Pharmacogenomics & Personalized Medicine最新文献

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

Objective: Gastric cancer is one of the most common malignancies worldwide; however, its overall mortality has not improved significantly over the last decade. Chemoresistance plays a critical role in this issue. This study aimed to clarify the role and mechanism of runt-related transcription factor 2 (RUNX2) in platinum-based chemotherapy resistance.

Methods: First, a drug-resistant model of gastric cancer cells was established to evaluate the relative expression level of the RUNX2 as a potential biomarker of chemotherapy resistance. Next, exogenous silencing was conducted to study whether RUNX2 could reverse drug resistance and understand the underlying mechanisms. Simultaneously, the correlation between the clinical outcomes of 40 patients after chemotherapy and the RUNX2 expression levels in tumor samples was analyzed.

Results: We discovered that RUNX2 was significantly expressed in drug-resistant gastric cancer cells and tissues; it was also reversibly resistant to transformation treatment by exogenous RUNX2 silencing. It is confirmed that RUNX2 negatively regulates the apoptosis pathway of the p53 to reduce the chemotherapeutic effects of gastric cancer.

Conclusion: RUNX2 is a possible target for platinum-based chemotherapy resistance.

Background: Primary ciliary dyskinesia (PCD) is a group of autosomal recessive genetic diseases caused by abnormal ciliary ultrastructure and/or function, resulting in reduced ciliary clearance function or other dysfunctions. PCD is one of the causes of recurrent respiratory tract infections in children. At present, there is no gold standard for diagnosis. In patients clinically suspected with PCD, a variety of examination methods are available to assist in diagnosis, such as high-speed video microscopic imaging to analyze ciliary movement patterns, transmission electron microscopy to observe ciliary ultrastructure, genetic testing, and detection of nitric oxide content in nasal expiratory air.

Case description: We present a case summary of the clinical data and treatment process of a child with PCD and short stature induced by Novel exon 1 of CCNO mutation (NM-021147.5) at c.323del, and the proband father and mother were heterozygous mutators, who was diagnosed and treated in the Pediatric Healthcare Department of our hospital. We treated the child with recombinant human growth hormone to increase the height, and the patient was also advised to improve nutrition, prevent and control infections, and encouraged sputum expectoration. We also recommended regular follow-up visits to the outpatient department, and to seek other symptomatic and supportive treatments as necessary.

Conclusion: The height and nutritional status of the child improved after treatment. We also reviewed relevant literature to help clinicians improve their understanding of this disease.

The metaplastic thymoma with giant multilocular-cyst formation had not been documented. The metaplastic thymoma is an extremely rare primary thymic epithelial tumor with an indolent clinical course. It is characterized by a histologic biphasic appearance, which is consisted of solid epithelial areas and spindle cells as the background. This specific pattern can be easily mistaken as the type A thymoma or the type A components of type AB thymoma. When cystic change occurs in metaplastic thymoma, it will bring more challenges for both imaging and pathological diagnosis. Herein, we reported an extremely rare case of a 14.9-cm giant tumor located in the anterior mediastinum of an elderly female. The tumor is consisted of both multilocular cysts and solid components, with the largest cyst measuring 6 cm in diameter. The multilocular cyst contained hemorrhage, calcification, and cholesterol crystal cracks without cell lining. In the solid area, the epithelial cell nests were surrounded by spindle cells with scattered lymphocytes. With immunostains, neither type of cells was CD20 positive. The epithelial cells were positive for CK and P63, while the spindle cells expressed vimentin and EMA. Fluorescence in situ hybridization analysis revealed that the tumor harbored YAP1-MAML2 gene fusions. Accordingly, although the multilocular cystic pattern set a diagnostic challenge, the diagnosis of metaplastic thymoma was rendered due to the immunohistochemistry staining and YAP1-MAML2 gene rearrangement detection.

Background: Long non-coding RNA FOXD2 antisense RNA 1 (FOXD2-AS1) has been reported in many malignancies. However, the molecular mechanism of many actions is not clarified. This study was conducted to investigate the function of FOXD2-AS1 in lung adenocarcinoma and its molecular mechanism.

Methods: Bioinformatics and in vitro analysis including RT-qPCR, CFU, CCK8, Transwell, Cell Apoptosis and Cell Cycle Assay were used for the analysis of gene expression and related effects.

Results: It revealed increased expression of lncRNA FOXD2-AS1 in lung adenocarcinoma cell lines (A549 cells), and abundant expression of lncRNA FOXD2-AS1 was also observed in the acquired lung adenocarcinoma tissues. In vitro results showed that knockdown of lncRNA FOXD2-AS1 in A549 cells weakened cell proliferation, invasion and increased apoptosis. At the same time, we found that reducing the expression of lncRNA FOXD2-AS1 caused cell cycle arrest in the G1/S phase. Differential gene analysis of lung adenocarcinoma and adjacent normal tissues showed that the cell cycle and its related process regulation were significantly enriched. Gene Set Enrichment Analysis (GSEA) analysis showed that miR-206, miR-143, lL6-JAK-STAT3 signalling pathway, STAT3, E2F targets, EZH2, P53 signalling pathway and E2F3 targets interacting with lncRNA FOXD2-AS1 were also enriched.

Conclusion: This study demonstrates the role and mechanism of the lncRNA FOXD2-AS1 in lung adenocarcinoma and provides a better understanding for the treatment of lung adenocarcinoma, which indicates that interfering with lncRNA FOXD2-AS1 expression may be a novel strategy.

Objective: The present study is to explore the association between NQO1 gene polymorphism and coronary heart disease (CHD) risk.

Methods: This research were selected 80 CHD patients as the observation group and 130 healthy people who participated in normal physical examination during the same period as the control group. NQO1 gene polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In addition, we conducted a meta-analysis to summarize the results of three relevant previously published adult population studies on the association between NQO1 gene polymorphism and coronary heart disease (CHD) risk.

Results: There were three genotypes (CC, CT, and TT) for NQO1 C609T polymorphism. The significant associations were found in TT genotype and T allele (all p<0.05). Specifically, People with the TT genotype have 2.06 times CHD risk as those with the CC genotype. And People with the T allele have 1.62 times CHD risk as those with the C allele. No significant association was found by any genetic models in the meta-analysis (all p >0.05).

Conclusion: NQO1 gene polymorphism increased the CHD risk in a Chinese population. Combined with individual gene polymorphism, the accuracy of risk assessment for CHD can be improved and individualized health education can be provided for CHD patients by nurses.

Objective: The context was designed to optimize the diagnostic utility of clinically focused exome sequencing (CFES) and shorten the diagnostic odyssey among pediatric patients suspected of monogenic disorders (MDs).

Methods: Here, we retrospectively analyzed the clinical notes of 372 patients from different areas in the Jiangxi province that were referred for a diagnostic CFES and analysis from June 2018 to March 2022 with symptoms suggestive of MDs. In our study, preliminary tests using the proband-only clinical exome sequencing as a cost-effective first-tier diagnostic test for pediatric patients with unidentified MDs, supplemented by family segregation studies for targeted variants when indicated.

Results: Probands with confirmed diagnostic (CD) or likely diagnostic (LD) genetic influences accounted for 12% of all cases, whereas those with an uncertain diagnosis accounted for 48%. We also found that systemic primary carnitine deficiency (CDSP) (SLC22A5 gene) and phenylketonuria (PAH gene) were relatively more prevalent, and these patients with CDSP had the most frequent c.1400C > G variant (p.S467C) and c.51C > G variant (p. F17L) in this study. In addition, statistical analysis revealed that the estimates of diagnostic yields varied across certain phenotypic features of patients, and patients with specific phenotypic traits tended to benefit more from CFES.

Conclusion: The CFES may be a first-line genetic test for diagnosing young children with suspected genetic conditions, as it validates the identification of molecular genetics alterations and facilitates comprehensive medical management. Moreover, we found that infants exhibiting metabolism/homeostasis abnormalities, craniofacial /otolaryngology/ ophthalmologic abnormalities, and/or the integument were significantly more likely to receive a genetic diagnosis via CFES than infants without such features. However, due to the current study's low diagnostic yield and inherent limitations, high-quality clinical studies with larger sample sizes are still needed to provide more likely results and confirm our findings.

One 59-year-old female patient with deep venous thrombosis (DVT) and pulmonary embolism (PE) was treated with 6 mg warfarin once daily as an anticoagulant. Before taking warfarin, her international normalized ratio (INR) was 0.98. Two days after warfarin treatment, her INR did not change from baseline. Due to the high severity of the PE, the patient needed to reach her target range (INR goal = 2.5, range = 2~3) rapidly, so the dose of warfarin was increased from 6 mg daily to 27 mg daily. However, the patient's INR did not improve with the dose escalation, still maintaining an INR of 0.97-0.98. We drew a blood sample half an hour before administering 27 mg warfarin and detected single nucleotide polymorphism for the following genes, which were identified to be relevant with warfarin resistance: CYP2C9 rs1799853, rs1057910, VKORC1 rs9923231, rs61742245, rs7200749, rs55894764, CYP4F2 rs2108622, and GGCX rs2592551. The trough plasma concentration of warfarin was 196.2 ng/mL after 2 days of warfarin administration with 27 mg QD, which was much lower than the therapeutic drug concentration ranges of warfarin (500-3,000 ng/mL). The genotype results demonstrate that the CYP4F2gene has rs2108622 mutation which can explain some aspect of warfarin resistance. Further investigations are necessary to fully characterize other pharmacogenomics or pharmacodynamics determinants of warfarin dose-response in Chinese.

Background: Ischemic stroke (IS) was a multifactorial disease, which was the main cause of death and adult disability. Genetic factors cannot be ignored.

Objective: The present study discussed the relationship between MMP17 variants and the susceptibility of IS.

Methods: Based on the Agena MassARRAY platform, we genotyped single nucleotide polymorphisms (SNPs) on the MMP17 gene in 1345 participants (670 controls and 675 cases). We used logistic regression analysis to analyze the association of MMP17 SNPs with the risk of IS in the Chinese population, with odds ratio (OR) and 95% confidence intervals (CIs). False-positive report probability (FPRP) detected false positives on the significant results. Besides, we detected the SNP-SNP interaction to predict IS risk by multi-factor dimensionality reduction (MDR) analysis.

Results: In the total analysis, MMP17 rs7975920 conferred an increased susceptibility to IS. After a stratified analysis by age and gender, the significant association between rs7975920 and IS risk was displayed in the subjects aged >55 years old and females. After stratified analysis by smoking and drinking, MMP17 rs6598163 was related to the risk of IS in smokers and rs7975920 was associated with the risk of IS in smokers and was in correlation with IS risk in drinkers.

Conclusion: In short, we first observed that MMP17 rs7975920 and rs6598163 were related to the risk of IS. The above results provided a theoretical basis for the elaboration of the role of MMP17 in IS in the Chinese population.