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Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity of the hypothalamic-pituitary-gonadal axis. Identified loss-of-function mutations in these genes are linked to various reproductive disorders. This study investigated genetic disorders linked to mutations in the KNDy genes related to premature ovarian insufficiency (POI). A cohort of 14 Mexican POI patients underwent genetic screening using PCR-SSCP and Sanger sequencing, assessing the genetic variations' impact on protein function thereafter using multiple in silico tools. The PCR excluded extensive deletions, insertions, and duplications, while SSCP detected five genetic variants. Variations occurred in the KISS1 (c.58G>A and c.242C>G), KISS1R (c.1091A>T), PDYN (c.600C>T), and OPRK1 (c.36G>T) genes, whereas no genetic anomalies were found in NK3/NK3R genes. Each single-nucleotide variant underwent genotyping using PCR-SSCP in 100 POI-free subjects. Their allelic frequencies paralleled the patient group. These observations indicate that allelic variations in the KNDy genes may not contribute to POI etiology. Hence, screening for mutations in KNDy genes should not be a part of the diagnostic protocol for POI.

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COVID-19 has a broad clinical spectrum, ranging from asymptomatic-mild form to severe phenotype. The severity of COVID-19 is a complex trait influenced by various genetic and environmental factors. Ethnic differences have been observed in relation to COVID-19 severity during the pandemic. It is currently unknown whether genetic variations may contribute to the increased risk of severity observed in Latin-American individuals The aim of this study is to investigate the potential correlation between gene variants at CCL2, OAS1, and DPP9 genes and the severity of COVID-19 in a population from Quito, Ecuador. This observational case-control study was conducted at the Carrera de Biologia from the Universidad Central del Ecuador and the Hospital Quito Sur of the Instituto Ecuatoriano de Seguridad Social (Quito-SUR-IESS), Quito, Ecuador. Genotyping for gene variants at rs1024611 (A>G), rs10774671 (A>G), and rs10406145 (G>C) of CCL2, OAS1, and DPP9 genes was performed on 100 COVID-19 patients (43 with severe form and 57 asymptomatic-mild) using RFLP-PCR. The genotype distribution of all SNVs throughout the entire sample of 100 individuals showed Hardy Weinberg equilibrium (P=0.53, 0.35, and 0.4 for CCL2, OAS1, and DPP9, respectively). The HWE test did not find any statistically significant difference in genotype distribution between the study and control groups for any of the three SNVs. The multivariable logistic regression analysis showed that individuals with the GG of the CCL2 rs1024611 gene variant had an increased association with the severe COVID-19 phenotype in a recessive model (P = 0.0003, OR = 6.43, 95% CI 2.19-18.89) and for the OAS1 rs10774671 gene variant, the log-additive model showed a significant association with the severe phenotype of COVID-19 (P=0.0084, OR=3.85, 95% CI 1.33-11.12). Analysis of haplotype frequencies revealed that the coexistence of GAG at CCL2, OAS1, and DPP9 variants, respectively, in the same individual increased the presence of the severe COVID-19 phenotype (OR=2.273, 95% CI: 1.271-4.068, P=0.005305). The findings of the current study suggests that the ethnic background affects the allele and genotype frequencies of genes associated with the severity of COVID-19. The experience with COVID-19 has provided an opportunity to identify an ethnicity-based approach to recognize genetically high-risk individuals in different populations for emerging diseases.

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INTRODUCTION: The interferon pathway plays a critical role in triggering the immune response to SARS-CoV-2, and these gene variants may be involved in the severity of COVID-19. This study aimed to analyze the frequency of three gene variants of OAS and RNASEL with the occurrence of COVID-19 symptoms and disease outcome. METHODS: This cross-sectional study included 104 patients with SARS-CoV-2 infection, of which 34 were asymptomatic COVID-19, and 70 were symptomatic cases. The variants rs486907 (RNASEL), rs10774671 (OAS1), rs1293767 (OAS2), and rs2285932 (OAS3) were screened and discriminated using a predesigned 5'-nuclease assay with TaqMan probes. RESULTS: Patients with the allele C of the OAS2 gene rs1293767 (OR = 0.36, 95% CI: 0.15-0.83, p = 0.014) and allele T of the OAS3 gene rs2285932 (OR = 0.39, 95% CI: 0.2-0.023, p = 0.023) have lower susceptibility to developing symptomatic COVID-19. The genotype frequencies (G/G, G/C, and C/C) of rs1293767 for that comparison were 64.7%, 29.4%, and 5.9% in the asymptomatic group and 95.2%, 4.8%, and 0% in severe disease (p < 0.05). CONCLUSIONS: Our data indicate that individuals carrying the C allele of the OAS2 gene rs1293767 and the T allele of the OAS3 gene rs2285932 are less likely to develop symptomatic COVID-19, suggesting these genetic variations may confer a protective effect among the Mexican study population. Furthermore, the observed differences in genotype frequencies between asymptomatic individuals and those with severe disease emphasize the potential of these variants as markers for disease severity. These insights enhance our understanding of the genetic factors that may influence the course of COVID-19 and underscore the potential for genetic screening in identifying individuals at increased risk for severe disease outcomes.

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Introduction: Mutations of the phosphatase and tensin homolog (PTEN) gene have been associated with a spectrum of disorders called PTEN hamartoma tumor syndrome, which predisposes the individual to develop various types of tumors and vascular anomalies. Its phenotypic spectrum includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, autism spectrum disorders (ASD), some sporadic cancers, Lhermitte-Duclos disease (LDD), and various types of associated vascular anomalies. Clinical presentation: A previously healthy 27-year-old woman was experiencing visual scintillating scotomas and mild chronic headaches for the past 2 years. The initial computed tomographic (CT) and magnetic resonance imaging (MRI) scans did not reveal any abnormalities, but the possibility of pseudotumor cerebri was considered. Furthermore, a cerebral angiogram showed a posterior fossa dural arteriovenous fistula (dAVF), which was initially treated through embolization. However, in spite of proper treatment, this patient experienced multiple recurrent dAVFs in different locations, requiring multiple embolizations and surgeries. Despite exhibiting altered cerebral perfusion and hemodynamics, the patient did not display any significant symptoms until she experienced a sudden stroke resulting from deep venous thrombosis, which was not associated with any medical procedures or medication use. A comprehensive analysis was performed due to the aggressive nature of the dAVFs. Surprisingly, exome sequencing of a blood sample revealed a PTEN gene variant in chromosome 10, indicative of Cowden syndrome. However, no tumors or other vascular lesions were detected in other systems that would constitute Cowden syndrome. Conclusion: The rapid formation of multiple and complex dAVFs, coupled with not meeting the criteria for any other PTEN-related syndrome, unequivocally leads to the presentation of a novel phenotype of the PTEN germline variant.

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BACKGROUND: The association of leptin (LEP) and vascular endothelial growth factor A (VEGFA) genes with the susceptibility to knee osteoarthritis (OA) has been analyzed; however, the epistasis between them has not been investigated. OBJECTIVE: The objective of the study was to analyze the association of LEP and VEGFA variants and their interaction with primary knee OA in a Mexican Mestizo population. METHODS: A case-control study was developed. Cases were ≥40 years, BMI ≤27 kg/m2, with primary knee OA and radiologic Grade ≥2. Controls were participants with no knee OA and a radiologic Grade < 2. The rs2167270 of LEP and rs2010963 of VEGFA were genotyped. Genotypic association was tested under codominant, dominant, and recessive models. Uni- and multi-variate analyses were developed through non-conditional logistic regression. The multifactor dimensionality reduction algorithm was developed to detect epistasis. RESULTS: Participants comprised 103 cases and 179 controls. Allelic and genotypic distributions did not show differences between the groups. Notwithstanding, a statistically significant interaction was observed between the LEP and VEGFA genes (p = 0.02) with a testing accuracy of 0.5199 and cross-validation consistency of 10/10. This interaction model confers an increased risk to knee OA (OR [95% CI] = 1.8 [1.1-2.9]). CONCLUSION: Interaction between LEP and VEGFA is related with genetic susceptibility to developing primary knee OA.

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INTRODUCTION: Breast cancer (BC) is the malignant neoplasm with the highest mortality rate in women and female dogs are good models to study BC. OBJECTIVE: We investigated the efficacy of liquid biopsy to detect gene mutations in the diagnosis and follow-up of women and female dogs with BC. MATERIALS AND METHODS: In this study, 57 and 37 BC samples were collected from women and female dogs, respectively. After core biopsy and plasma samples were collected, the DNA and ctDNA of the tumor fragments and plasma were processed for next generation sequencing (NGS) assay. After preprocessing of the data, they were submitted to the Genome Analysis ToolKit (GATK). RESULTS: In women, 1788 variants were identified in tumor fragments and 221 variants in plasma; 66 variants were simultaneously detected in tumors and plasma. Conversely, in female dogs, 1430 variants were found in plasma and 695 variants in tumor fragments; 59 variants were simultaneously identified in tumors and plasma. The most frequently mutated genes in the tumor fragments of women were USH2A, ATM, and IGF2R; in female dogs, they were USH2A, BRCA2, and RRM2. Plasma of women showed the most frequent genetic variations in the MAP3K1, BRCA1, and GRB7 genes, whereas plasma from female dogs had variations in the NF1, ERBB2, and KRT17 genes. Mutations in the AKT1, PIK3CA, and BRIP genes were associated with tumor recurrence, with a highly pathogenic variant in PIK3CA being particularly prominent. We also detected a gain-of-function mutation in the GRB7, MAP3K1, and MLH1 genes. CONCLUSION: Liquid biopsy is useful to identify specific genetic variations at the beginning of BC manifestation and may be accompanied over the entire follow-up period, thereby supporting the clinicians in refining interventions.

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Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose.

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The main purpose of this study was to investigate if the rs11091046 (A>C) polymorphism in AGTR2 gene is associated with athletic status in top-level athletes from Brazil. Since the AGTR2 gene is located on the X chromosome, the case-control association study was done separately for women and men. The female cohort was composed of 205 athletes and 241 non-athletes, and the male cohort was composed of 419 athletes and 490 non-athletes. We did not identify an association between the C-allele and the endurance phenotype. However, power athletes had a higher frequency of the A-allele. In women, A/A genotype was overrepresented in international-level power group compared with non-athletes or international-level endurance athletes (23.2% vs. 16.6% or 8.8%, respectively; p < 0.05). In men, the A-allele frequency observed in power athletes or international-level power athletes was statistically different from that observed in non-athletes (51.6% or 57.8% vs. 40.4%; p < 0.009). Furthermore, men sprinters with the A-allele showed significantly faster personal best times for the 100 m than those with the C-allele (10.56 ± 0.32 s vs. 10.93 ± 0.49 s; p < 0.02). In conclusion, it was found that the AGTR2 A-allele is a candidate genetic marker for top-level power athletes.

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Body weight excess has an increasingly high prevalence in the world. Obesity is a complex disease of multifactorial origin with a polygenic condition affected by environmental factors. Weight loss is a primary strategy to treat obesity and its morbidities. Weight changes through life depend on the interaction of environmental, behavioral and genetic factors. Interindividual variation of weight loss in response to different types of interventions (behavioral, caloric restriction, exercise, drug or surgery) has been observed. In this article, currently available data on the role of candidate gene polymorphisms in weight loss are reviewed. Even though control of weight loss by genotype was described in twin and family studies, it is premature to recommend use of genotyping in the design of therapeutic diets or drug treatment. Future studies will have to be large in order to assess the effects of multiple polymorphisms, and will have to control factors other than diet.

A prevalência do excesso de peso cresce no mundo todo. De origem multifatorial, a obesidade é uma doença complexa, com condição poligênica afetada por fatores ambientais. A perda de peso é a estratégia primária utilizada para prevenir e tratar a obesidade bem como suas comorbidades. Mudanças de peso durante a vida dependem da interação entre fatores ambientais, comportamentais e genéticos. Observa-se grande variação da perda de peso entre indivíduos em resposta a diferentes modelos de intervenções (comportamentais, restrições da ingesta cálorica, exercícios físicos, drogas antiobesidade ou cirurgias). Este artigo é uma revisão atual da literatura disponível, que busca abordar o papel dos polimorfismos dos genes candidatos à obesidade e sua influência na perda de peso. Apesar da interação do genótipo na perda de peso corporal, descrita nos estudos de gêmeos e familiares, é prematuro recomendar o uso da genotipagem para estratégias de perda de peso. É necessário ampliar as pesquisas sobre os efeitos sinérgicos dos polimorfismos genéticos com coorte maior e associá-los não somente à restrição alimentar mas também às outras intervenções que auxiliam na perda de peso.

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