado do Tratamento , Adulto JovemRESUMO
Background Therapeutic drug monitoring (TDM) of adalimumab (ADA) in inflammatory bowel diseases (IBDs) has gained increased attention since several studies showed a correlation between drug levels and mucosal healing. The limitations of routine usage of enzyme-linked immunoabsorbent assay (ELISA) kits for measuring serum ADA concentrations have prompted the development of rapid methods, such as Quantum Blue (QB). We evaluated the interchangeability and agreement between the QB method and two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT). Methods Fifty samples from patients with IBD were included. Quantitative analysis was performed using the ANOVA test for repeated measures, Deming regression and the Bland-Altman plot. Clinical implications were evaluated by concordance in classifying patients into therapeutic windows according to the proposed cut-off levels for subtherapeutic (either <5 or <7.5 µg/mL) and supratherapeutic (>12 µg/mL) ranges. Results Statistical differences were detected between the QB method and the two ELISA kits, with QB overestimating ADA serum values compared to them. A lack of interchangeability was observed between methods, with greater differences as ADA levels increased. An analysis of a sub-set of samples with ADA values below 9 µg/mL (n = 25) showed that QB fulfilled the criteria to be interchangeable with the LT assay. Concordance for patient classification into ADA therapeutic windows was better for QB vs. LT than for QB vs. PM, with high agreement (>75%) for subtherapeutic levels among the three methods. Conclusions Although quantitative differences existed between the rapid method and ELISA kits that hampered their interchangeability, the agreement for identifying patients with subtherapeutic values of ADA was high.
Assuntos
Adalimumab/análise , Ensaio de Imunoadsorção Enzimática/métodos , Adalimumab/sangue , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Ensaios Enzimáticos , Feminino , Fármacos Gastrointestinais/sangue , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/sangue , Masculino , Pessoa de Meia-Idade , EspanhaRESUMO
Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Irinotecano/efeitos adversos , Inibidores da Topoisomerase I/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Feminino , Genótipo , Glucuronosiltransferase/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P<0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/toxicidade , Capecitabina/uso terapêutico , Capecitabina/toxicidade , Neoplasias Colorretais/tratamento farmacológico , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: A primary challenge in identifying replicable pharmacogenomic markers from clinical genomewide association study (GWAS) trials in oncology is the difficulty in performing a second large clinical trial with the same drugs and dosage regimen. We sought to overcome this challenge by incorporating GWAS results from cell-based studies using the same chemotherapy as a clinical cohort. METHODS: In this study, we test whether the overlap between genetic variants identified in a preclinical study and a clinical study on capecitabine is more than expected by chance. A GWAS of capecitabine-induced cytotoxicity was performed in 164 lymphoblastoid cell lines derived from the CEU HapMap population and compared with a GWAS of hand-foot syndrome (HFS), the most frequent capecitabine-induced adverse drug reaction, in Spanish breast and colorectal cancer patients (n=160) treated with capecitabine. RESULTS: We observed an overlap of 16 single nucleotide polymorphisms associated with capecitabine-induced cytotoxicity (P<0.001) in lymphoblastoid cell lines and HFS (P<0.05) in patients, which is a greater overlap than expected by chance (genotype-phenotype permutation empirical P=0.015). Ten tag single nucleotide polymorphisms, which cover the overlap loci, were genotyped in a second patient cohort (n=85) and one of them, rs9936750, was associated with capecitabine-induced HFS (P=0.0076). CONCLUSION: The enrichment results imply that cellular models of capecitabine-induced cytotoxicity may capture components of the underlying polygenic architecture of related toxicities in patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias Colorretais/genética , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Síndrome Mão-Pé/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Capecitabina , Ensaios Clínicos como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Estudo de Associação Genômica Ampla , Genômica , Síndrome Mão-Pé/patologia , Humanos , Farmacogenética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. OBJECTIVE: The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. METHODS: This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). RESULTS: Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066 L/h/46.4 kg, 0.0055 L/h/46.4 kg, 0.0081 L/h/46.4 kg, 0.0029 L/h/46.4 kg, 0.6750 L/46.4 kg, and 1.19 L/46.4 kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. CONCLUSIONS: A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.
Assuntos
Biomarcadores , Monitoramento de Medicamentos , Doenças Inflamatórias Intestinais , Infliximab , Polimorfismo de Nucleotídeo Único , Humanos , Infliximab/farmacocinética , Infliximab/uso terapêutico , Criança , Masculino , Adolescente , Feminino , Pré-Escolar , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Biomarcadores/sangue , Monitoramento de Medicamentos/métodos , Lactente , Fármacos Gastrointestinais/farmacocinética , Fármacos Gastrointestinais/uso terapêutico , Modelos Biológicos , EspanhaRESUMO
BACKGROUND/AIMS: Changes in gene expression profiles among individuals with inflammatory bowel diseases (IBDs) could potentially influence the responsiveness to anti-TNF treatment. The aim of this study was to identify genes that could serve as predictors of early response to anti-TNF therapies in pediatric IBD patients prior to the initiation of treatment. METHODS: We conducted a prospective, longitudinal, and multicenter study, enrolling 24 pediatric IBD patients aged less than 18 years who were initiating treatment with either infliximab or adalimumab. RNA-seq from blood samples was analyzed using the DESeq2 library by comparing responders and non-responders to anti-TNF drugs. RESULTS: Bioinformatic analyses unveiled 102 differentially expressed genes, with 99 genes exhibiting higher expression in responders compared to non-responders prior to the initiation of anti-TNF therapy. Functional enrichment analyses highlighted defense response to Gram-negative bacteria (FDR = 2.3 ×10-7) as the most significant biological processes, and hemoglobin binding (FDR = 0.002), as the most significant molecular function. Gene Set Enrichment Analysis (GSEA) revealed notable enrichment in transcriptional misregulation in cancer (FDR = 0.016). Notably, 13 genes (CEACAM8, CEACAM6, CILP2, COL17A1, OLFM4, INHBA, LCN2, LTF, MMP8, DEFA4, PRTN3, AZU1, and ELANE) were selected for validation, and a consistent trend of increased expression in responders prior to drug administration was observed for most of these genes, with findings for 4 of them being statistically significant (CEACAM8, LCN2, LTF2, and PRTN3). CONCLUSIONS: We identified 102 differentially expressed genes involved in the response to anti-TNF drugs in children with IBDs and validated CEACAM8, LCN2, LTF2, and PRTN3. Genes participating in defense response to Gram-negative bacterium, serine-type endopeptidase activity, and transcriptional misregulation in cancer are good candidates for anticipating the response to anti-TNF drugs in children with IBDs.
Assuntos
Doenças Inflamatórias Intestinais , Neoplasias , Criança , Humanos , Biomarcadores/metabolismo , Expressão Gênica , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Preparações Farmacêuticas , Estudos Prospectivos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa , AdolescenteRESUMO
BACKGROUND: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. RESULTS: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (Preplication=0.042; Ppooled=5.523x10-03; OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (Preplication=0.039; Ppooled=6.985x10-5; OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance. CONCLUSIONS: We have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction.
Assuntos
Neoplasias Colorretais/genética , Genoma Humano , Estudo de Associação Genômica Ampla , População Branca/genética , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 8 , Estudos de Coortes , Fosfatases de Especificidade Dupla/genética , Feminino , Loci Gênicos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Fatores de Risco , EspanhaRESUMO
We studied changes in gene expression induced by the carbosilane dendrimer 2G-NN16 to evaluate their potential as a vehicle for gene therapy and as medication. Global gene expression profiles on CD8+ T lymphocytes reveal that ribosomal proteins are induced in the presence of 2G-NN16. IL17A and IL17F, the principal interleukins secreted by Tc17 cells, a subset of CD8+ T lymphocytes, were down-regulated when cultured in the presence of this dendrimer. Microarray results were confirmed by real time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). 2G-NN16 also showed a high potential for in vitro inhibition of Tc17 differentiation of CD8+ T lymphocytes in the presence of the Tc17 differentiation molecules IL6 and TGF-B1. These findings suggest that 2G-NN16 could facilitate drug delivery and may be used to treat inflammatory processes driven by Tc17 cells.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Dendrímeros/farmacologia , Regulação para Baixo/efeitos dos fármacos , Silanos/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dendrímeros/efeitos adversos , Dendrímeros/química , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes/efeitos adversos , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Nanopartículas/efeitos adversos , Nanopartículas/química , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Silanos/efeitos adversos , Silanos/química , Regulação para Cima/efeitos dos fármacosRESUMO
Although a cure is the main goal of a treatment, serious adverse reactions associated with these treatments are a major problem in clinical practice and cost a lot of money for health systems [...].