Clinical and pulmonary function analysis in long-COVID revealed that long-term pulmonary dysfunction is associated with vascular inflammation pathways and metabolic syndrome.

Introduction: Long-term pulmonary dysfunction (L-TPD) is one of the most critical manifestations of long-COVID. This lung affection has been associated with disease severity during the acute phase and the presence of previous comorbidities, however, the clinical manifestations, the concomitant consequences and the molecular pathways supporting this clinical condition remain unknown. The aim of this study was to identify and characterize L-TPD in patients with long-COVID and elucidate the main pathways and long-term consequences attributed to this condition by analyzing clinical parameters and functional tests supported by machine learning and serum proteome profiling. Methods: Patients with L-TPD were classified according to the results of their computer-tomography (CT) scan and diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLCOc) tests at 4 and 12-months post-infection. Results: Regarding the acute phase, our data showed that L-TPD was favored in elderly patients with hypertension or insulin resistance, supported by pathways associated with vascular inflammation and chemotaxis of phagocytes, according to computer proteomics. Then, at 4-months post-infection, clinical and functional tests revealed that L-TPD patients exhibited a restrictive lung condition, impaired aerobic capacity and reduced muscular strength. At this time point, high circulating levels of platelets and CXCL9, and an inhibited FCgamma-receptor-mediated-phagocytosis due to reduced FcγRIII (CD16) expression in CD14+ monocytes was observed in patients with L-TPD. Finally, 1-year post infection, patients with L-TPD worsened metabolic syndrome and augmented body mass index in comparison with other patient groups. Discussion: Overall, our data demonstrated that CT scan and DLCOc identified patients with L-TPD after COVID-19. This condition was associated with vascular inflammation and impair phagocytosis of virus-antibody immune complexes by reduced FcγRIII expression. In addition, we conclude that COVID-19 survivors required a personalized follow-up and adequate intervention to reduce long-term sequelae and the appearance of further metabolic diseases.

Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients.

Tamoxifen (TAM), a selective oestrogen receptor modulator, is one of the most used treatments in oestrogen receptor-positive (ER+) early and metastatic breast cancer (BC) patients. The response to TAM has a high degree of inter-individual variability. This is mainly due to genetic variants in CYP2D6 gene, as well as other genes encoding proteins involved in the TAM pharmacokinetic and/or pharmacodynamic. Therefore, prediction of the TAM response using these genetic factors together with other non-genetic variables may be relevant to improve breast cancer treatment. Thus, in this work, we used genetic polymorphisms and clinical variables for TAM response modelling. One hundred sixty-two ER + BC patients with 2 years of TAM treatment were retrospectively recruited, and the genetic polymorphisms CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESRA V364E were analyzed by PCR-RFLP. Concomitantly, the therapeutic response was obtained from clinical records for association with genotypes using univariate and multivariate biostatistical models. Our results show that UGT2B15*1/*2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A5*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A1*1/*2 genotype avoids vaginal bleeding (OR = 0.09; p = 0.03) and ESRA 364E/364E genotype increases the probability of vaginal bleeding (OR = 5.68; p = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (p = 0.010), endometrial hyperplasia (p = 0.002) and vaginal bleeding (p = 0.014). Our results suggest that the response to TAM treatment in ER + BC patients might be associated with the presence of the studied genetic variants in UGT2B15, CYP3A5, SULT1A1 and ESRA genes. After clinical validation protocols, these models might be used to help to predict a percentage of BC relapse and adverse reactions, improving the individual response to TAM-based treatment.

Effect of CYP3A4, CYP3A5, MDR1 and POR Genetic Polymorphisms in Immunosuppressive Treatment in Chilean Kidney Transplanted Patients.

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.

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity. METHODS: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. RESULTS: Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. CONCLUSION: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Análisis y consideraciones técnicas acerca de dispositivos intrauterinos de levonorgestrel para la evaluación de productos similares y genéricos / Analysis and technical considerations about levonorgestrel intrauterine devices for the evaluation of generic and similar products

Los dispositivos intrauterinos hormonales de levonorgestrel son métodos anticonceptivos seguros y eficaces. Al igual que los medicamentos convencionales, una vez expirada la patente, las autoridades regulatorias de salud pueden aprobar el registro de productos similares. El objetivo de ello es disminuir los costos, considerando el elevado precio del producto original. Este tipo de productos están regulados y se aplican requisitos generales similares a los medicamentos tradicionales para demostración de seguridad y eficacia. Las propiedades mecánicas únicas del producto de referencia plantean un gran desafío a los productos similares. El presente artículo analiza de manera comparativa las características de los diversos sistemas intrauterinos hormonales de levonorgestrel, disponibles en el mercado. La autoridad sanitaria y los diversos centros clínicos deben considerar que en este tipo de productos no hay, hasta la fecha en el mundo, genéricos intercambiables y que por lo tanto, se debe decidir la intercambiabilidad de éstos sobre la base de estudios de bioequivalencia in vivo, luego de la demostración de equivalencia farmacéutica in vitro, tal y como sugiere la FDA, o en su defecto deberían ser registrados como productos nuevos, con estudios clínicos apropiados que demuestren seguridad y eficacia.

Levonorgestrel hormonal intrauterine systems are safe and effective contraceptive methods. Like conventional drugs, once the patent expires, health regulatory authorities can approve the registration of similar products. The objective of this is to reduce costs, considering the high price of the original product. These types of products are regulated as drugs and similar general requirements apply to traditional drugs for demonstration of safety and efficacy. The unique mechanical properties of the reference product pose a great challenge to similar products. This article comparatively analyzes the characteristics of the various levonorgestrel hormonal intrauterine systems available on the market. Therefore, the health authority and clinical centers must consider that up to date, there are no interchangeable generics in this type of products worldwide. Thus, their interchangeability must be decided on the basis of in vivo bioequivalence studies after the demonstration of in vitro pharmaceutical equivalence, as suggested by the FDA. Without that, they should be registered as new products, with appropriate clinical studies that demonstrate safety and efficacy.

Resolvin D1 reduces expression and secretion of cytokines and monocyte adhesion triggered by Angiotensin II, in rat cardiac fibroblasts.

Cardiac fibroblasts (CF) play an important role in the healing process and in pathological remodeling of cardiac tissue. As sentinel cells in the heart, they respond to inflammatory stimuli, expressing cytokines and cell adhesion proteins, which ultimately lead to increased recruitment of monocytes and enhancement of the inflammatory response. Angiotensin II (Ang II) triggers an inflammatory response, leading to cardiac tissue remodeling. On the other hand, RvD1 has been shown to contribute to the resolution of inflammation; however, its role in Ang II-treated CF has not been addressed until now. The present research aimed to study the effect of RvD1 on cytokine levels, cell adhesion proteins expression in a model of Ang II-triggered inflammatory response. CF from adult Sprague Dawley rats were used to study mRNA and protein levels of MCP-1, IL-6, TNF-a, IL-10, ICAM-1 and VCAM-1; and adhesion of spleen mononuclear cells to CF after Ang II stimulation. Our results show that Ang II increased IL-6, MCP-1 and TNF-a mRNA levels, but only increased IL-6 and MCP-1 protein levels. These effects were blocked by Losartan, but not by PD123369. Moreover, RvD1 was able to prevent all Ang II effects in CF. Additionally, RvD1 reduced the intracellular Ca2+ increase triggered by Ang II, indicating that RvD1 acts in an early manner to block Ang II signaling. Conclusion: our findings confirm the pro-resolutive effects of inflammation by RvD1, which at the cardiovascular level, could contribute to repair damaged cardiac tissue.

Pharmacogenetic Associations Between Atazanavir/UGT1A1*28 and Efavirenz/rs3745274 (CYP2B6) Account for Specific Adverse Reactions in Chilean Patients Undergoing Antiretroviral Therapy.

Background: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and atazanavir (ATV), a protease inhibitor, are drugs widely used in antiretroviral therapy (ART) for people living with HIV. These drugs have shown high interindividual variability in adverse drug reactions (ADRs). UGT1A1*28 and CYP2B6 c.516G>T have been proposed to be related with higher toxicity by ATV and EFV, respectively. Objective: To study the association between genetic polymorphisms and ADRs related to EFV or ATV in patients living with HIV treated at a public hospital in Chile. Methods: Epidemiologic, case-control, retrospective, observational study in 67 adult patients under EFV or ATV treatment was conducted, in the San Juan de Dios Hospital. Data were obtained from patients' medical records. Genotype analyses were performed using rtPCR for rs887829 (indirect identification of UGT1A1*28 allele) and rs3745274 (CYP2B6 c.516G>T), with TaqMan® probes. The association analyses were performed with univariate logistic regression between genetic variants using three inheritance models (codominant, recessive, and dominant). Results: In ATV-treated patients, hyperbilirubinemia (total bilirubin >1.2 mg/dl) had the main incidence (61.11%), and moderate and severe hyperbilirubinemia (total bilirubin >1.9 mg/dl) were statistically associated with UGT1A1*28 in recessive and codominant inheritance models (OR = 16.33, p = 0.028 and OR = 10.82, p = 0.036, respectively). On the other hand, in EFV-treated patients adverse reactions associated with CNS toxicity reached 34.21%. In this respect, nightmares showed significant association with CYP2B6 c.516G>T, in codominant and recessive inheritance models (OR = 12.00, p = 0.031 and OR = 7.14, p = 0.042, respectively). Grouped CNS ADRs (nightmares, insomnia, anxiety, and suicide attempt) also showed a statistically significant association with CYP2B6 c.516G > T in the codominant and recessive models (OR = 30.00, p = 0.011 and OR = 14.99, p = 0.021, respectively). Conclusion: Our findings suggest that after treatment with ATV or EFV, UGT1A1*28 and CYP2B6 c.516G>T influence the appearance of moderate-to-severe hyperbilirubinemia and CNS toxicity, respectively. However, larger prospective studies will be necessary to validate these associations in our population. Without a doubt, improving adherence in patients living with HIV is a critical issue to the success of therapy. Hence, validating and applying international pharmacogenetic recommendations in Latin American countries would improve the precision of ART: a fundamental aspect to achieve the 95-95-95 treatment target proposed by UNAIDS.

Smartphone screen testing, a novel pre-diagnostic method to identify SARS-CoV-2 infectious individuals.

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.

A New Insight for the Identification of Oncogenic Variants in Breast and Prostate Cancers in Diverse Human Populations, With a Focus on Latinos.

Background: Breast cancer (BRCA) and prostate cancer (PRCA) are the most commonly diagnosed cancer types in Latin American women and men, respectively. Although in recent years large-scale efforts from international consortia have focused on improving precision oncology, a better understanding of genomic features of BRCA and PRCA in developing regions and racial/ethnic minority populations is still required. Methods: To fill in this gap, we performed integrated in silico analyses to elucidate oncogenic variants from BRCA and PRCA driver genes; to calculate their deleteriousness scores and allele frequencies from seven human populations worldwide, including Latinos; and to propose the most effective therapeutic strategies based on precision oncology. Results: We analyzed 339,100 variants belonging to 99 BRCA and 82 PRCA driver genes and identified 18,512 and 15,648 known/predicted oncogenic variants, respectively. Regarding known oncogenic variants, we prioritized the most frequent and deleterious variants of BRCA (n = 230) and PRCA (n = 167) from Latino, African, Ashkenazi Jewish, East Asian, South Asian, European Finnish, and European non-Finnish populations, to incorporate them into pharmacogenomics testing. Lastly, we identified which oncogenic variants may shape the response to anti-cancer therapies, detailing the current status of pharmacogenomics guidelines and clinical trials involved in BRCA and PRCA cancer driver proteins. Conclusion: It is imperative to unify efforts where developing countries might invest in obtaining databases of genomic profiles of their populations, and developed countries might incorporate racial/ethnic minority populations in future clinical trials and cancer researches with the overall objective of fomenting pharmacogenomics in clinical practice and public health policies.

NOD1 rs2075820 (p.E266K) polymorphism is associated with gastric cancer among individuals infected with cagPAI-positive H. pylori.

BACKGROUND: Helicobacter pylori is detected by pathogen recognition receptors including toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori. RESULTS: A case-control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal-type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41-5.13, p = 0.0026). The association was not statistically significant in diffuse-type gastric cancer cases (OR = 1.26, 95% CI 0.63-2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80-3.36, p = 0.0019), in particular for intestinal-type gastric cancer cases (OR = 7.16, 95% CI 2.40-21.33, p = 4.1 × 10- 4) but not among diffuse-type gastric cancer cases (OR = 3.39, 95% CI 1.13-0.10, p = 0.03). CONCLUSIONS: NOD1 rs2075820 increases the risk of intestinal-type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

Pharmacogenetics-Based Preliminary Algorithm to Predict the Incidence of Infection in Patients Receiving Cytotoxic Chemotherapy for Hematological Malignancies: A Discovery Cohort.

Introduction: Infections in hematological cancer patients are common and usually life-threatening; avoiding them could decrease morbidity, mortality, and cost. Genes associated with antineoplastics' pharmacokinetics or with the immune/inflammatory response could explain variability in infection occurrence. Objective: To build a pharmacogenetic-based algorithm to predict the incidence of infections in patients undergoing cytotoxic chemotherapy. Methods: Prospective cohort study in adult patients receiving cytotoxic chemotherapy to treat leukemia, lymphoma, or myeloma in two hospitals in Santiago, Chile. We constructed the predictive model using logistic regression. We assessed thirteen genetic polymorphisms (including nine pharmacokinetic-related genes and four inflammatory response-related genes) and sociodemographic/clinical variables to be incorporated into the model. The model's calibration and discrimination were used to compare models; they were assessed by the Hosmer-Lemeshow goodness-of-fit test and area under the ROC curve, respectively, in association with Pseudo-R2. Results: We analyzed 203 chemotherapy cycles in 50 patients (47.8 ± 16.1 years; 56% women), including 13 (26%) with acute lymphoblastic and 12 (24%) with myeloblastic leukemia. Pharmacokinetics-related polymorphisms incorporated into the model were CYP3A4 rs2242480C>T and OAT4 rs11231809T>A. Immune/inflammatory response-related polymorphisms were TLR2 rs4696480T>A and IL-6 rs1800796C>G. Clinical/demographic variables incorporated into the model were chemotherapy type and cycle, diagnosis, days in neutropenia, age, and sex. The Pseudo-R2 was 0.56, the p-value of the Hosmer-Lemeshow test was 0.98, showing good goodness-of-fit, and the area under the ROC curve was 0.93, showing good diagnostic accuracy. Conclusions: Genetics can help to predict infections in patients undergoing chemotherapy. This algorithm should be validated and could be used to save lives, decrease economic costs, and optimize limited health resources.

Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX.

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

Novel Risk Associations between microRNA Polymorphisms and Gastric Cancer in a Chilean Population.

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.

NOD1 rs2075820 (p.E266K) polymorphism is associated with gastric cancer among individuals infected with cagPAI-positive H. pylori

BACKGROUND: Helicobacter pylori is detected by pathogen recognition receptors including toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori. RESULTS: A case-control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal-type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41-5.13, p = 0.0026). The association was not statistically significant in diffuse-type gastric cancer cases (OR = 1.26, 95% CI 0.63-2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80-3.36, p = 0.0019), in particular for intestinal-type gastric cancer cases (OR = 7.16, 95% CI 2.40-21.33, p = 4.1 × 10- 4) but not among diffuse-type gastric cancer cases (OR = 3.39, 95% CI 1.13-0.10, p = 0.03). CONCLUSIONS: NOD1 rs2075820 increases the risk of intestinal-type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

HLA-DRB1*07:01 and *08:02 Alleles Confer a Protective Effect Against ACPA-Positive Rheumatoid Arthritis in a Latin American Admixed Population.

HLA-DRB1 shared epitope (SE) alleles are important genetic contributors for the risk of developing anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis (RA), particularly in Caucasians. We aimed to analyze the contribution of HLA-DRB1 alleles and single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) region to the susceptibility to develop ACPA-positive RA in a Latin American (LA) population with admixed ancestry. A total of 289 ACPA-positive RA patients and 510 controls were enrolled in this study. The presence of HLA-DRB1*04:01, *09:01 and *10:01 was increased in ACPA-positive RA patients compared with healthy controls (p < 0.0001, p < 0.001 and p < 0.01, respectively), whereas DRB1*07:01 and *08:02 was associated with a decreased risk of ACPA-positive RA (p < 0.001 and p < 0.01, respectively). These results showed a strong correlation with estimates from studies in Asians but not in Caucasian populations. The present study describes the protective effects of the HLA-DRB1*07:01 and *08:02 alleles in ACPA-positive RA patients in a LA population for the first time. Identifying relationships between HLA-DRB1 alleles and RA is important for identifying disease associations in different ethnic groups in order to reach a better understanding of RA worldwide.

Polymorphisms PSCA rs2294008, IL-4 rs2243250 and MUC1 rs4072037 are associated with gastric cancer in a high risk population.

Genetic variants are considered risk factors for gastric cancer. To date, 61 polymorphisms have been identified as associated with this disease. The aim of the present study was to analyze the association of some of those polymorphisms with GC in Chile. We performed a case-control study including 310 gastric cancer cases and 311 controls to assess the association of 36 single-nucleotide polymorphisms genotyped by Global Screening Array (GSA). Three polymorphisms was significantly associated: PSCA rs2294008 (allele model, OR = 1.49, 95%CI 1.17-1.88, P = 1.08 × 10-3), IL-4 rs2243250 (allele model, OR = 1.28, 95%CI 1.01-1.62, P = 0.04), and MUC1 rs4072037 (allele model, OR = 0.78, 95%CI 0.61-0.99, P = 0.04).PSCA rs2294008, IL-4 rs2243250 and MUC1 rs4072037 are associated with gastric cancer in Chile. It suggests that those polymorphisms could be used as biomarkers to assess the genetic risk for this cancer outside of the previously studied populations, not only for East Asians and Caucasians populations.

Latin American Genes: The Great Forgotten in Rheumatoid Arthritis.

The successful implementation of personalized medicine will rely on the integration of information obtained at the level of populations with the specific biological, genetic, and clinical characteristics of an individual. However, because genome-wide association studies tend to focus on populations of European descent, there is a wide gap to bridge between Caucasian and non-Caucasian populations before personalized medicine can be fully implemented, and rheumatoid arthritis (RA) is not an exception. In this review, we discuss advances in our understanding of genetic determinants of RA risk among global populations, with a focus on the Latin American population. Geographically restricted genetic diversity may have important implications for health and disease that will remain unknown until genetic association studies have been extended to include Latin American and other currently under-represented ancestries. The next few years will witness many breakthroughs in personalized medicine, including applications for common diseases and risk stratification instruments for targeted prevention/intervention strategies. Not all of these applications may be extrapolated from the Caucasian experience to Latin American or other under-represented populations.