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INTRODUCTION: Gastric cancer (GC) is one of the most lethal malignancies worldwide. Helicobacter pylori is the primary cause of GC; therefore, its eradication reduces the risk of developing this neoplasia. There is extensive evidence regarding quadruple therapy with relevance to the European population. However, in Latin America, data are scarce. Furthermore, there is limited information about the eradication rates achieved by antibiotic schemes in European and Latin American populations. OBJECTIVE: To compare the effectiveness of standard triple therapy (STT), quadruple concomitant therapy (QCT), and bismuth quadruple therapy (QBT) in six centers in Europe and Latin America. METHODS: A retrospective study was carried out based on the LEGACy registry from 2017 to 2022. Data from adult patients recruited in Portugal, Spain, Chile, Mexico, and Paraguay with confirmed H. pylori infection who received eradication therapy and confirmatory tests at least 1 month apart were included. Treatment success by each scheme was compared using a mixed multilevel Poisson regression, adjusting for patient sex and age, together with country-specific variables, including prevalence of H. pylori antibiotic resistance (clarithromycin, metronidazole, and amoxicillin), and CYP2C19 polymorphisms. RESULTS: 772 patients were incorporated (64.64% females; mean age of 52.93 years). The total H. pylori eradication rates were 75.20% (255/339) with STT, 88.70% (159/178) with QCT, and 91.30% (191/209) with QBT. Both quadruple therapies (QCT-QBT) showed significantly higher eradication rates compared with STT, with an adjusted incidence risk ratio (IRR) of 1.25 (p: <0.05); and 1.24 (p: <0.05), respectively. The antibiotic-resistance prevalence by country, but not the prevalence of CYP2C19 polymorphism, showed a statistically significant impact on eradication success. CONCLUSIONS: Both QCT and QBT are superior to STT for H. pylori eradication when adjusted for country-specific antibiotic resistance and CYP2C19 polymorphism in a sample of individuals residing in five countries within two continents.
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Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.
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Ácido Fólico , Síndrome del Ovario Poliquístico , Vitamina B 12 , Humanos , Femenino , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/genética , Vitamina B 12/sangre , Ácido Fólico/sangre , Adulto , Chile/epidemiología , Adulto Joven , Triglicéridos/sangre , Homocisteína/sangre , Índice de Masa Corporal , Glucemia/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Resistencia a la Insulina , HDL-Colesterol/sangre , Estudios de Casos y Controles , Biomarcadores/sangreRESUMEN
BACKGROUND: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. METHODS: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni's multiple adjustment tests determined statistical differences between allele frequencies. RESULTS: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031-0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. CONCLUSIONS: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.
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Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug (FOLFOX, CapeOX). Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic response, considering their interaction with oncogene mutations (KRAS, NRAS, PI3KCA, AKT1, BRAF). In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1, and MTHFR polymorphisms are independent indicators of poor prognosis, irrespective of oncogene mutations. BRAF wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.
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Neoplasias Colorrectales , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Mutación , Fluorouracilo/uso terapéutico , BiomarcadoresRESUMEN
Siponimod es un medicamento inmunosupresor selectivo, desarrollado como la primera terapia oral para la esclerosis múltiple secundaria progresiva activa. Este medicamento actúa modulando el receptor de esfingosina 1 fosfato (S1P), como antagonista de S1P1 y S1P5, evitando así la salida de linfocitos desde los nódulos linfáticos y previniendo procesos inflamatorios en el Sistema Nervioso Central que desencadenan una desmielinización. Existe amplio conocimiento científico respecto a que la administración del medicamento a pacientes va a depender de sus características farmacogenéticas, por lo que la FDA recomienda fuertemente realizar un estudio de genotipificación de la enzima que metaboliza siponimod, CYP2C9, cuyas variantes genéticas *2 y *3 clasifican a pacientes como metabolizadores pobres, extensivos o rápidos. Para pacientes homocigotos de CYP2C9*3 siponimod está totalmente contraindicado. Adicionalmente, antes de su prescripción se debe realizar un electrocardiograma, evaluaciones del estado de anticuerpos, oftálmica, estado de vacunación contra varicela y recuento de linfocitos periféricos, ya que el efecto del medicamento es dependiente de la dosis administrada, por lo que se realiza un proceso de titulación en dosis desde los 0,25mg hasta los 2 mg. El protocolo farmacoterapéutico de siponimod es reflejo fidedigno de la utilidad de la farmacogenética en la medicina personalizada..
Siponimod is a selective immunosuppressive medication, developed as the first oral therapy for active secondary progressive multiple sclerosis. This medication acts by modulating the sphingosine 1 phosphate (S1P) receptor, as an antagonist of S1P1 and S1P5, thus preventing the egress of lymphocytes from lymph nodes and preventing inflammatory processes in the Central Nervous System that trigger demyelination. There is extensive scientific knowledge regarding the administration of the medication to patients, which will depend on their pharmacogenetic characteristics. Therefore, the FDA strongly recommends conducting a genotyping study of the enzyme that metabolizes siponimod, CYP2C9, whose genetic variants *2 and *3 classify patients as poor, extensive, or rapid metabolizers. Siponimod is completely contraindicated for patients who are homozygous for CYP2C9*3. Additionally, before prescribing it, an electrocardiogram, assessments of antibody status, ophthalmic evaluation, varicella vaccination status, and peripheral lymphocyte count should be conducted, as the medication's effect is dose-dependent. Therefore, a titration process is carried out starting from 0.25mg up to 2 mg. The pharmacotherapeutic protocol of siponimod is a reliable reflection of the utility of pharmacogenetics in personalized medicine.
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Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region's continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the "need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics". Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%-99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC.
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Siponimod is a selective immunosuppressive medication, developed as the first oral therapy for active secondary progressive multiple sclerosis. This medication acts by modulating the sphingosine 1 phosphate (S1P) receptor, as an antagonist of S1P1 and S1P5, thus preventing the egress of lymphocytes from lymph nodes and preventing inflammatory processes in the Central Nervous System that trigger demyelination. There is extensive scientific knowledge regarding the administration of the medication to patients, which will depend on their pharmacogenetic characteristics. Therefore, the FDA strongly recommends conducting a genotyping study of the enzyme that metabolizes siponimod, CYP2C9, whose genetic variants *2 and *3 classify patients as poor, extensive, or rapid metabolizers. Siponimod is completely contraindicated for patients who are homozygous for CYP2C9*3. Additionally, before prescribing it, an electrocardiogram, assessments of antibody status, ophthalmic evaluation, varicella vaccination status, and peripheral lymphocyte count should be conducted, as the medication's effect is dose-dependent. Therefore, a titration process is carried out starting from 0.25mg up to 2 mg. The pharmacotherapeutic protocol of siponimod is a reliable reflection of the utility of pharmacogenetics in personalized medicine.
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Azetidinas , Compuestos de Bencilo , Esclerosis Múltiple Crónica Progresiva , Humanos , Compuestos de Bencilo/administración & dosificación , Compuestos de Bencilo/uso terapéutico , Azetidinas/administración & dosificación , Azetidinas/uso terapéutico , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/genética , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/uso terapéutico , Farmacogenética , Relación Dosis-Respuesta a DrogaRESUMEN
Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs characterized by a narrow therapeutic range and high pharmacokinetic variability. The effect of polymorphisms in genes related to the metabolism and transport of these drugs, namely CYP3A4, CYP3A5, MDR1 and POR genes, has been evaluated in diverse populations. However, the impact of these polymorphisms on drug disposition is not well established in Latin American populations. Using TaqMan® probes, we determined the allelic frequency of seven variants in CYP3A4, CYP3A5, MDR1 and POR in 139 Chilean renal transplant recipients, of which 89 were treated with CsA and 50 with TAC. We tested associations between variants and trough and/or 2-hour concentrations, normalized by dose (C0/D and C2/D) at specific time points post-transplant. We found that CYP3A5*3/*3 carriers required lower doses of TAC. In TAC treated patients, most CYP3A5*3/*3 carriers presented higher C0/D and a high proportion of patients with C0 levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering CYP3A5 genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.
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The COVID-19 pandemic will likely take years to control globally, and constant epidemic surveillance will be required to limit the spread of SARS-CoV-2, especially considering the emergence of new variants that could hamper the effect of vaccination efforts. We developed a simple and robust - Phone Screen Testing (PoST) - method to detect SARS-CoV-2-positive individuals by RT-PCR testing of smartphone screen swab samples. We show that 81.3-100% of individuals with high-viral-load SARS-CoV-2 nasopharyngeal-positive samples also test positive for PoST, suggesting this method is effective in identifying COVID-19 contagious individuals. Furthermore, we successfully identified polymorphisms associated with SARS-CoV-2 Alpha, Beta, and Gamma variants, in SARS-CoV-2-positive PoST samples. Overall, we report that PoST is a new non-invasive, cost-effective, and easy-to-implement smartphone-based smart alternative for SARS-CoV-2 testing, which could help to contain COVID-19 outbreaks and identification of variants of concern in the years to come.
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Prueba de Ácido Nucleico para COVID-19 , COVID-19 , Pandemias , SARS-CoV-2/genética , Teléfono Inteligente , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/genética , HumanosRESUMEN
Prognostic markers for cancer can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities. Gallbladder cancer (GBC) is a rare tumor that causes 165 087 deaths in the world annually. It is the most common cancer of the biliary tract and has a particularly high incidence in Chile, Japan, and northern India. Currently, there is no accurate diagnosis test or effective molecular markers for GBC identification. Several studies have focused on the discovery of genetic alterations in important genes associated with GBC to propose novel diagnosis pathways and to create prognostic profiles. To achieve this, we performed data-mining of GBC in public repositories, harboring 133 samples of GBC, allowing us to describe relevant somatic mutations in important genes and to propose a genetic alteration atlas for GBC. In our results, we reported the 14 most altered genes in GBC: arid1a, arid2, atm, ctnnb1, erbb2, erbb3, kmt2c, kmt2d, kras, pik3ca, smad4, tert, tp53, and znf521 in samples from Japan, the United States, Chile, and China. Missense mutations are common among these genes. The annotations of many mutations revealed their importance in cancer development. The observed annotations mentioned that several mutations found in this repository are probably oncogenic, with a putative loss-of-function. In addition, they are hotspot mutations and are probably linked to poor prognosis in other cancers. We identified another 11 genes, which presented a copy number alteration in gallbladder database samples, which are ccnd1, ccnd3, ccne1, cdk12, cdkn2a, cdkn2b, erbb2, erbb3, kras, mdm2, and myc. The findings reported here can help to detect GBC cancer through the development of systems based on genetic alterations, for example, the development of a mutation panel specifically for GBC diagnosis, as well as the creation of prognostic profiles to accomplish the development of GBC and its prevalence.
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Laryngeal squamous cell carcinoma (LSCC) is a highly disabling disease to the patient, affecting speech, swallowing and respiratory skills. Smoking and alcohol abuse are principal risk factors linked to this disease. Genetic factors can be involved in carcinogenesis by controlling the cell cycle, cell survival, angiogenesis, and invasiveness. Single nucleotide polymorphisms (SNPs) involving specific genes could modulate the risk of LSCC related to known carcinogens by modifying cellular responses, but not all genetic associations are known. In a case-control study, we assess the associations between cyclooxygenase-2 (COX2), epidermal growth factor (EGF), EGF receptor (EGFR), and tumor suppressor P53 SNPs on the risk of LSCC development in the Chilean population. A total of 85 LSCC patients and 95 healthy volunteers were recruited. SNPs genotype were analyzed from genomic DNA by Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (RFLP) and associations were estimated by odds ratios (ORs) using unconditional logistic regressions. A significant association between COX2 and TP53 SNP and LSCC risk was found, with an OR = 3.27 for COX2 c.-1329A>G (rs689466) SNP, and an OR = 1.94 for TP53 c.215C>G, Pro72Arg (rs1042522) SNP. These findings suggest that COX2 c.-1329A>G and TP53 c.215C>G (Pro72Arg) SNPs may be risk factors for LSCC. Through this research, we identify two low penetrance genetic variants that may be evaluated as novel biomarkers for this disease, in South American Mestizo populations.
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Biomarcadores de Tumor/genética , Predisposición Genética a la Enfermedad , Neoplasias Laríngeas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Anciano , Consumo de Bebidas Alcohólicas/epidemiología , Estudios de Casos y Controles , Chile/epidemiología , Fumar Cigarrillos/epidemiología , Ciclooxigenasa 2/genética , Factor de Crecimiento Epidérmico/genética , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Laríngeas/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/epidemiología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Testicular cancer (TCa) is a malignant tumor with highest incidence and mortality rates in Chile. The genes coding for cytochrome P450, glutathione-S-transferases (GSTs), and UDP glucuronyl transferases (UGT) participate in the biotransformation and detoxification of xenobiotics. Mutations in these genes have been associated with a high incidence of various types of cancer and an increased risk of presenting adverse reactions to drugs. OBJECTIVE: The aim of this study was to relate the presence of genetic polymorphisms in cytochrome P450 1A1 (CYP1A1), CYP3A4, GSTM1, GSTP1, GSTT1, and UGT1A1 genes and nongenetic factors with the risk of developing TCa. METHODS: A total of 276 volunteers from the Chilean general population and 251 Chilean TCa patients were recruited for the study. Genotypic analyses were performed using qPCR and PCR-RFLP. RESULTS: Variant alleles found to increase the risk of developing TCa were CYP1A1*2C (rs1048943), GSTP1 (rs1695), and GSTT1null, especially when in conjunction with a cancer family history and/or a smoking habit. The results of the multivariate analysis showed that the presence of variant alleles of GSTP1 (rs1695) together with a smoking habit and a family history of cancer accounted for a 15.9% risk of developing TCa in the Chilean population. CYP1A1*2C, GSTM1null, GSTT1null, and GSTP1 (rs1695) are statistically related to the risk of appearance of TCa, alone or associated with nongenetic factors. CONCLUSION: Therefore, phase I and II variant alleles might be useful in evaluating susceptibility to TCa in the studied population.
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Consumo de Bebidas Alcohólicas/epidemiología , Sistema Enzimático del Citocromo P-450/genética , Glucuronosiltransferasa/genética , Glutatión Transferasa/genética , Fumar/epidemiología , Neoplasias Testiculares/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/genética , Chile , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Fumar/efectos adversos , Fumar/genética , Adulto JovenRESUMEN
Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan ®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III-IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III-IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III-IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy.