New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes

Background Two new SNPs have been recently associated to Alzheimer's disease in African American populations: FCGRIIB rs1050501 C/T, and PILRA rs1859788 A/G. The risk of Alzheimer's disease in FCGRIIB C and PILRA A allele carriers is three times higher than in non-carriers. However, the association between these and other single nucleotide polymorphisms (SNPs) has not been assessed. Methods Linkage disequilibrium analysis, with r= 0.8 as a threshold value, was used to impute new candidate SNPs, on genomic data from both genes in 26 populations worldwide (n= 2504) from the 1000Genomes database. Results Four SNPs (rs13376485, rs3767640, rs3767639 and rs3767641) were linked to rs1050501 and one (rs2405442) to rs1859788 in the whole sample. Conclusions Five novel SNPs could be associated with Alzheimer's disease susceptibility and play a causal role, even if none of them are exon variants since their potential roles in the regulation of gene expression.

Antecedentes Recientemente se han asociado dos nuevos polimorfismos de un solo nucleótido (SNP) a la enfermedad de Alzheimer en poblaciones afroamericanas: FCGRIIB rs1050501 C/T, y PILRA rs1859788 A/G. El riesgo de enfermedad de Alzheimer en los portadores de los alelos FCGRIIB C y PILRA A es tres veces mayor que en los no portadores. Sin embargo, no se ha evaluado la asociación entre estos y otros SNP. Métodos Se utilizó el análisis de desequilibrio de ligamiento, con r2= 0,8 como valor umbral, para imputar nuevos SNPs candidatos, sobre datos genómicos de ambos genes en 26 poblaciones de todo el mundo (n= 2504) de la base de datos 1000Genomes. Resultados Cuatro SNPs (rs13376485, rs3767640, rs3767639 y rs3767641) se vincularon al rs1050501 y uno (rs2405442) al rs1859788 en toda la muestra. Conclusiones Cinco nuevos SNP podrían estar asociados con la susceptibilidad a la enfermedad de Alzheimer y desempeñar un papel causal, aunque ninguno de ellos sea una variante de exón, dado su papel potencial en la regulación de la expresión génica.

A Rapid PCR-RFLP Method for Assessing Heterozygosity of Murraya paniculata Germplasm / 中国实验方剂学杂志

ObjectiveTo establish a rapid method for evaluating the heterozygosity of Murraya paniculata germplasm materials and provide as a foundation for developing germplasm breeding and innovation measures for M. paniculata. MethodSingle nucleotide polymorphisms （SNPs） were screened from the genome resequencing data of 65 plants of M. paniculata. A self-written script was used to transform 20 SNPs into restriction fragment length polymorphism （RFLP） markers. Polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） was employed to detect the 20 RFLP markers in 12 M. paniculata germplasm accessions， and the heterozygosity of M. paniculata germplasm accessions was calculated based on the number of enzyme-cutting bands at the 20 RFLP marker sites. Plink was used to calculate the whole genome heterozygosity of 12 M. paniculata germplasm accessions， and the results obtained with different methods were compared. ResultThere was no significant difference in the heterozygosity calculated by the PCR-RFLP method and the genome resequencing method. The PCR-RFLP and genome resequencing methods identified 8 and 9 germplasm accessions， respectively， with a heterozygosity level less than 30%. Seven germplasm accessions with heterozygosity less than 30.00% were calculated by both methods. ConclusionThe PCR-RFLP method established in this study for evaluating the heterozygosity of M. paniculata germplasm demonstrates the precision of 87.5% and the accuracy of 77.8%. This method serves as a reference for developing heterozygosity evaluation methods in other medicinal plant germplasm resources.

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus

Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (e.g., SLC2A4/GLUT4), glucose reabsorption (e.g., SLC5A2/SGLT2), thermogenesis (e.g., SLC25A7/UCP-1), and ATP production (e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (SLCO1B1/OATP1B1) and metformin (SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.

Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study

Abstract Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Resumo Várias razões podem estar subjacentes ao aumento dramático da diabetes mellitus tipo 2. Um desses motivos é a base genética e variações. Os polimorfismos do receptor da vitamina D estão associados a diferentes doenças, como artrite reumatoide e diabetes. O objetivo deste estudo é investigar a possível associação de duas mutações identificadas ApaI (rs7975232) e TaqI (rs731236). Oitenta e nove indivíduos saudáveis e 56 pacientes com diabetes tipo 2 (T2D) foram investigados usando a técnica RFLP para genotipagem e haplotipagem também. A distribuição dos genótipos Apal não foi estatisticamente significativa entre o controle (P = 0,65), bem como para os pacientes diabéticos (P = 0,58). Para as frequências do alelo Taql, o alelo T foi de 0,61, onde o alelo G foi de 0,39. A distribuição de frequência dos genótipos Taql não foi estatisticamente significativa entre o controle (P = 0,26), bem como os pacientes diabéticos (P = 0,17). O risco relativo do alelo T do gene Apa1 é 1,28 e a razão de chances do mesmo alelo é 1,53, enquanto ambas as estimativas foram 1,0 do alelo G. Da mesma forma, com o gene Taq1, os valores de risco relativo e razão de chances para o alelo T são 1,09 e 1,27, respectivamente, e ambas as estimativas do alelo C foram de 0,86 para o risco relativo e 0,79 para o odds ratio. O desequilíbrio de ligação par a par entre os dois SNPs Taq1 / apa1 foi estatisticamente significativo no grupo de controle (D = 0,218, D' = 0,925 e valor P 0,001) e dados semelhantes em grupos diabéticos (D = 0,2, D' = 0,875 e valor P 0,001). Esses dados sugerem que o alelo T de ambos os genes Apa1 e Taq1 está associado ao aumento do risco de diabetes tipo 2. Achamos que precisamos de um número maior de voluntários para chegar a uma conclusão mais precisa.

Molecular genetic association of rs8099917 and rs1800795 polymorphisms in the progression of hepatitis Delta virus liver disease

Background: The relationship between viral infections and host factors holds high hopes for identifying the role of Interferon Lambda 3 (IFNL3) and Interleukin 6 (IL-6) polymorphisms in the development of Chronic Liver Disease (CLD) in patients infected with hepatitis Delta virus (HDV) in the Western Brazilian Amazon. Methods: Cross-sectional study conducted with a cohort of 40 chronic HDV patients, 27 with CLD and 13 without evident liver damage. Biological samples from the participants were analyzed using the polymerase chain reaction (PCR) technique, followed by sequencing by the automated Sanger method. Results: The rs8099917 T allele, from the IFNL3 gene, showed a higher frequency in both groups; however, it was not possible to establish an association with HDV infection [OR = 1.42 (0.42 - 4.75; p = 0.556 (95% CI). For IL-6, the rs1800795 G allele was superior to rs1800795 C. Analyzing both distributions in the studied groups, any association with HDV was absent (p > 0.05). Conclusion: The results suggest that the rs8099917 T/G (IFNL3) and rs1800795 G/C (IL-6) polymorphisms are not associated with the evolution of HDV in the studied population.

Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study / Associação de polimorfismos do gene do receptor de vitamina D com diabetes mellitus tipo 2 na população Taif: um estudo de caso-controle

Abstract Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were < 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value < 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value < 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Resumo Várias razões podem estar subjacentes ao aumento dramático da diabetes mellitus tipo 2. Um desses motivos é a base genética e variações. Os polimorfismos do receptor da vitamina D estão associados a diferentes doenças, como artrite reumatoide e diabetes. O objetivo deste estudo é investigar a possível associação de duas mutações identificadas ApaI (rs7975232) e TaqI (rs731236). Oitenta e nove indivíduos saudáveis ​​e 56 pacientes com diabetes tipo 2 (T2D) foram investigados usando a técnica RFLP para genotipagem e haplotipagem também. A distribuição dos genótipos Apal não foi estatisticamente significativa entre o controle (P = 0,65), bem como para os pacientes diabéticos (P = 0,58). Para as frequências do alelo Taql, o alelo T foi de 0,61, onde o alelo G foi de 0,39. A distribuição de frequência dos genótipos Taql não foi estatisticamente significativa entre o controle (P = 0,26), bem como os pacientes diabéticos (P = 0,17). O risco relativo do alelo T do gene Apa1 é 1,28 e a razão de chances do mesmo alelo é 1,53, enquanto ambas as estimativas foram < 1,0 do alelo G. Da mesma forma, com o gene Taq1, os valores de risco relativo e razão de chances para o alelo T são 1,09 e 1,27, respectivamente, e ambas as estimativas do alelo C foram de 0,86 para o risco relativo e 0,79 para o odds ratio. O desequilíbrio de ligação par a par entre os dois SNPs Taq1 / apa1 foi estatisticamente significativo no grupo de controle (D = 0,218, D' = 0,925 e valor P < 0,001) e dados semelhantes em grupos diabéticos (D = 0,2, D' = 0,875 e valor P < 0,001). Esses dados sugerem que o alelo T de ambos os genes Apa1 e Taq1 está associado ao aumento do risco de diabetes tipo 2. Achamos que precisamos de um número maior de voluntários para chegar a uma conclusão mais precisa.

The prognostic values of the IL?10 (G1082A) and TNF?? (G308A) polymorphisms in Egyptian patients with acute lymphoblastic leukemia: A single?center study

Background: Interleukin?10 (IL?10) and tumor necrosis factor?alpha (TNF??) genes contribute to oncogenesis. We evaluated the influence of the IL?10 (G1082A) and TNF?? (G308A) polymorphisms on the prognosis and outcomes of Egyptian patients with acute lymphoblastic leukemia (ALL). Materials and Methods: We investigated 64 children and 76 adults with ALL, between 2016 and 2019, for the IL?10 (G1082A) and TNF?? (G308A) polymorphisms using allele?specific polymerase chain reaction and polymerase chain reaction杛estriction fragment length polymorphism. Survival analyses were performed using the Kaplan朚eier estimator and the log?rank test. Results: In children with ALL, the A allele of TNF?? and IL?10 polymorphisms was associated with older age (P = 0.04 and 0.03), more extramedullary disease (P = 0.02 and 0.001), positive breakpoint cluster region朅belson (BCR?ABL) rearrangement (p190; P = 0.04 and 0.001), and more relapse (P = 0.002). The IL?10 GG genotype was associated with higher overall survival in children (P = 0.026). Adults carrying the TNF?? A allele showed more extramedullary disease (P = 0.009) and relapse (P = 0.003). We also found a higher frequency of IL?10 A allele in adults with older age (P = 0.03), lower hemoglobin level (P = 0.04), positive BCR?ABL rearrangement (P = 0.001), more extramedullary disease (P = 0.001), more relapse (P = 0.002), and a longer time for the first complete remission (P = 0.003). Conclusion: A possible association exists between the A allele of IL?10 and TNF?? polymorphisms and poor prognosis in Egyptian patients with ALL, while the IL?10 GG genotype may be associated with better survival in children with ALL.

Helicobacter pylori infection: A balance between bacteria and host / Helicobacter pylori: un balance entre bacterias y huésped

Abstract In Argentina, despite the important studies conducted on the prevalence of infection and the antibiotic resistance of Helicobacter pylori, there are no reports simultaneously analyzing a profile of virulence factors of the bacterium and polymorphisms in cytokine genes in patients with different alterations in the gastric mucosa (including intestinal metaplasia, IM). Our aim was to evaluate H. pylori genotypes in 132 adult patients with chronic gastritis presenting three different histological findings (inactive chronic gastritis, active chronic gastritis IM( and active chronic gastritis IM+) along with SNP-174 G>C in the IL-6 gene. cagA, vacA and babA2 genes were analyzed by multiplex PCR. The -174 G>C SNP IL-6 gene was analyzed by PCR-RFLP. Patients with active chronic gastritis IM+ showed the highest proportion of the cagA(+)/IL-6GG, cagA(+)/vacAm1s1/IL-6GG and cagA(+)/vacAm1s1/babA2(+)/IL-6GG combinations (p<0.05). There was 4-5 times greater probability of finding patients presenting the GG genotype for SNP-174 G>C IL-6, which in turn were infected with the most virulent H. pylori genotypes -cagA(+), cagA(+)/vacAm1s1 and cagA(+)/vacAm1s1/babA2- in the ACGIM+ group in comparison to the ICG group. Our results provide regional data to the idea that the transition towards severe alterations in the gastric mucosa would be the result of a balance between specific factors of H. pylori and inherent host factors. This fact can be useful to identify patients at greater risk and to select those individuals requiring appropriate eradication treatment to prevent progression to gastric cancer.

Resumen En Argentina, a pesar de los importantes estudios realizados sobre la prevalencia de infección y la resistencia a antibióticos de Helicobacter pylori, no existen reportes que analicen simultáneamente un perfil de factores de virulencia de la bacteria y polimorfismos en genes de citoquinas en pacientes con diferentes alteraciones en la mucosa gástrica (incluida la metaplasia intestinal [MI]). Nuestro objetivo fue evaluar genotipos de H. pylori en 132 pacientes adultos con gastritis crónica, con tres diferentes hallazgos histológicos (gastritis crónica inactiva [GCI], gastritis crónica activa [MI(] y gastritis crónica activa [MI+]), junto con el SNP-174 G>C en el gen de IL- 6. Los genes cagA, vacA y babA2 se analizaron mediante PCR multiplex. El SNP-174 G>C IL-6 se analizó mediante PCR-RFLP. Los pacientes con gastritis crónica activa MI+ mostraron la mayor proporción de combinaciones cagA(+)/IL-6GG, cagA(+)/vacAm1s1/IL-6GG y cagA(+)/vacAm1s1/babA2(+)/IL-6GG (p<0,05). Hubo 4-5 veces mayor probabilidad de encontrar pacientes con el genotipo GG en SNP-174 G>C IL-6 y a su vez infectados con los genotipos más virulentos de H. pylori-cagA(+), cagA(+)/vacAm1s1 y cagA(+)/vacAm1s1/babA2-en el grupo gastritis crónica activa MI+ en comparación con el grupo GCI. Nuestros resultados aportan datos regionales a la idea de que la transición hacia alteraciones más graves en la mucosa gástrica resultaría de un equilibrio entre factores específicos de H. pylori y factores inherentes al huésped. Esto puede ser útil para identificar pacientes con mayor riesgo y seleccionar aquellos individuos que requieran un apropiado tratamiento de erradicación para prevenir la progresión al cáncer gástrico.

Effect of pharmacogenetic polymorphism on the antiplatelet aggregation effect of ticagrelor / 药学实践杂志

Objective To develop a pharmacogenomics study of ticagrelor in patients with acute coronary syndrome (ACS), identify the genetic factors that can predict individual differences in antiplatelet aggregation effects of ticagrelor, and provide a reference for the development of individualized regimens for ticagrelor. Methods 75 ACS patients of Chinese Han in a hospital in Fujian province in 2018 who met the entry criteria were recruited. The patient was given the tests for platelet function test, platelet aggregation rate and DNA detection. The whole exon sequencing method (WES) was used to detect the single nucleotide polymorphisms of SLO1B1, UGT2B7, P2Y12, PEAR1, ITGA2B and ITGB3. At the same time, the general clinical data of the patients were collected and recorded. The correlation between antiplatelet aggregation effects of ticagrelor and pharmacogenetic polymorphism was analyzed by one-way analysis of variance, multiple linear regression analysis and binary logistic regression analysis. Results One-way analysis of variance showed that SLCO1B1 rs2306283 mutant allele G could affect the antiplatelet aggregation effect of ticagrelor, the average platelet aggregation rate of patients carrying at least one allele G (AG+GG type) was significantly lower than that of wild homozygotes AA patients (8.07%±6.17% vs 13.88%±6.39%, P≤0.05). However, multivariate regression analysis after adjusting for confounding factors showed that SLCO1B1 rs2306283 mutant allele G was not an independent variable affecting the antiplatelet effects of ticagrelor (P>0.05). Conclusion Single nucleotide polymorphisms of genes related to ticagrelor transport receptors, targets, and platelet membrane receptors (including SLO1B1, UGT2B7, P2Y12, PEAR1, ITGA2B, ITGB3) in ACS patients of Han Chinese in Fujian province will not significantly affect the antiplatelet aggregation effect of ticagrelor, which provides a new treatment option for patients with genetic defects who are not suitable for clopidogrel.

Progress on methotrexate gene polymorphisms in allogeneic hematopoietic stem cell transplantation / 国际儿科学杂志

Methotrexate(MTX)is one of the main drugs used to prevent graft-versus-host disease(GVHD)after hematopoietic stem cell transplantation, but it can cause a variety of adverse reactions, including severe mucositis, bone marrow suppression and hepatotoxicity.Studies on MTX gene polymorphisms mainly focused on the efficacy and complications of high-dose MTX therapy for various cancers, with relatively few studies on hematopoietic stem cell transplantation.From the perspective of allogeneic hematopoietic stem cell transplantation(allo-HSCT), this article provided a comprehensive review on the pharmacokinetics, complications, and prognosis with MTX gene polymorphisms in allo-HSCT patients, in order to provide clinical reference.

Aldehyde dehydrogenase 2 rs671 genetic polymorphisms are associated with chemotherapy-induced nausea and vomiting / 南方医科大学学报

OBJECTIVE@#To investigate the correlation between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and chemotherapy-induced nausea and vomiting (CINV).@*METHODS@#A total of 90 Chinese patients with malignant tumors receiving chemotherapy for the first time were recruited in this study. The occurrence of CINV was observed within 120 h after treatment with docetaxel and cis-platinum chemotherapy (DP regimen). The data of the patients (including age, gender, tumor stage, habitual alcohol consumption, motion sickness, morning sickness, and average sleep time prior to chemotherapy) were collected through a questionnaire. ALDH2 rs671 polymorphisms of the patients were analyzed using a multiple single nucleotide polymorphism genotyping, and the Hardy-Weinberg equation was used for genetic linkage analysis. The correlations between the factors including ALDH2 rs671 polymorphisms and the occurrence of CINV were analyzed.@*RESULTS@#The incidence of CINV was 48.9% among the patients receiving their first chemotherapy with DP regimen. Univariate analysis indicated that the genetic polymorphisms of ALDH2 rs671 were significantly correlated with the occurrence of CINV (P < 0.05). Multivariate logistic analysis indicated that ALDH2 rs671 mutation (OR: 3.019, 95% CI: 1.056-8.628, P < 0.05) and average sleep time prior to chemotherapy no longer than 6 h (OR: 2.807, 95% CI: 1.033-7.628, P < 0.05) were risk factors for CINV in patients with malignant tumors receiving the first chemotherapy with DP regimen.@*CONCLUSION@#ALDH2 gene mutation at rs671 is a risk factor contributing to the occurrence of CINV, and understanding of the underlying mechanism may help to more effectively control the occurrence of CINV.

Cytokine polymorphisms and genotypic susceptibility of HCV infection in ribavirin response to peg interferon

@#Immune responses are largely regulated by cytokines. Genetic polymorphisms of the regulatory coding regions are recognized to impact the expression of cytokines. The abnormal cytokine levels in hepatitis C virus (HCV) infection seems to be involved in disease progression, viral survival, and therapeutic response. The current study assesses the polymorphisms associated with IL-6, IL-10, IL28B, IFN-γ, TGF-β, and TNF-α on the genotypic susceptibility to HCV infection and Ribavirin response to Peg interferon. Droplet digital polymerase chain reaction (PCR) was used to assess the gene polymorphisms associated with IL-6 A/G (rs2069837), IL-10-1082 G/A (rs1800896)], IL28B C/T (rs12979860), IFN-γ +874 A/T (rs2430561), TGF-β 1-509 C/T (rs1800469) and TNF-α-308 G/A promoter (rs1800629) from stored samples of 200 healthy individuals and 300 HCV infected patients. There was a significant association of AG and AA genotypes of IL28B, IFN-γ, TGF-β1, and TNF-α over HCV susceptibility and treatment outcome. However, no association between IL-6 and IL-10 gene polymorphism to HCV susceptibility response to the treatment. The observations indicate IL28B CT, TGF-β1 CT, TT and TNF- AG with AA genotypes influence the cytokine expression, which is related to susceptibility and resistance to HCV infection and combined antiviral therapy.

Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy

Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival. Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers. However, the study and knowledge on drug resistance to CDK9 inhibitors are very limited. In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152. Through genomic sequencing, we identified in the kinase domain of CDK9 a mutation L156F, which is also a coding SNP in the CDK9 gene. By knocking in L156F into cancer cells using CRISPR/Cas9, we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors, not only ATP competitive inhibitor but also PROTAC degrader. Mechanistically, CDK9 L156F disrupts the binding with inhibitors due to steric hindrance, further, the mutation affects the thermal stability and catalytic activity of CDK9 protein. To overcome the drug resistance mediated by the CDK9-L156F mutation, we discovered a compound, IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.

A novel mutation in the WNT6 gene of congenital tooth agenesis / 口腔疾病防治

Objective @#This article explores the relationship between congenital tooth agenesis and related gene mutations, providing a reference for early diagnosis of the disease.@*Methods @# Clinical and radiographic examinations of a rare case of congenital tooth agenesis were conducted to evaluate the abnormal morphology and quantity of the teeth, as well as the overall health of the patient. Bidirectional sequencing of the PAX9 and MSX1 genes and whole-exome sequencing were conducted to identify potential genetic abnormalities. Sanger sequencing of the newly discovered mutation site was performed on the proband's son. Subsequently, the impacts of the mutations were evaluated through computational tools and a cell-based gene transfection assay. @*Results @#This is a rare case of tooth agenesis characterized by a congenitally missing first molar, a second molar with one single root and a supernumerary second premolar in the right mandibular dentition. The c.717 C>C/T in PAX9 is synonymous. The c.119C>G in MSX1 is a missense mutation predicted to be “benign” by Polyphen. Through whole-exome sequencing, we found a novel mutation, c.637-7 C>A in intron 3 of the WNT6 gene, which is predicted by MAXENT to influence the splicing of mRNA. Both the proband and his son carry this mutation. A cell-based gene transfection assay demonstrated that it did not alter the mRNA splicing of WNT6. @* Conclusion @#The interaction between single nucleotide polymorphisms may contribute to congenital tooth agenesis.

Variations in heterochromatin content reveal important polymorphisms for studies of genetic improvement in garlic (Allium sativum L) / Conteúdo de heterocromatina revela polimorfismos importantes para o melhoramento genético do alho (Allium sativum L)

Allium sativum L. is an herb of the Alliaceae family with a specific taste and aroma and medicinal and nutraceutical properties that are widely marketed in several countries. Brazil is one of the largest importers of garlic in the world, despite of its production is restricted and limited to internal consumption. Thus, explore the genetic diversity of commercial garlic conserved at germplasm banks is essential to generate additional genetic information about its economically important crop. A suitable tool for this purpose is the cytogenetic characterisation of these accessions. This study aimed to characterise the cytogenetic diversity among seven accessions of garlic from a Germplasm Bank in Brazil. The karyotypes were obtained by conventional staining and with chromomycin A3 (CMA) and 4,6-diamidino-2-phenylindole (DAPI) fluorochromes. All accessions analysed showed chromosome number 2n= 16, karyotype formula 6M+2SM, symmetrical karyotypes, reticulate interphase nuclei, and chromosomes with uniform chromatin condensation from prophase to metaphase. The fluorochromes staining showed differences in the amount and distribution of heterochromatin along the chromosomes and between accessions studied. Based on the distribution pattern of these small polymorphisms, it was possible to separate the seven accessions into three groups. It was also possible to differentiate some of the accessions individually. One of the results obtained showed a heteromorphic distension of the nucleolar organiser region observed on the chromosome pairs 6 or 7 with peculiar characteristics. It was suggested for example, that the heteromorphic block of heterochromatin (CMA+++/DAPI-) on chromosome 6 of the "Branco Mineiro Piauí" accession can be used as a marker to identify this genotype or may be associated with some character of economic interest.

Allium sativum L. é uma erva da família Alliaceae com sabor e aroma específicos e propriedades medicinais e nutracêuticas amplamente comercializada em diversos países. O Brasil é um dos maiores importadores de alho do mundo, apesar da sua produção ser restrita e limitada ao consumo interno. Assim, explorar a diversidade genética do alho comercial conservado em bancos de germoplasma é essencial para fornecer informações genéticas adicionais acerca dessa cultura economicamente importante. Uma ferramenta adequada para esse fim é a caracterização citogenética desses acessos. Este estudo teve como objetivo caracterizar a diversidade citogenética entre sete acessos de alho de um Banco de Germoplasma no Brasil. Os cariótipos foram obtidos por coloração convencional e com os fluorocromos de cromomicina A3 (CMA) e 4,6-diamidino-2-fenilindol (DAPI). Todos os acessos analisados apresentaram número cromossômico 2n = 16, fórmula cariotípica 6M + 2SM, cariótipos simétricos, núcleos reticulados em intérfase e cromossomos com condensação uniforme da cromatina da prófase para a metáfase. A coloração com fluorocromos mostrou diferenças na quantidade e distribuição de heterocromatina ao longo dos cromossomos e entre os acessos estudados. Com base no padrão de distribuição desses pequenos polimorfismos, foi possível separar os sete acessos em três grupos. Também foi possível diferenciar individualmente alguns dos acessos. Um dos resultados obtidos mostrou distensão heteromórfica da região organizadora nucleolar observada nos pares dos cromossomos 6 ou 7 com características peculiares. Foi sugerido, por exemplo, que o bloco heteromórfico de heterocromatina (CMA +++ / DAPI-) no cromossomo 6 do acesso “Branco Mineiro Piauí” pode ser usado como um marcador para identificar esse genótipo ou pode estar associado a algum caráter de interesse econômico.

Variations in heterochromatin content reveal important polymorphisms for studies of genetic improvement in garlic (Allium sativum L.)

Abstract Allium sativum L. is an herb of the Alliaceae family with a specific taste and aroma and medicinal and nutraceutical properties that are widely marketed in several countries. Brazil is one of the largest importers of garlic in the world, despite of its production is restricted and limited to internal consumption. Thus, explore the genetic diversity of commercial garlic conserved at germplasm banks is essential to generate additional genetic information about its economically important crop. A suitable tool for this purpose is the cytogenetic characterisation of these accessions. This study aimed to characterise the cytogenetic diversity among seven accessions of garlic from a Germplasm Bank in Brazil. The karyotypes were obtained by conventional staining and with chromomycin A3 (CMA) and 4,6-diamidino-2-phenylindole (DAPI) fluorochromes. All accessions analysed showed chromosome number 2n = 16, karyotype formula 6M+2SM, symmetrical karyotypes, reticulate interphase nuclei, and chromosomes with uniform chromatin condensation from prophase to metaphase. The fluorochromes staining showed differences in the amount and distribution of heterochromatin along the chromosomes and between accessions studied. Based on the distribution pattern of these small polymorphisms, it was possible to separate the seven accessions into three groups. It was also possible to differentiate some of the accessions individually. One of the results obtained showed a heteromorphic distension of the nucleolar organiser region observed on the chromosome pairs 6 or 7 with peculiar characteristics. It was suggested for example, that the heteromorphic block of heterochromatin (CMA+++/DAPI-) on chromosome 6 of the Branco Mineiro Piauí accession can be used as a marker to identify this genotype or may be associated with some character of economic interest.

Resumo Allium sativum L. é uma erva da família Alliaceae com sabor e aroma específicos e propriedades medicinais e nutracêuticas amplamente comercializada em diversos países. O Brasil é um dos maiores importadores de alho do mundo, apesar da sua produção ser restrita e limitada ao consumo interno. Assim, explorar a diversidade genética do alho comercial conservado em bancos de germoplasma é essencial para fornecer informações genéticas adicionais acerca dessa cultura economicamente importante. Uma ferramenta adequada para esse fim é a caracterização citogenética desses acessos. Este estudo teve como objetivo caracterizar a diversidade citogenética entre sete acessos de alho de um Banco de Germoplasma no Brasil. Os cariótipos foram obtidos por coloração convencional e com os fluorocromos de cromomicina A3 (CMA) e 4,6-diamidino-2-fenilindol (DAPI). Todos os acessos analisados apresentaram número cromossômico 2n = 16, fórmula cariotípica 6M + 2SM, cariótipos simétricos, núcleos reticulados em intérfase e cromossomos com condensação uniforme da cromatina da prófase para a metáfase. A coloração com fluorocromos mostrou diferenças na quantidade e distribuição de heterocromatina ao longo dos cromossomos e entre os acessos estudados. Com base no padrão de distribuição desses pequenos polimorfismos, foi possível separar os sete acessos em três grupos. Também foi possível diferenciar individualmente alguns dos acessos. Um dos resultados obtidos mostrou distensão heteromórfica da região organizadora nucleolar observada nos pares dos cromossomos 6 ou 7 com características peculiares. Foi sugerido, por exemplo, que o bloco heteromórfico de heterocromatina (CMA +++ / DAPI-) no cromossomo 6 do acesso Branco Mineiro Piauí pode ser usado como um marcador para identificar esse genótipo ou pode estar associado a algum caráter de interesse econômico.

Polimorfismo genético associado a doença renal crônica e periodontite: uma revisão sistemática de literatura / Genetic polymorphism associated with chronic kidney disease and periodontitis: a systematic literature review / Polimorfismo genético asociado a enfermedad renal crónica y periodontitis: una revisión sistemática de la literatura

A periodontite é uma doença infecto-inflamatória associada ao biofilme disbiótico que afeta os tecidos de proteção e de suporte dos dentes. O processo inflamatório que ocorre durante a periodontite tem sido associado à inflamação sistêmica em pacientes com doença renal crônica. Os polimorfismos genéticos são alterações no DNA que podem ter classificações diferentes dependendo da mutação gerada, e podem ser criados ou destruídos. Objetivo: O objetivo desta revisão sistemática da literatura foi elucidar a seguinte questão: os polimorfismos genéticos estão associados à doença renal crônica e à periodontite? Material e Métodos: A pesquisa foi realizada no PubMed, Biblioteca Cochrane, EMBASE, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Bibliografia Brasileira de Odontologia (BBO), Biblioteca Virtual em Saúde (BVS), SciELO, Scopus, Web of Science e bases de dados de literatura cinzenta (Google Scholar) sem restrições de data ou idioma em 28 de junho de 2021 e atualizada em 26 de janeiro de 2023. Os descritores padronizados (Medical Subject Headings, MeSH) utilizados foram: "polimorfismo genético", "doença renal crônica" e "periodontite", de acordo com o banco de dados consultado, utilizando os operadores booleanos "AND". Resultado: 25 publicações foram identificadas. Após a análise do título, do resumo e do texto completo, 6 estudos de caso-controle foram selecionados para análise. Todos incluíam artigos investigando o papel de diferentes polimorfismos genéticos em ambas as doenças. Alguns genes apresentavam uma relação próxima com o perfil inflamatório que caracteriza ambas as doenças. Conclusão: Entre os polimorfismos estudados, os polimorfismos VNTR no gene IL4 e MCP-1-2518 A/G apresentaram uma associação positiva tanto com a periodontite quanto com a doença renal crônica. Entretanto, são necessários mais estudos para melhor compreensão do papel dos polimorfismos genéticos nessas doenças.

Periodontitis is an infectious-inflammatory disease associated with dysbiotic biofilm that affects the protective and supporting tissues of the teeth. The inflammatory process that occurs during periodontitis has been associated with systemic inflammation in patients with chronic kidney disease. Genetic polymorphisms are changes in DNA that can have different classifications depending on the mutation generated, and can be created or destroyed. Objective: The aim of this systematic review of the literature was to elucidate the following question: are genetic polymorphisms associated with chronic kidney disease and periodontitis? Material and Methods: The search was conducted in PubMed, Cochrane Library, EMBASE, Latin American and Caribbean Literature on Health Sciences (LILACS), Brazilian Bibliography of Dentistry (BBO), Virtual Health Library (VHL), SciELO, Scopus, Web of Science and gray literature databases (Google Scholar) without date or language restrictions on June 28, 2021 and updated on January 26, 2023. The standardized descriptors (Medical Subject Headings, MeSH) used were: "genetic polymorphism", "chronic kidney disease" and "periodontitis", according to the database consulted, using the Boolean operators "AND". Result: 25 publications were identified. After reviewing the title, abstract, and full text, 6 case-control studies were selected for analysis. All included articles investigating the role of different genetic polymorphisms in both diseases. Some genes showed a close relationship with the inflammatory profile that characterizes both diseases. Conclusion: Among the polymorphisms studied, the VNTR polymorphisms in the IL4 gene and MCP- 1-2518 A/G showed a positive association with both periodontitis and chronic kidney disease. However, further studies are needed to better understand the role of genetic polymorphisms in these diseases.

La periodontitis es una enfermedad infeccioso-inflamatoria asociada a un biofilm disbiótico que afecta a los tejidos protectores y de soporte de los dientes. El proceso inflamatorio que se produce durante la periodontitis se ha asociado con la inflamación sistémica en pacientes con enfermedad renal crónica. Los polimorfismos genéticos son cambios en el ADN que pueden tener diferentes clasificaciones dependiendo de la mutación generada, pudiendo ser creados o destruidos. Objetivo: El objetivo de esta revisión sistemática de la literatura fue dilucidar la siguiente pregunta: ¿están asociados los polimorfismos genéticos con la enfermedad renal crónica y la periodontitis? Material y Métodos: La búsqueda fue realizada en PubMed, Cochrane Library, EMBASE, Literatura Latinoamericana y del Caribe en Ciencias de la Salud (LILACS), Bibliografía Brasileña de Odontología (BBO), Biblioteca Virtual en Salud (BVS), SciELO, Scopus, Web of Science y bases de datos de literatura gris (Google Scholar) sin restricciones de fecha o idioma el 28 de junio de 2021 y actualizada el 26 de enero de 2023. Los descriptores normalizados (Medical Subject Headings, MeSH) utilizados fueron: "polimorfismo genético", "enfermedad renal crónica" y "periodontitis", según la base de datos consultada, utilizando los operadores booleanos "AND". Resultado: Se identificaron 25 publicaciones. Tras analizar el título, el resumen y el texto completo, se seleccionaron 6 estudios de casos y controles para su análisis. Todos los trabajos incluidos investigaban el papel de diferentes polimorfismos genéticos en ambas enfermedades. Algunos genes mostraron una estrecha relación con el perfil inflamatorio que caracteriza a ambas enfermedades. Conclusión: Entre los polimorfismos estudiados, los polimorfismos VNTR en el gen IL4 y MCP-1-2518 A/G mostraron una asociación positiva tanto con la periodontitis como con la enfermedad renal crónica. Sin embargo, se necesitan más estudios para comprender mejor el papel de los polimorfismos genéticos en estas enfermedades.

Influence of host genetic polymorphisms involved in immune response and their role in the development of Chikungunya disease: a review

Chikungunya virus (CHIKV) is transmitted by the bite of infected mosquitoes and can cause significant pathogenicity in humans. Moreover, its importance has increased in the Americas since 2013. The primary vectors for viral delivery are the mosquito species Aedes aegypti and Aedes albopictus. Several factors, including host genetic variations and immune response against CHIKV, influence the outcomes of Chikungunya disease. This work aimed to gather information about different single nucleotide polymorphisms (SNPs) in genes that influence the host immune response during an infection by CHIKV. The viral characteristics, disease epidemiology, clinical manifestations, and immune response against CHIKV are also addressed. The main immune molecules related to this arboviral disease elucidated in this review are TLR3/7/8, DC-SIGN, HLA-DRB1/HLA-DQB1, TNF, IL1RN, OAS2/3, and CRP. Advances in knowledge about the genetic basis of the immune response during CHIKV infection are essential for expanding the understanding of disease pathophysiology, providing new genetic markers for prognosis, and identifying molecular targets for the development of new drug treatments.

Polimorfismos genéticos implicados en el desarrollo de la purpura trombocitopénica inmune / Genetic polymorphisms involved in the development of Immune Thrombocytopenic Purpura

Introducción: los cambios en el ácido desoxirribonucleico se conocen como mutaciones, estas dan lugar a los polimorfismos, los cuales generan variación alélica entre individuos y diversidad de la misma especie. Se ha sugerido que los polimorfismos genéticos en los mediadores inmunitarios desempeñan un papel fundamental en la patogénesis de muchos trastornos autoinmunes, como en la púrpura trombocitopénica inmune, siendo esta el tipo más común de púrpura trombocitopénica y, a menudo, se diagnostica como un tipo de trastorno autoinmune, debido a la destrucción de las plaquetas mediadas por el sistema inmunitario. Objetivo: realizar una revisión bibliográfica sobre el papel de los polimorfismos genéticos y su influencia en el desarrollo de la púrpura trombocitopénica inmune. Métodos: se realizó revisión literaria en inglés y español en PubMed y Elsevier, desde marzo hasta mayo del 2021, con el uso de combinación de palabras clave y términos MeSH, como púrpura trombocitopénica y polimorfismos genéticos. Se realizó análisis y resumen de la literatura encontrada. Conclusión: la púrpura trombocitopénica inmune es considerada como una patología multifactorial, causada por factores ambientales y genéticos, dentro de los cuales se encuentran los polimorfismos para los mediadores inmunitarios que pueden llevar a una exacerbación de la enfermedad o no intervenir en la misma.

Introduction: Changes in deoxyribonucleic acid are known as mutations, these give place to polymorphisms, which generate allelic variation between individuals and provide diversity among same species. Genetic polymorphisms in immune mediators have been suggested to play a key role in the pathogenesis of many autoimmune disorders, such as immune thrombocytopenic purpura, this being the most common type of thrombocytopenic purpura and is often diagnosed as a type of autoimmune disorder, due to the destruction of platelets mediated by the immune system. Objective: To execute a bibliographic review on the role of genetic polymorphisms and their influence on the development of immune thrombocytopenic purpura. Methods: A literary review in English and Spanish was performed in PubMed and Elsevier from March to May 2021, with the use of a combination of keywords and MeSH terms such as Thrombocytopenic Purpura and genetic polymorphisms. Analysis and summary of the literature found was executed. Conclusion: Immune thrombocytopenic purpura is considered a multifactorial pathology, caused by environmental and genetic factors, among which are polymorphisms for immune mediators that can lead to an exacerbation of the disease or not intervene in the same.

Genetic variability in the neurobiology of nicotine dependence: effects on smoking behavior / A variabilidade genética na neurobiologia da adição à nicotina: reflexos no comportamento tabágico

Abstract Background Smoking dependence is a chronic disease and a public health problem. The neurobiology of nicotine addiction can explain smoking behavior. This system has genetic variability that has been associated with vulnerability to dependence. Genetic variability in the neurobiology of smoking can help to understand why individuals exposed to drugs may or may not become addicted. Objective This study aims to address genetic variability in the neurobiology of smoking addiction with a focus on polymorphic genes related to the nicotinic response and the dopaminergic reward pathway. Method This work involved a search of the main scientific research on genetic variability in the neurobiology of smoking and its effects on smoking behavior. One hundred and five studies were selected, most of which highlighted polymorphisms in the genes of nicotinic receptors, dopamine receptors, and nicotine metabolism. Results The majority of studies have focused on genes related to the activation of the dopaminergic reward system by nicotine. Combinations between different polymorphisms were also highlighted, showing that interactions can determine a genetic profile of predisposition to smoking addiction. Additionally, gender and ethnicity were identified as relevant factors. Conclusion Knowledge of the genetic bases involved in the individual response to smoking can enable a better understanding of inter-individual differences in smoking behavior, and contribute to improving the treatment of addiction.

Resumo Introdução A dependência nicotínica é uma doença crônica e um problema de saúde pública. O comportamento tabágico pode ser explicado pela neurobiologia da adição, cujas variações genéticas têm sido associadas à dependência. A variabilidade genética na neurobiologia do tabagismo pode ajudar a entender por que indivíduos expostos a drogas podem ou não se tornar viciados. Objetivo Este estudo tem como objetivo abordar a variabilidade genética na neurobiologia do tabagismo com foco em genes polimórficos relacionados à resposta nicotínica e à via de recompensa dopaminérgica. Método Uma pesquisa foi realizada nas principais bases de dados científicos sobre a variabilidade genética na neurobiologia do tabagismo e seus efeitos no comportamento do tabagismo. 105 estudos foram selecionados, em sua maioria destacando polimorfismos nos genes de receptores nicotínicos, receptores de dopamina e de metabolismo da nicotina. Resultados A maioria dos estudos concentrou-se em genes relacionados à ativação do sistema de recompensa dopaminérgico pela nicotina. Determinadas combinações entre genótipos de diferentes polimorfismos também se destacaram, mostrando que interações gênicas podem determinar um perfil genético de predisposição ao tabagismo. Além disso, gênero e etnia foram identificados como fatores relevantes. Conclusão O conhecimento das bases genéticas envolvidas na resposta individual ao tabagismo pode permitir uma melhor compreensão das diferenças interindividuais no comportamento tabágico e contribuir para melhoria dos tratamentos disponíveis para a dependência.