Pharmacogenomics & Personalized Medicine最新文献

This paper systematically reviews recent advances in clopidogrel clinical applications to optimize therapeutic precision and medication safety. Using a literature review methodology, we elucidate clopidogrel's pharmacokinetic properties and pharmacodynamic mechanisms, while evaluating its clinical efficacy and adverse reactions in disease management. Recent studies have emphasized the key role of genetic polymorphisms in regulating the efficacy and safety of clopidogrel. Polymorphisms in the CYP2C19 gene have a significant effect on the metabolism of clopidogrel, with loss-of-function (LOF) alleles (*2, *3) reducing the production of active metabolites, leading to elevated platelet reactivity and increasing the risk of major adverse cardiovascular events (MACE), particularly in the Asian populations, where the prevalence of LoF alleles is as high as 29-35%. In contrast, the gain-of-function allele CYP2C19*17 results in a reduced risk of cardiovascular events but increases the risk of bleeding. This article summarizes the latest research progress and monitoring methods of clopidogrel, and suggests that clinics should combine genotyping and platelet function testing with monitoring of blood levels to optimize treatment and provide data reference for clinical administration of clopidogrel.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disease that is characterized by progressive proximal muscle weakness and pseudohypertrophy. Currently, genetic diagnosis of DMD relies largely on multiplex ligation-dependent probe analysis (MLPA) and Sanger sequencing to identify pathogenic mutations. This study aimed to confirm the genetic etiology of a boy presenting with clinical manifestations that are highly indicative of DMD. A 14-year-old boy with heart failure and extreme muscle weakness along with his family members was recruited for this study. DNA from each participant was isolated from peripheral blood samples. We used MLPA to detect the deletion or duplication mutations of the DMD gene and Sanger sequencing to verify the missing region of the exon in the proband. Furthermore, the functional role of the mutation was assessed using bioinformatics. We found that the proband carried a small deletion in the DMD gene (c.6808_6811delTTAA). The deletion of those four nucleotides resulted in a frameshift mutation and a premature nonsense codon, which resulted in a truncated dystrophin that lost its most critical function and underwent post-transcriptional degradation. Our study demonstrated that MLPA, in combination with Sanger sequencing, is a reliable and practical approach for the genetic diagnosis of DMD, which is a significant step towards developing personalized therapy.

Background: Neuroblastoma (NB) is a malignancy of neural crest cells that primarily affects children. Single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) gene, a well-conserved gene, have been implicated in tumorigenesis. However, there is currently insufficient evidence to establish the relationship between FTO gene SNPs and susceptibility to NB.

Methods: A TaqMan assay was conducted to examine the potential associations between FTO gene SNPs and the risk of NB in a cohort of 898 patients and 1734 controls from eight medical centers in China. Additionally, stratification analysis was performed to evaluate the relationship between the selected FTO SNPs and the susceptibility to NB among various subgroups.

Results: No significant association was found between the selected FTO polymorphisms and the risk of NB in either the single locus analysis or the combined analysis.

Conclusion: However, our study reveals that individuals with retroperitoneal NB and those with stage III+IV NB are more prone to exhibit FTO SNPs compared to other patients. Moreover, participants with the FTO rs8047395 GG genotype displayed a higher likelihood of developing stage III+IV NB in comparison to other participants.

Background: The family with the sequence similarity 198 member B (FAM198B) has been found to contribute to the progression of gastric cancer (GC). However, the role and molecular mechanism of FAM198B in GC remains poorly understood. This work found a link between FAM198B and quercetin, and the regulatory effect of FAM198B on the MAPK pathway of GC.

Methods: FAM198B expression was identified through multiple public data sets and verified in clinical tissue samples. The associations between FAM198B and the prognosis of patients with GC were analyzed via the Kaplan‒Meier plotter and Cox regression analysis. Gene set enrichment analysis, coexpressed genes, and RNA sequencing were used to explore the related functions and signaling pathways of FAM198B in GC. In vitro assays assessed the effects of FAM198B knockdown on GC cells. FAM198B was found as a quercetin target by the HERB database and in vitro assays.

Results: FAM198B was highly expressed in tissues from GC patients (p<0.001) and was positively associated with poor prognosis (p<0.001) and immune cell infiltration in GC patients. FAM198B knockdown inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells (all p<0.05). In addition, FAM198B knockdown decreased the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.01). Quercetin inhibited FAM198B expression and the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.05).

Conclusion: Quercetin inhibits the proliferation, migration, invasion, and EMT of GC cells by inhibiting the FAM198B/MAPK signaling pathway. These discoveries lay the groundwork for developing the treatment of GC by quercetin and targeting FAM198B. In the future, more preclinical and clinical studies are needed to confirm the efficacy and safety of quercetin and target FAM198B in GC.

Background and purpose: The CYP2C19 enzyme is essential for activation of the antiplatelet drug clopidogrel. Genetic variations in CYP2C19 are known to influence individual drug responses. Here, differences in CYP2C19 alleles, genotypes, and phenotypes in patients with cardiovascular disease from the Yunnan-Guizhou Plateau were systematically surveyed to provide a reference for appropriate treatment approaches.

Methods: The CYP2C19*2, *3, and *17 variants were determined by RT-qPCR in 1934 patients with cardiovascular disease from 10 different areas of the Yunnan-Guizhou Plateau. Clinical data were analyzed using χ² tests.

Results: The proportions of the CYP2C19*1, *2, *3, and *17 alleles in the study cohort were 64.94, 29.81, 4.42, and 0.83%, respectively, while the frequencies of nine observed genotypes (*1/*17, *1/*1, *2/*17, *3/*17, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3) were 1.03, 42.09, 0.57, 0.05, 38.73, 5.95, 8.89, 2.53, and 0.16%, respectively. Four metabolic phenotypes were found in the population, namely, rapid (1.03%), normal (42.09%), intermediate (45.29%), and poor (11.58%) metabolizers. Regional differences in allele and phenotype distribution were observed.

Conclusion: These results represent the first comprehensive profile of CYP2C19 variants in patients with cardiovascular disease from the Yunnan-Guizhou Plateau, offering a valuable genetic reference for the selection of optimal treatment strategies.

Background: Inflammatory myofibroblastic tumor (IMT) in the nasal cavity and sinuses is rare and has special clinical and pathological characteristics with poor prognosis. This study aimed to investigate the clinicopathological and molecular features of primary IMT in the nasal cavity and paranasal sinuses.

Methods: The clinical features, histopathological findings, immunohistochemical findings and results of molecular genetic examination were retrospectively analyzed in 25 patients who were diagnosed with IMT in the nasal cavity and paranasal sinuses.

Results: Tumor tissues were mainly composed of obese spindle-shaped myofibroblasts, fibroblasts, and chronic inflammatory cells. The inflammatory cells included plasma cells, lymphocytes, eosinophils, foam histiocytes and multinuclear giant cells. Immunohistochemical staining showed the tumor was positive to anaplastic lymphoma kinase (ALK) in two patients. ALK fusion mutation was detected by PCR in only 1 patient.

Conclusion: Nasal and paranasal sinus IMTs are rare, exhibit histopathological diversity with low specificity, and require careful differentiation from inflammatory and autoimmune disorders. These tumors demonstrate a worse prognosis compared to IMTs in other anatomic locations, along with a significantly lower rate of ALK gene rearrangement. Identifying molecular target alterations can enhance precision diagnosis and targeted therapeutic strategies.

Background: Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked neurodevelopmental disorder caused by mutations in the solute carrier family 16-member 2 (SLC16A2) gene. This syndrome leads to significant psychomotor disabilities, thyroid dysfunction, and abnormal brain development. This case report describes the genetic cause of AHDS in a male proband and to expanding the mutation spectrum of the SLC16A2 gene.

Methods: A blood specimen was collected from a one-year-old child with delayed development and abnormal thyroid function and this was followed by whole-exome sequencing (WES) was performed on the proband to identify potential genetic mutations. Sanger sequencing was subsequently used to confirm the findings and determine the inheritance pattern of the mutation within the family.

Results: The proband, who presented with developmental delay, thyroid dysfunction, and abnormal brain development, was found to have a novel hemizygous frameshift mutation, c.513_538del (p.Ile172Cysfs*60), in the SLC16A2 gene (NM_006517.5). This mutation was inherited from his asymptomatic mother, confirming the X-linked inheritance pattern. The mutation is classified as likely pathogenic, contributing to the clinical presentation observed in the proband.

Conclusion: This study identified a novel frameshift mutation in the SLC16A2 gene associated with AHDS, thereby expanding the known mutation spectrum of this gene. Given the significant impact of AHDS on neural development and hormone secretion, it is recommended that this gene be included in carrier screening panels in China, particularly for families with a history of related neurodevelopmental disorders.

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.