Pharmacogenomics & Personalized Medicine最新文献

Background: Pharmacogenomics holds significant promise in improving the efficacy and safety of chemotherapy for childhood cancers. However, the field remains underexplored in Africa, where high genetic diversity and substantial disease burdens, including cancers, create unique challenges. This review investigates the current state of pharmacogenomics research in childhood cancer chemotherapies across Africa, focusing on genetic variations influencing chemotherapy efficacy and adverse drug reactions. It also highlights critical gaps, such as limited infrastructure and insufficient healthcare worker knowledge, and emphasizes the importance of capacity-building initiatives in the region.

Methods: A scoping review was conducted encompassing studies published up to September 2024 that examined pharmacogenomic variations associated with chemotherapies in childhood cancer patients across Africa. The review included laboratory genetic analyses and surveys assessing healthcare workers' knowledge, attitudes, and perceptions regarding pharmacogenomics, particularly in the context of pediatric oncology.

Results: A total of 12 genes were identified across eight studies, including TPMT, CYP3A5, MDR1, MAPT, NUDT15, ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3, ABCC4, and MTHFR. The most studied genes were TPMT and CYP3A5, which are involved in the metabolism of 6-mercaptopurine (6-MP) and vincristine, respectively. These studies spanned five African countries, including Kenya, Egypt, Zimbabwe, Nigeria, Tunisia, and Libya, and focused primarily on childhood cancers, particularly acute lymphoblastic leukemia. Chemotherapies frequently studied were 6-MP (reported in five studies), vincristine, cyclophosphamide, and methotrexate. Knowledge of pharmacogenomics among healthcare workers in Africa remains low, though a positive attitude towards its clinical applications was observed.

Conclusion: Pharmacogenomic variants, such as TPMT*3A, 3C, and CYP3A53, *6, significantly impact drug metabolism in African children with cancer. However, research remains regionally limited, and gaps in infrastructure and healthcare worker training persist. Expanding research efforts and improving pharmacogenomics capacity through pharmacist training and capacity-building initiatives are essential to advancing personalized medicine in Africa, ultimately improving treatment outcomes for pediatric cancer patients.

Background: Single nucleotide polymorphisms (SNPs) in miRNA genes can influence the expression of miRNAs that modulate the PI3K/AKT/GSK3β pathway and play crucial roles in type 2 diabetes mellitus (T2DM) susceptibility. The purpose of this study was to investigate the association of SNPs in miRNA genes targeting the PI3K/AKT/GSK3β pathway with T2DM.

Methods: This case-control study included 1,416 subjects with T2DM and 1,694 non-diabetics. Eleven SNPs in miRNA genes (rs895819 in miR-27a, rs11888095 in miR-128a, rs2292832 in miR-149, rs6502892 in miR-22, rs13283671 in miR-31, rs1076063 and rs1076064 in miR-378a, rs10061133 in miR-449b, rs3746444 in miR-499a and rs678956 and rs476364 in miR-326) involved in PI3K/AKT/GSK3β pathway were genotyped by TaqMan Genotyping Assay, and the associations of these SNPs with T2DM were analyzed using online SHesis and SNPstats.

Results: The results showed that miR-378a rs1076064 G allele could be a protective factor against T2DM (p<0.001, OR=0.828; 95% CI:0.749-0.916), whereas the miR-31 rs13283671 C allele could increase the risk of developing T2DM (p=0.003, OR=1.193; 95% CI:1.060-1.342). In addition, the miR-378a rs1076063A-rs1076064G haplotype could be a protective against T2DM (p<0.001, OR=0.731; 95% CI:0.649-0.824). According to inheritance mode analysis, compared with the AA-AG genotype, the GG genotype of rs1076064 showed a protective effect in T2DM in the recessive mode (p<0.01, OR=0.71; 95% CI: 0.59-0.84). For rs13283671, compared with the TT genotype, the CT-CC genotype showed a risk effect in T2DM in the dominant inheritance model (p<0.01, OR=1.29; 95% CI: 1.12-1.49). Genotype-Tissue Expression (GTEx) Portal database analysis showed that miR-31 rs13283671 CT and CC genotypes had lower AKT expression than TT genotypes.

Conclusion: In conclusion, rs13283671 in miR-31 and rs1076064 in miR-378a involved in the PI3K/AKT/GSK3β pathway were associated with T2DM susceptibility in a Chinese population.

Joubert syndrome (JS) is an infrequent congenital neurodevelopmental ciliopathy, typically identified in children around the average age of 33 months. This disorder is characterized by developmental delay, cognitive impairment, and infantile hypotonia that may evolve into ataxia. Mutations in OFD1 results in Joubert syndrome with a variety of phenotypes. Here, we identified a child who presented with Joubert syndrome exhibiting orofaciodigital spectrum anomalies, polydactyly, and retinitis pigmentosa. Whole exome sequencing and Sanger sequencing revealed a splicing mutation (NM_003611.2, c.2387+1G>A) in the OFD1 gene of the patient and his mother. mRNA sequencing further confirmed this mutation. However, since the patient is homozygous and the mother is heterozygous, only the patient has the phenotype and the mother is normal. This mutation can lead to the loss of sixth coiled-coil domains of OFD1 protein, which further disrupt the ciliary signaling pathway and Hedgehog signaling pathway. This study presents a new case of JS and expands the mutant spectrum of OFD1, but also enhances our understanding of the mechanism by which OFD1 is associated with ciliosis.

Objective: To explore the effect of Naoxintong (NXT) on warfarin anticoagulation therapy and its potential mechanism.

Methods: TCSMP, SwissTargetprediction, SuperPred, SEA, and Batmanic-TCM were used to search for active ingredients and targets of NXT and warfarin; the DisGENT database was used to find disease targets of coagulation disorders. Cytoscape software was applied to construct the "drug-target"network; the protein interaction network (PPI) was used to study the protein-protein interaction. GO and KEGG were used for functional analysis. The effect of NXT on warfarin anticoagulation was then tested in rats by analyzing coagulation factors in blood before and after drug administration. The expression of MAPK in the liver tissue was determined by Western blot.

Results: The top five components of NXT affecting warfarin anticoagulation degree value were MOL000098, MOL000422, MOL000006, MOL000358, and MOL000449. TP53, AKT1, SRC, TNF, HSP90AA1, STAT3, JUN, IL6, EGFR, and ESR1 were the core targets of NXT, while MAPK9, MAP3K5, MAPK8, and MAPK1 in the MAPK family were important targets of NXT in the coagulation process. In vivo testing indicated that NXT may be able to participate in the regulation of the warfarin coagulation process through multiple targets and multiple pathways, which may be related to MAPK.

Conclusion: Our data suggests that NXT is involved in the coagulation regulation of warfarin through the MAPK pathway.

Pharmacogenomics is the integration of genomics and pharmacology to optimize drug response and reduce side effects. In terms of personalized or individualized medicine, PGx is defined as the identification and analysis of specific genetic variants associated with particular drug treatments for each patient. Under a precision public health (PPH) approach, population-level data are analyzed to generate public health strategies. The objective of this study was to conduct a scoping review of technological tools, examining their evolution, the predominance of high-income countries in their development, and the gaps and needs for genomic data and advances in low- and middle-income countries (LMICs). This review was conducted in accordance with the ScPRISMA guidelines. A search was conducted in PubMed, Web of Science and Embase until January 2024. A total of 40 documents were selected, which revealed the continuous evolution and progressive development of pharmacogenomic tools. The technological tools developed come from high-income countries, particularly the United States, Canada, China, and several European nations, where international collaboration has been essential to maintain and expand these tools, which have evolved to keep pace with the rapid generation of genomic data. This trend shows a scarce development of technological tools for public health precision in LMICs, which evidences the need to increase investment in genomic research infrastructure in this aspect and in the development of capacities to guarantee global accessibility and boost PPH for all populations.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by diverse symptoms affecting social interaction, communication, and behavior. This research aims to explore bacterial lipopolysaccharide (LPS)- and immune-related (BLI) molecular subgroups in ASD to enhance understanding of the disorder.

Methods: We analyzed 89 control samples and 157 ASD samples from the GEO database, identifying BLI signatures using least absolute shrinkage and selection operator regression (LASSO) and logistic regression machine learning algorithms. A nomogram prediction model was developed based on these signatures, and we performed Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and immune cell infiltration analysis to assess the impact of BLI subtypes and their underlying mechanisms.

Results: Our findings revealed 17 differentially expressed BLI genes in children with ASD, with BLNK, MAPK8, PRKCQ, and TNFSF12 identified as potential biomarkers. The nomogram demonstrated high diagnostic accuracy for ASD. We delineated two distinct molecular subtypes (Cluster 1 and Cluster 2), with GSVA indicating that Cluster 2 showed upregulation of immune- and inflammation-related pathways. This cluster exhibited increased levels of antimicrobial agents, chemokines, cytokines, and TNF family cytokines, alongside activation of bacterial lipoprotein-related pathways. A significant correlation was found between these pathways and distinct immune cell subtypes, suggesting a potential mechanism for neuroinflammation and immune cell infiltration in ASD.

Conclusion: Our research highlights the role of BLI-associated genes in the immune responses of individuals with ASD, indicating their contribution to the disorder's typification. The interplay between bacterial components, genetic predisposition, and immune dysregulation offers new insights for understanding ASD and developing personalized interventions.

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. The disease's complexity is underpinned by a variety of genetic and molecular abnormalities that drive its progression.

Methods: This review was conducted through a state-of-The-art literature search, primarily utilizing PubMed to gather peer-reviewed articles. We focused on the most comprehensive and cited studies to ensure a thorough understanding of the genetic and molecular landscapes of MM.

Results: We detail primary and secondary alterations such as translocations, hyperdiploidy, single nucleotide variants (SNVs), copy number alterations (CNAs), gene fusions, epigenetic modifications, non-coding RNAs, germline predisposing variants, and the influence of the tumor microenvironment (TME). Our analysis highlights the heterogeneity of MM and the challenges it poses in treatment and prognosis, emphasizing the distinction between driver mutations, which actively contribute to oncogenesis, and passenger mutations, which arise due to genomic instability and do not contribute to disease progression.

Conclusion & future perspectives: We report key controversies and challenges in defining the genetic drivers of MM, and examine their implications for future therapeutic strategies. We discuss the importance of systems biology approaches in understanding the dependencies and interactions among these alterations, particularly highlighting the impact of double and triple-hit scenarios on disease outcomes. By advancing our understanding of the molecular drivers and their interactions, this review sets the stage for novel therapeutic targets and strategies, ultimately aiming to improve clinical outcomes in MM patients.

Purpose: This study aimed to investigate the distribution patterns of PLA2G7 gene variants in Han Chinese patients with coronary heart disease (CHD), and their relationships with serum lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and lipid profiles.

Methods: A total of 93 han Chinese CHD patients were recruited. Serum Lp-PLA2 levels were determined using enzyme-linked immunosorbent assay (ELISA), while comprehensive analysis of PLA2G7 gene polymorphisms was conducted through whole-exome sequencing. Concurrently, multiple lipid parameters were measured and analyzed.

Results: Among these Han Chinese CHD patients, the PLA2G7 gene rs1051931 (c.1136T>C p.Val379Ala) rare variant was highly prevalent (variant rate: 94.62%) among the study population, and showed negative correlation with serum Lp-PLA2 activity. The rs1765208290 (c.233G>A p.Gly78Asp) rare variant showed positive correlation with TG, ApoA, ApoB, HDL, LDL and TCHO levels in the serum. Strong linkage disequilibrium was observed between the rs1805018 (c.593T>C p.Ile198Thr) and rs76863441 (c.835G>T p.Val279Phe), both of which were related to lower Lp-PLA2 activity.

Conclusion: In these Han Chinese CHD patients, the rs1051931 (c.1136T>C p.Val379Ala) rare variant in the PLA2G7 gene is closely linked to decreased Lp-PLA2 activity, whereas the rs1765208290 (c.233G>A p.Gly78Asp) rare variant influences lipid homeostasis. The strong LD between rs1805018 (c.593T>C p.Ile198Thr) and rs76863441 (c.835G>T p.Val279Phe) loci may act synergistically to reduce Lp-PLA2 activity.

Objective: The objective of this study was to evaluate the impact of clopidogrel-related gene polymorphisms on the occurrence of recurrent thrombotic events and cardiovascular death in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI).

Methods: We conducted genotype testing for 26 specific loci mapped to 18 clopidogrel-associated genes in ACS patients who had undergone PCI and were receiving dual antiplatelet therapy only involving clopidogrel. We documented major adverse cardiovascular events (MACE) and clinical endpoints, analyzing the effect of genetic polymorphisms on treatment outcomes.

Results: A total of 200 patients were enrolled in the study, with ischemic events occurring in 21 cases. Carriers of the T-allele for rs41273215 (PEAR1), rs662 (PON1), and the A-allele for rs4244285 (CYP2C19), as well as the C-allele for rs762551 (CYP1A2), exhibited a significant increase in the risk of MACE (OR = 2.76, 95% CI = 1.46-5.22, P = 0.002; OR = 3.72, 95% CI = 1.82-7.64, P = 0.0003; OR = 3.86, 95% CI = 1.89-7.86, P = 0.0002; OR = 2.40, 95% CI = 1.27-4.55, P = 0.007). Notably, the variant T-allele of rs168753 (F2R) was associated with a significant reduction in the risk of such events (OR = 0.29, 95% CI = 0.12-0.67, P = 0.004). No significant associations were found between other single nucleotide polymorphisms (SNPs) and clinical endpoints.

Conclusion: Polymorphisms in rs41273215 (PEAR1), rs662 (PON1), rs4244285 (CYP2C19), and rs762551 (CYP1A2) were correlated with an increased risk of MACE in PCI patients. Conversely, the rs168753 (F2R) polymorphism was linked to improved cardiovascular outcomes. Genotyping for these polymorphisms could be instrumental in identifying patients at heightened risk for MACE.

Purpose: Atorvastatin is commonly used to treat dyslipidemia; however, individual responses vary considerably. This study endeavors to evaluate the relationship between polymorphisms in the coding sequence (CDS) of SLCO1B1 gene and blood lipid levels before and after atorvastatin treatment among the Chinese Han adults with dyslipidemia.

Patients and methods: A total of 165 Chinese Han adults undergoing atorvastatin therapy were enrolled in this study and followed up quarterly. The complete CDS of the SLCO1B1 gene was sequenced to detect polymorphisms. Statistical analysis was utilized to assess the impacts of sex, age, body mass index (BMI), and polymorphisms on blood lipid levels before and after atorvastatin treatment.

Results: Fourteen polymorphisms were identified in the SLCO1B1 CDS. Among them, four polymorphisms had mutant alleles present in over 20 patients. No polymorphism was found to correlate with blood lipid levels before treatment; in contrast, age, sex, and BMI did show correlations (P<0.05). Notably, females had higher baseline blood lipid levels than males, indicating that sex had a more significant impact on baseline levels than age and BMI. The polymorphism rs2306283 was significantly correlated with the efficacy of atorvastatin (P<0.05), whereas age, sex, and BMI were not. Carriers of the rs2306283 AA allele experienced a substantially greater reduction in total cholesterol (TC) and triglyceride (TG) levels after atorvastatin treatment. The other polymorphisms did not demonstrate any significant impact on atorvastatin's efficacy.

Conclusion: This study delved into the intricate genetic structure of polymorphisms in SLCO1B1 CDS and their roles in lipid metabolism and atorvastatin's efficacy among Chinese Han adults with dyslipidemia. The findings underscore the crucial role of the rs2306283 polymorphism in the response to atorvastatin's efficacy, highlighting the significance of pharmacogenomics in personalized medicine. It is thus advisable to consider genetic testing for SLCO1B1 variants to optimize atorvastatin therapy.