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PURPOSE OF REVIEW: Marked inter-individual differences in the clinical manifestation of coronavirus disease 2019 (COVID-19) has initiated studies in the field of genetics. This review evaluates recent genetic evidence (predominantly in the last 18âmonths) related to micronutrients (vitamins and trace elements) and COVID-19. RECENT FINDINGS: In patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), altered circulating levels of micronutrients may serve as prognostic markers of disease severity. Mendelian randomization (MR) studies did not find significant effect of variable genetically predicted levels of micronutrients on COVID-19 phenotypes, however, recent clinical studies on COVID-19 point out to vitamin D and zinc supplementation as a nutritional strategy to reduce disease severity and mortality. Recent evidence also points to variants in vitamin D receptor ( VDR ) gene, most notably rs2228570 (FokI) "f" allele and rs7975232 (ApaI) "aa" genotype as poor prognostic markers. SUMMARY: Since several micronutrients were included in the COVID-19 therapy protocols, research in the field of nutrigenetics of micronutrients is in progress. Recent findings from MR studies prioritize genes involved in biological effect, such as the VDR gene, rather than micronutrient status in future research. Emerging evidence on nutrigenetic markers may improve patient stratification and inform nutritional strategies against severe COVID-19.
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COVID-19 , Oligoelementos , Vitaminas , COVID-19/genética , COVID-19/inmunología , COVID-19/metabolismo , Vitamina D/sangre , Vitamina D/metabolismo , Zinc/metabolismo , Micronutrientes/metabolismo , Humanos , Nutrigenómica , Vitaminas/metabolismo , Oligoelementos/metabolismo , SARS-CoV-2/fisiologíaRESUMEN
Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133 and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS) model. Association was found between MTHFR rs1801133 and higher risk for elevated systolic pressure in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS rank and elevated systolic pressure. Our results open a door wide for more extensive research on pharmacogenomics markers in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with SSc and help in prevention of adverse drug reactions.
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Variantes Farmacogenómicas , Esclerodermia Sistémica , Humanos , Genotipo , Azatioprina/uso terapéutico , Metotrexato/efectos adversos , Esclerodermia Sistémica/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genéticaRESUMEN
Gastrointestinal disturbances, nutritional deficiencies, and food intolerances are frequently observed in children with neurodevelopmental disorders (NDD). To reveal possible association of celiac disease risk variants (HLA-DQ), lactose intolerance associated variant (LCT-13910C>T) as well as variant associated with vitamin D function (VDR FokI) with NDD, polymerase chain reaction-based methodology was used. Additionally, intestinal peptide permeability was estimated in NDD patients and healthy children by measuring the level of peptides in urine using high-performance liquid chromatography. Levels of opioid peptides, casomorphin 8, and gluten exorphin C were significantly elevated in urine samples of NDD patients (P = 0.004 and P = 0.005, respectively), but no association of genetic risk variants for celiac disease and lactose intolerance with NDD was found. Our results indicate that increased intestinal peptide permeability observed in analyzed NDD patients is not associated with genetic predictors of celiac disease or lactose intolerance. We have also found that FF genotype of VDR FokI and lower serum levels of vitamin D (25-OH) showed association with childhood autism (CHA), a subgroup of NDD. We hypothesize that vitamin D might be important for the development of CHA.
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Enfermedad Celíaca/genética , Intolerancia a la Lactosa/genética , Trastornos del Neurodesarrollo/orina , Péptidos/orina , Receptores de Calcitriol/sangre , Vitamina D/sangre , Estudios de Casos y Controles , Enfermedad Celíaca/sangre , Enfermedad Celíaca/orina , Niño , Preescolar , Femenino , Variación Genética , Técnicas de Genotipaje , Antígenos HLA-DQ/metabolismo , Humanos , Intolerancia a la Lactosa/sangre , Intolerancia a la Lactosa/orina , Masculino , Trastornos del Neurodesarrollo/sangre , Trastornos del Neurodesarrollo/genética , Péptidos/farmacocinética , Receptores de Calcitriol/genética , Factores de Riesgo , UrinálisisRESUMEN
BACKGROUND AND AIMS: Mucosal gene expression have not been fully enlightened in inflammatory bowel disease (IBD). Aim of this study was to define IL23A, IL17A, IL17F and TLR9 expression in different IBD phenotypes. METHODS: Evaluation of mRNA levels was performed in paired non-inflamed and inflamed mucosal biopsies of newly diagnosed 50 Crohn's disease (CD) and 54 ulcerative colitis (UC) patients by quantitative real-time PCR analysis. RESULTS: IL17A and IL17F expression levels were significantly increased in inflamed IBD mucosa. Inflamed CD ileal and UC mucosa showed increased IL23A, while only inflamed CD ileal samples showed increased TLR9 mRNA level. Correlation between analysed mRNAs levels and endoscopic and clinical disease activity were found in UC, but only with clinical activity in CD. CONCLUSION: Both CD and UC presented expression of Th17-associated genes. Nevertheless, expression profiles between different disease forms varies which should be taken into account for future research and therapeutics strategies.
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Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Interleucina-17/genética , Subunidad p19 de la Interleucina-23/genética , Receptor Toll-Like 9/genética , Adulto , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Colon/inmunología , Colon/metabolismo , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Estudios Transversales , Femenino , Perfilación de la Expresión Génica , Humanos , Íleon/inmunología , Íleon/metabolismo , Interleucina-17/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Serbia , Transducción de Señal , Receptor Toll-Like 9/inmunologíaRESUMEN
BACKGROUND: Stress is a potentially significant risk factor for the occurrence and progression of inflammatory bowel disease (IBD). METHODS: The study analyzed the level of stress, anxiety, and depression in patients with Crohn's disease (CD; nâ =â 50) and ulcerative colitis (UC; nâ =â 54) in comparison with non-IBD controls (nâ =â 100), using Perceived Stress Scale (PSS), Patient Health Questionnaire (PHQ-9), and Hospital Anxiety and Depression Scale (HADS) questionnaires. Additionally, a correlation between psychological scores and expression of IL17A, IL17F, and IL23A genes in the intestinal mucosa of IBD patients was assessed. RESULTS: Compared to controls, CD and UC patients had higher PSS (Pâ =â 4 × 10-14, Pâ =â 2.5 × 10-16), PHQ-9 (Pâ =â 2 × 10-16, Pâ =â 2 × 10-16), HADS depression (Pâ =â 2.6 × 10-10, Pâ =â 2.5 × 10-11), and HADS anxiety (Pâ =â 3.5 × 10-9, Pâ =â 1.2 × 10-11). We found a positive correlation between PSS and IL17F mRNA (rsâ =â 0.43, Pâ =â .036) while HADS depression and HADS anxiety positively correlated with the IL23A mRNA in inflamed ileal mucosa of CD subjects (rsâ =â 0.55, Pâ =â .0048; rsâ =â 0.53, Pâ =â .0062). CONCLUSIONS: A significantly higher psychological distress was identified in IBD patients. CD patients with increased ileal expression of IL17F and IL23A genes had higher PSS and HADS, suggesting a potential interplay between psychological distress and inflammation.
The study found elevated levels of perceived stress, depression, and anxiety in IBD. IL17F mRNA correlated with perceived stress while IL23A mRNA correlated with anxiety and depression (HADS) in the ileal mucosa of CD patients.
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Hereditary persistence of fetal hemoglobin (HPFH) is a rare hereditary condition resulting in elevated levels of fetal hemoglobin (HbF) in adults. Typical HPFH is associated with promoter mutations or large deletions affecting the human fetal globin (HBG1 and HBG2) genes, while genetic defects in other genes involved in human erythropoiesis, e.g. KLF1, also result in atypical HPFH. Here, we report the first KLF1 gene promoter mutation (KLF1:g.-148G > A) that is associated with increased HbF level. This mutation was shown to result in drastically reduced CAT reporter gene expression in K562 cells, compared to the wild-type sequence (p = 0.009) and also in reduced KLF1 gene expression in vivo. Furthermore, consistent with in silico analysis, electrophoretic mobility shift analysis showed that the KLF1:g.-148G > A mutation resides in a Sp1 binding site and further that this mutation leads to the ablation of Sp1 binding in vitro. These data suggest that the KLF1:g-148G > A mutation could play a role in increasing HbF levels in adults and further underlines the role of KLF1 as one of the key transcription factors involved in human fetal globin gene switching.
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Hemoglobina Fetal/biosíntesis , Hemoglobinopatías/genética , Factores de Transcripción de Tipo Kruppel/genética , Mutación , Regiones Promotoras Genéticas/genética , Adulto , Sitios de Unión/genética , Ensayo de Cambio de Movilidad Electroforética , Femenino , Hemoglobina Fetal/genética , Regulación de la Expresión Génica , Genes Reporteros , Humanos , Células K562/metabolismo , Factores de Transcripción de Tipo Kruppel/fisiología , Unión Proteica , Reacción en Cadena en Tiempo Real de la Polimerasa , Serbia , Factor de Transcripción Sp1/metabolismo , Transcripción GenéticaRESUMEN
Host genetics, an important contributor to the COVID-19 clinical susceptibility and severity, currently is the focus of multiple genome-wide association studies (GWAS) in populations affected by the pandemic. This is the first study from Serbia that performed a GWAS of COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128 hospitalized COVID-19 patients from the Serbian population was enrolled in the study. We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients, using a genotyping array followed by imputation of missing genotypes. We have detected a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with a peak residing upstream of the gene KLHL1 (p = 1.91 × 10-8). Our study also replicated a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 × 10-6) and severe COVID-19 (p = 6.88 × 10-7), respectively. Suggestive association with COVID-19 pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6, MRPL36, p = 2.81 × 10-6), 5q11.2 (ESM1, p = 6.59 × 10-6), and 9p23 (TYRP1, LURAP1L, p = 8.69 × 10-6). The genes located in or near the risk loci are expressed in neural or lung tissues, and have been previously associated with respiratory diseases such as asthma and COVID-19 or reported as differentially expressed in COVID-19 gene expression profiling studies. Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which could contribute to a better understanding of the COVID-19 host genetics in different populations.
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Inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are complex diseases whose etiology is associated with genetic and environmental risk factors, among which are diet and gut microbiota. To date, IBD is an incurable disease and the main goal of its treatment is to reduce symptoms, prevent complications, and improve nutritional status and the quality of life. Patients with IBD usually suffer from nutritional deficiency with imbalances of specific micronutrient levels that contribute to the further deterioration of the disease. Therefore, along with medications usually used for IBD treatment, therapeutic strategies also include the supplementation of micronutrients such as vitamin D, folic acid, iron, and zinc. Micronutrient supplementation tailored according to individual needs could help patients to maintain overall health, avoid the triggering of symptoms, and support remission. The identification of individuals' genotypes associated with the absorption, transport and metabolism of micronutrients can modify future clinical practice in IBD and enable individualized treatment. This review discusses the personalized approach with respect to genetics related to micronutrients commonly used in inflammatory bowel disease treatment.
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Research of inflammatory bowel disease (IBD) has identified numerous molecular players involved in the disease development. Even so, the understanding of IBD is incomplete, while disease treatment is still far from the precision medicine. Reliable diagnostic and prognostic biomarkers in IBD are limited which may reduce efficient therapeutic outcomes. High-throughput technologies and artificial intelligence emerged as powerful tools in search of unrevealed molecular patterns that could give important insights into IBD pathogenesis and help to address unmet clinical needs. Machine learning, a subtype of artificial intelligence, uses complex mathematical algorithms to learn from existing data in order to predict future outcomes. The scientific community has been increasingly employing machine learning for the prediction of IBD outcomes from comprehensive patient data-clinical records, genomic, transcriptomic, proteomic, metagenomic, and other IBD relevant omics data. This review aims to present fundamental principles behind machine learning modeling and its current application in IBD research with the focus on studies that explored genomic and transcriptomic data. We described different strategies used for dealing with omics data and outlined the best-performing methods. Before being translated into clinical settings, the developed machine learning models should be tested in independent prospective studies as well as randomized controlled trials.
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Diagnóstico por Computador/métodos , Enfermedades Inflamatorias del Intestino/diagnóstico , Aprendizaje Automático , Algoritmos , Bases de Datos Genéticas , Humanos , Enfermedades Inflamatorias del Intestino/genética , Proteómica , TranscriptomaRESUMEN
Background: COVID-19 pandemic has proved to be an unrelenting health threat for more than a year now. The emerging amount of data indicates that vitamin D, zinc and selenium could be important for clinical presentation of COVID-19. Here, we investigated association of genetic variants related to the altered level and bioavailability of vitamin D, zinc and selenium with clinical severity of COVID-19. Methods: We analyzed variants in genes significant for the status of vitamin D (DHCR7/NADSYN1 rs12785878, GC rs2282679, CYP2R1 rs10741657, and VDR rs2228570), zinc (PPCDC rs2120019) and selenium (DMGDH rs17823744) in 120 Serbian adult and pediatric COVID-19 patients using allelic discrimination. Furthermore, we carried out comparative population genetic analysis among European and other worldwide populations to investigate variation in allelic frequencies of selected variants. Results: Study showed that DHCR7/NADSYN rs12785878 and CYP2R1 rs10741657 variants were associated with severe COVID-19 in adults (p = 0.03, p = 0.017, respectively); carriers of DHCR7/NADSYN TG+GG and CYP2R1 GG genotypes had 0.21 and 5.9 the odds for developing severe disease, OR 0.21 (0.05-0.9) and OR 5.9 (1.4-25.2), respectively. There were no associations between selected genetic variants and disease severity in pediatric patients. Comparative population genetic analysis revealed that Serbian population had the lowest frequency of CYP2R1 rs10741657 G allele compared to other non-Finish Europeans (0.58 compared to 0.69 and 0.66 in Spanish and Italian population, respectively), suggesting that other populations should also investigate the relationship of CYP2R1 variant and the COVID-19 disease course. Conclusion: The results of the study indicated that vitamin D related genetic variants were implicated in severe COVID-19 in adults. This could direct prevention strategies based on population specific nutrigenetic profiles.
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BACKGROUND: Thiopurine drugs are used for the treatment of pediatric diseases. Inter-individual differences in the metabolism of these drugs greatly influence the risk of thiopurine induced toxicity and therapy failure. These differences are the consequence of genomic, epigenomic and transcriptomic variability among patients. Pharmacogenomics aims to individualize therapy according to the specific genetic signature of a patient. Treatment protocols based on thiopurine drugs have already been improved by applying pharmacogenomics in pediatric clinical practice. OBJECTIVE: The aim of this review was to summarize the application of thiopurine pharmacogenomics in pediatric patients suffering from acute leukemias, different types of autoimmune and inflammatory diseases, as well as in posttransplant care. METHODS: We searched PubMed/Medline database to identify thiopurine pharmacogenomic markers clinically relevant in pediatric diseases. RESULTS: TPMT and NUDT15 pharmacogenomic testing is done in pediatric care, contributing to the reduction of thiopurine induced toxicity. Data on numerous novel potential pharmacogenomic markers relevant for optimization of thiopurine treatment are still controversial (ITPA, ABCC4, NT5C2, PRPS1, GSTM1, FTO gene variants). Majority of evidences regarding thiopurine pharmacogenomics in pediatrics have been acquired by studying acute lymphoblastic leukemia and inflammatory bowel disease. For other pediatric diseases, namely acute myeloid leukemia, non-Hodgkin lymphoma, juvenile idiopathic arthritis, atopic dermatitis, juvenile autoimmune hepatitis and renal allograft transplantation, data are still scarce. CONCLUSION: Thiopurine pharmacogenomics has shown to be one of the best examples of successful application of pharmacogenomics in pediatrics.
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Azatioprina/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Marcadores Genéticos/genética , Humanos , Pediatría/métodos , Farmacogenética/métodosRESUMEN
New coronavirus SARS-CoV-2 is capable to infect humans and cause a novel disease COVID-19. Aiming to understand a host genetic component of COVID-19, we focused on variants in genes encoding proteases and genes involved in innate immunity that could be important for susceptibility and resistance to SARS-CoV-2 infection. Analysis of sequence data of coding regions of FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population identified 22 variants with potential functional effect. In silico analyses (PolyPhen-2, SIFT, MutPred2 and Swiss-Pdb Viewer) predicted that 10 variants could impact the structure and/or function of proteins. These protein-altering variants (p.Gly146Ser in FURIN; p.Arg261His and p.Ala494Val in PLG; p.Asn54Lys in PRSS1; p.Arg52Cys, p.Gly54Asp and p.Gly57Glu in MBL2; p.Arg47Gln, p.Ile99Val and p.Arg130His in OAS1) may have predictive value for inter-individual differences in the response to the SARS-CoV-2 infection. Next, we performed comparative population analysis for the same variants using extracted data from the 1000 Genomes project. Population genetic variability was assessed using delta MAF and Fst statistics. Our study pointed to 7 variants in PLG, TMPRSS11a, MBL2 and OAS1 genes with noticeable divergence in allelic frequencies between populations worldwide. Three of them, all in MBL2 gene, were predicted to be damaging, making them the most promising population-specific markers related to SARS-CoV-2 infection. Comparing allelic frequencies between Serbian and other populations, we found that the highest level of genetic divergence related to selected loci was observed with African, followed by East Asian, Central and South American and South Asian populations. When compared with European populations, the highest divergence was observed with Italian population. In conclusion, we identified 4 variants in genes encoding proteases (FURIN, PLG and PRSS1) and 6 in genes involved in the innate immunity (MBL2 and OAS1) that might be relevant for the host response to SARS-CoV-2 infection.
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Infecciones por Coronavirus/genética , Resistencia a la Enfermedad/genética , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno/genética , Metagenómica , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , Glicoproteína de la Espiga del Coronavirus/genética , Alelos , Enzima Convertidora de Angiotensina 2 , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/inmunología , Proteínas del Ojo/genética , Proteínas del Ojo/inmunología , Furina/genética , Furina/inmunología , Frecuencia de los Genes , Variación Genética , Genoma Humano , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Pandemias , Peptidil-Dipeptidasa A/inmunología , Plasminógeno/genética , Plasminógeno/inmunología , Neumonía Viral/inmunología , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/inmunología , Tripsina/genética , Tripsina/inmunologíaRESUMEN
BACKGROUND: Since there are no certified therapeutics to treat COVID-19 patients, drug repurposing became important. With lack of time to test individual pharmacogenomics markers, population pharmacogenomics could be helpful in predicting a higher risk of developing adverse reactions and treatment failure in COVID-19 patients. Aim of our study was to identify pharmacogenes and pharmacogenomics markers associated with drugs recommended for COVID-19 treatment, chloroquine/hydroxychloroquine, azithromycin, lopinavir and ritonavir, in population of Serbia and other world populations. METHODS: Genotype information of 143 individuals of Serbian origin was extracted from database previously obtained using TruSight One Gene Panel (Illumina). Genotype data of individuals from different world populations were extracted from the 1000 Genome Project. Fisher's exact test was used for comparison of allele frequencies. RESULTS: We have identified 11 potential pharmacogenomics markers in 7 pharmacogenes relevant for COVID-19 treatment. Based on high alternative allele frequencies in population and the functional effect of the variants, ABCB1 rs1045642 and rs2032582 could be relevant for reduced clearance of azithromycin, lopinavir and ritonavir drugs and UGT1A7 rs17868323 for hyperbilirubinemia in ritonavir treated COVID-19 patients in Serbian population. SLCO1B1 rs4149056 is a potential marker of lopinavir response, especially in Italian population. Our results confirmed that pharmacogenomics profile of African population is different from the rest of the world. CONCLUSIONS: Considering population specific pharmacogenomics landscape, preemptive testing for pharmacogenes relevant for drugs used in COVID-19 treatment could contribute to better understanding of the inconsistency in therapy response and could be applied to improve the outcome of the COVID-19 patients.
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BACKGROUND: Crohn's disease (CD) is chronic inflammatory bowel disease with different phenotypic characteristics influencing disease prognosis and therapeutic strategies. The aim of this pilot study was to analyze selected inflammatory and apoptotic markers in non-inflamed and inflamed samples of ileal mucosa of non-stricturing/non-penetrating (NS/NP) and stricturing (S) CD mucosal phenotypes in order to characterize their distinct profiles. METHODS: From twenty CD patients (9 NS/NP, 11 S) paired non-inflamed and inflamed ileal biopsies were collected and used for analysis of cytokine (TNF and IL6) and apoptotic (Bcl2, Bax, Fas and FasL) genes' expression levels by real-time PCR, while NFκB transcriptional potency was assessed by electromobility gel shift assay. RESULTS: Our results demonstrated significant upregulation of TNF and IL6 in inflamed area of both NS/NP (pâ¯=â¯0.03, pâ¯=â¯0.01) and S phenotypes (pâ¯=â¯0.04, pâ¯=â¯0.04), respectively. However, TNF increase was more prominent in NS/NP compared to S inflamed mucosa (pâ¯=â¯0.02). Also, level of proapoptotic Bax was significantly higher in NS/NP compared to S inflamed mucosa (pâ¯=â¯0.01). Opposing transcription potency of NFκB has been detected between two phenotypes: being decreased in NS/NP (pâ¯=â¯0.07) and increased in S (pâ¯=â¯0.1) inflamed compared to non-inflamed mucosa, demonstrating trend towards statistical significance. CONCLUSIONS: We found that two distinct CD phenotypes have specific molecular signatures. Obtained results could direct improvement of current and development of new therapeutic strategies based on more specific molecular stratification of CD patients.
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Apoptosis/genética , Enfermedad de Crohn/patología , Inflamación/genética , Transcriptoma , Adulto , Citocinas/genética , Femenino , Humanos , Inflamación/patología , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Fenotipo , Proyectos Piloto , Adulto JovenRESUMEN
Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.
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Biomarcadores de Tumor/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Metotrexato/efectos adversos , Farmacogenética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Antimetabolitos Antineoplásicos/efectos adversos , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologíaRESUMEN
Background: This study analyzed poorly understood relationship of two overlapping conditions: metabolic syndrome (MeS) and inflammatory bowel disease (IBD), both associated with inflammation in the visceral adipose tissue. Methods: Newly diagnosed 104 IBD patients, of which 50 Crohn's disease (CD) and 54 ulcerative colitis (UC), and 45 non-IBD controls were examined for MeS-related obesity and lipid markers. Th-17 immune genes IL17A, IL17F, IL23A, and TLR9 mRNAs were measured in intestinal mucosa by qRT-PCR. Subjects were genotyped for obesity-associated FTO variant rs9939609 by polymerase chain reaction-amplification refractory mutation system. Results: CD was associated with MeS (P = 0.01), while both CD and UC were associated with central obesity (P = 10-5, P = 0.002, respectively) and low levels of high-density lipoprotein (HDL) cholesterol (P = 5 × 10-6, P = 6 × 10-6, respectively). IBD lipid profile was characterized by decreased total and HDL cholesterol, while low-density lipoprotein cholesterol was reduced only in CD. Negative correlations were found between total cholesterol and CD activity index (P = 0.005), waist circumference and IL17A as well as IL17F mRNA levels in inflamed CD colon (P = 0.003, P = 0.001, respectively). Carriers of FTO rs9939609 AA genotype showed increased risk of CD (OR 2.6, P = 0.01). Conclusions: MeS, central obesity, and dyslipidemia could be important for IBD pathogenesis. This could influence therapeutic approaches and prevention strategies in high-risk groups.
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Inflamación/genética , Enfermedades Inflamatorias del Intestino/genética , Síndrome Metabólico/genética , Obesidad/genética , Grasa Abdominal/metabolismo , Adolescente , Adulto , Anciano , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Estudios Transversales , Citocinas/biosíntesis , Citocinas/genética , Femenino , Regulación de la Expresión Génica/genética , Marcadores Genéticos/genética , Genotipo , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Masculino , Síndrome Metabólico/etiología , Persona de Mediana Edad , Células Th17/inmunología , Adulto JovenRESUMEN
Personalized medicine is focused on research disciplines which contribute to the individualization of therapy, like pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. It is one of the pediatric malignancies with the highest cure rate, but still a lethal outcome due to therapy accounts for 1%â»3% of deaths. Further improvement of treatment protocols is needed through the implementation of pharmacogenomics and pharmacotranscriptomics. Emerging high-throughput technologies, including microarrays and next-generation sequencing, have provided an enormous amount of molecular data with the potential to be implemented in childhood ALL treatment protocols. In the current review, we summarized the contribution of these novel technologies to the pharmacogenomics and pharmacotranscriptomics of childhood ALL. We have presented data on molecular markers responsible for the efficacy, side effects, and toxicity of the drugs commonly used for childhood ALL treatment, i.e., glucocorticoids, vincristine, asparaginase, anthracyclines, thiopurines, and methotrexate. Big data was generated using high-throughput technologies, but their implementation in clinical practice is poor. Research efforts should be focused on data analysis and designing prediction models using machine learning algorithms. Bioinformatics tools and the implementation of artificial i Lack of association of the CEP72 rs924607 TT genotype with intelligence are expected to open the door wide for personalized medicine in the clinical practice of childhood ALL.
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Perfilación de la Expresión Génica/métodos , Pruebas de Farmacogenómica/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Variantes Farmacogenómicas , Medicina de Precisión , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
PURPOSE: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). METHODS: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). RESULTS: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680, -675, -556, -464, -317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. CONCLUSIONS: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteína Portadora de Folato Reducido/genética , Tetrahidrofolato Deshidrogenasa/genética , Timidilato Sintasa/genética , Adolescente , Alelos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Biomarcadores de Tumor/genética , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/inmunología , Niño , Preescolar , Femenino , Ácido Fólico/metabolismo , Variación Genética/genética , Humanos , Inmunofenotipificación , Lactante , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing GAS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. METHODS: GAS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. RESULTS: Our results have shown interindividual differences in GAS5 expression at all time points. For each ALL patient, GAS5 expression was higher on day 15 in comparison to its level at diagnosis (p<0.0005). On day 33, the level of GAS5 expression decreased in comparison with day 15 (p<0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per µL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). CONCLUSIONS: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.
RESUMEN
BACKGROUND: Chronic hepatitis C (CHC) is a significant cause of liver related morbidity and mortality worldwide. The role of genetics in the host response to hepatitis C virus is not elucidated. Genetic variations in UGT1A1 gene are the most common cause of hereditary unconjugated hyperbilirubinemia-Gilbert syndrome. This is the first study investigating the association of UGT1A1 TA repeats promoter genotypes with the degree of liver injury, viremia and biochemical markers in CHC patients with advanced liver injury and late virological relapse. METHODS: Genetic testing of UGT1A1 TA repeats promoter genotypes was performed in 42 CHC patients with advanced fibrosis and cirrhosis who achieved sustained virological response and 42 healthy blood donors. CHC patients were evaluated for clinical findings, laboratory tests and imaging. RESULTS: UGT1A1*28 genotype (7/7 TA repeats) was observed in 23.8% CHC patients and 16.7% healthy controls with no significant difference in genotype frequencies (p=0.49). Pretreatment levels of ferritin and bilirubin were associated with the presence of UGT1A1*28 genotype, indicating its potential as a predictive marker. However, in our study, there was no correlation of UGT1A1*28 genotype with the degree of fibrosis or viremia. During antiviral treatment, dose reductions and treatment interruptions, as well as treatment success and occurrence of late virological relapse were not related to the presence of UGT1A1*28 genotype in CHC patients with severe liver injury. CONCLUSIONS: Frequencies of UGT1A1*28 genotype are high in both Serbian CHC patients and healthy subjects. The presence of UGT1A1*28 genotype was not associated with ribavirin-related adverse effects and had no effect on long term outcome in CHC patients.