Pharmacogenomics and Personalized Medicine最新文献

{"title":"Prognostic Value of LHFPL Tetraspan Subfamily Member 6 <i>(LHFPL6)</i> in Gastric Cancer: A Study Based on Bioinformatics Analysis and Experimental Validation.","authors":"Yuan-Jie Liu,&nbsp;Sheng-Yan Yin,&nbsp;Shu-Hong Zeng,&nbsp;Yi-Dou Hu,&nbsp;Meng-Qi Wang,&nbsp;Pan Huang,&nbsp;Jie-Pin Li","doi":"10.2147/PGPM.S332345","DOIUrl":"https://doi.org/10.2147/PGPM.S332345","url":null,"abstract":"<p><strong>Purpose: </strong>The identification of biomarkers and effective therapeutic targets for gastric cancer (GC), the most common cause of cancer-related deaths around the world, is currently a major focus in research. Here, we examined the utility of LHFPL6 as a prognostic biomarker and therapeutic target for GC.</p><p><strong>Methods: </strong>We explored the clinical relevance, function, and molecular role of LHFPL6 in GC using the MethSurv, cBioPortal, TIMER, Gene Expression Profiling Interactive Analysis, ONCOMINE, MEXPRESS, and EWAS Atlas databases. The GSE118919, GSE29272, and GSE13861 datasets were used for differential expression analysis. Using The Cancer Genome Atlas, we developed a Cox regression model and assessed the clinical significance of LHFPLs. In addition, we used the \"CIBERSORT\" algorithm to make reliable immune infiltration estimations. Western blot and immunohistochemistry were used to examine protein expression. Cell migration and invasion were assessed using transwell experiments. THP-1-derived macrophages and GC cells were co-cultured in order to model tumor-macrophage interactions in vitro. The levels of CD206 and CD163 were measured using immunofluorescence assays. The results were visualized with the \"ggplot2\" and \"circlize\" packages.</p><p><strong>Results: </strong>Our results showed that in GC, LHFPL6 overexpression was significantly associated with a poor prognosis. Our findings also suggested that LHFPL6 may be involved in the activation of the epithelial-mesenchymal transition. Furthermore, LHFPL6 expression showed a positive correlation with the abundance of M2 macrophages, which are potent immunosuppressors.</p><p><strong>Conclusion: </strong>LHFPL6 could be a prognostic biomarker and therapeutic target for GC.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1483-1504"},"PeriodicalIF":1.9,"publicationDate":"2021-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/58/4a/pgpm-14-1483.PMC8612673.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39769045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients.","authors":"Fang Cheng,&nbsp;Qiang Li,&nbsp;Jinglin Wang,&nbsp;Min Hu,&nbsp;Fang Zeng,&nbsp;Zhendi Wang,&nbsp;Yu Zhang","doi":"10.2147/PGPM.S337947","DOIUrl":"https://doi.org/10.2147/PGPM.S337947","url":null,"abstract":"<p><strong>Background: </strong>Tacrolimus is a key drug in kidney transplantation with a narrow therapeutic index. However, whether tacrolimus exposure variability affects clinical outcomes and adverse reactions remains unknown.</p><p><strong>Objective: </strong>Our study investigated the factors that influence tacrolimus exposure in kidney transplantation recipients and the relationship between tacrolimus concentration and clinical outcomes and adverse reactions.</p><p><strong>Settings and methods: </strong>We examined the effect of tacrolimus concentration on clinical outcomes and adverse reactions in 201 kidney transplantation recipients, and identified clinical and pharmacogenetic factors that explain tacrolimus exposure.</p><p><strong>Results: </strong>The CYP3A5 genotype was clearly associated with dose-adjusted trough blood tacrolimus concentrations (C₀/D), whereas no significant difference was observed in patients with the CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. Clinical factors such as red blood cell count, hemoglobin, and albumin were the most useful influence factors affecting tacrolimus C₀/D. Besides, Wuzhi capsule increased tacrolimus C₀/D in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and post-transplant diabetes mellitus (PTDM) risk but not with acute rejection and chronic allograft kidney dysfunction.</p><p><strong>Conclusion: </strong>Clinical factors, medication, and CYP-enzyme polymorphisms accounted for tacrolimus concentration variability in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and PTDM risk.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1463-1474"},"PeriodicalIF":1.9,"publicationDate":"2021-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/db/ba/pgpm-14-1463.PMC8610755.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39659553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between the Interferon-γ +874 T/A Polymorphism and the Risk and Clinical Manifestations of Systemic Lupus Erythematosus: A Preliminary Study.","authors":"Shanshan Liu,&nbsp;Ju Li,&nbsp;Yongsheng Li,&nbsp;Yan Liu,&nbsp;Kai Wang,&nbsp;Wenyou Pan","doi":"10.2147/PGPM.S323491","DOIUrl":"https://doi.org/10.2147/PGPM.S323491","url":null,"abstract":"<p><strong>Background: </strong>Interferon-gamma (IFN-γ) is a pivotal cytokine involved in the development of systemic lupus erythematosus (SLE). The IFN-γ +874 T/A polymorphism has been shown to be related to the susceptibility to SLE in other races, but this has not been investigated in the Chinese Han population.</p><p><strong>Methods: </strong>We designed this study to interpret the potential correlation between this polymorphism and SLE risk in a Chinese Han population. We included 374 SLE patients and 405 controls in this study. Odds ratios and relevant 95% confidence intervals were figured out to evaluate the potential strength of the association.</p><p><strong>Results: </strong>Data revealed that the IFN-γ +874 T/A polymorphism showed an association with an enhanced risk of SLE in this Chinese Han population. TA or TA +AA genotype carriers showed an increased risk of developing SLE. Subgroup analyses found that this polymorphism elevated the risk of SLE among females. Additionally, this polymorphism was associated with clinical manifestations of SLE including lupus nephritis, proteinuria, anti-dsDNA antibodies, anti-Sm antibodies, and SLICC/ACR damage index. Furthermore, we conducted a meta-analysis and found that this polymorphism was associated with the risk of SLE, especially among Asians.</p><p><strong>Conclusion: </strong>Totally, this study detects that the IFN-γ +874 T/A polymorphism is related to the risk and clinical manifestations of SLE in a Chinese Han population.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1475-1482"},"PeriodicalIF":1.9,"publicationDate":"2021-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/55/e2/pgpm-14-1475.PMC8612291.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39769044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Help of HPV Integration Testing to Avoid the Misdiagnosis of a Patient with Stage Ia1 Cervical Cancer: A Case Report and Literature Review.","authors":"Jialu Li,&nbsp;Xiaoli Zhang,&nbsp;Pengpeng Wang,&nbsp;Weiping Li","doi":"10.2147/PGPM.S310345","DOIUrl":"https://doi.org/10.2147/PGPM.S310345","url":null,"abstract":"<p><p>Screening and prevention in the early stage of cervical cancer could improve the 5-year survival rate of cervical cancer by up to 90%. The occurrence rate of human papillomavirus (HPV) integration has gradually increased with the development of cervical lesions. Here, we report the case of a 43-year-old woman diagnosed with chronic cervicitis based on cervical biopsy results. After medical consultation, surgery was recommended to the patient considering her 64 HPV integration sites and other biochemical and clinical test results. The pathology result of the conical biopsy obtained during operation confirmed that both her cervix and the glands had high-grade squamous intraepithelial lesion or cervical intraepithelial neoplasia III (HSIL/CIN III). The patient underwent uterectomy and bilateral salpingectomy and was discharged thereafter. The diagnosis of the patient was revised to stage Ia1 cervical cancer. The number of HPV integration sites is suggested to be an auxiliary indicator in the early screening of cervical cancer for predicting high-grade CIN and invasive cervical cancer.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1457-1461"},"PeriodicalIF":1.9,"publicationDate":"2021-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b0/ae/pgpm-14-1457.PMC8608241.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39768209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Two Novel <i>DNAAF2</i> Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia.","authors":"Chenyang Lu,&nbsp;Danhui Yang,&nbsp;Cheng Lei,&nbsp;Rongchun Wang,&nbsp;Ting Guo,&nbsp;Hong Luo","doi":"10.2147/PGPM.S338981","DOIUrl":"https://doi.org/10.2147/PGPM.S338981","url":null,"abstract":"<p><strong>Background: </strong>Dynein axonemal assembly factor 2 (<i>DNAAF2</i>) is involved in the early preassembly of dynein in the cytoplasm, which is essential for motile cilia function. Primary ciliary dyskinesia (PCD) associated with <i>DNAAF2</i> variants has rarely been reported in females with infertility. Moreover, there is no report linking <i>DNAAF2</i> to scoliosis in human.</p><p><strong>Materials and methods: </strong>We recruited patients from two consanguineous families with a clinical diagnosis of PCD and collected their clinical history, laboratory tests, and radiographic data. Sequencing and bioinformatics analysis were then performed. Immunofluorescence and high-speed microscope analysis were used to support the pathogenicity of the variant.</p><p><strong>Results: </strong>Proband 1, a 26-year-old female from family I, exhibited scoliosis, bronchiectasis, sinusitis, situs inversus, and infertility. We found a novel homozygous missense variant in <i>DNAAF2</i>, c.491T>C, p.(Leu164Pro) in this patient. Subsequent immunofluorescence indicated the absence of outer dynein arm and inner dynein arm of cilia, and high-speed microscopy analysis showed that the most of the cilia are static, which support the pathogenicity of this variant. Proband 2, a 53-year-old female, presented with bronchiectasis, sinusitis, and infertility. In this patient, a new homozygous frameshift variant <i>DNAAF2</i>, c.822del, p.(Ala275Profs*10) was identified. The disease-causing variants mentioned above are not included in the current authorized genetic databases.</p><p><strong>Conclusion: </strong>Our findings expand the spectrum of <i>DNAAF2</i> variants and link <i>DNAAF2</i> to female infertility and likely scoliosis in patients with PCD.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1415-1423"},"PeriodicalIF":1.9,"publicationDate":"2021-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/18/40/pgpm-14-1415.PMC8591118.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39896982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ARNTL2 is a Prognostic Biomarker and Correlates with Immune Cell Infiltration in Triple-Negative Breast Cancer.","authors":"Xiaoyu Wang,&nbsp;Yan Li,&nbsp;Jianchang Fu,&nbsp;Kewen Zhou,&nbsp;Tinghuai Wang","doi":"10.2147/PGPM.S331431","DOIUrl":"https://doi.org/10.2147/PGPM.S331431","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is associated with poor prognosis. The aberrant expression of circadian genes contributes to the origin and progression of breast cancer. The present study was designed to explore the potential function and prognosis value of circadian genes in TNBC.</p><p><strong>Methods: </strong>The transcriptome data of circadian genes were downloaded from The Cancer Genomic Atlas (TCGA), GSE25066 and GSE31448 datasets. The differential expressed circadian genes between non-TNBC and TNBC patients were analysed by Wilcoxon test. Univariate and multivariate Cox regression analyses were employed to identify the prognostic circadian genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were performed to study the biological functions of ARNTL2. The composition of 22 immune cells in the tumour samples was estimated with CIBERSORT algorithm. The correlations between ARNTL2 expression and tumour-infiltrating immune cells were evaluated by Spearman correlation coefficient.</p><p><strong>Results: </strong>A total of 8 circadian genes were found to be differentially expressed between non-TNBC and TNBC, but only ARNTL2 has prognostic value. Multivariate Cox analysis identified that ARNTL2 was an independent prognosis factor for overall survival and relapse-free survival in TNBC patients. Functionally, ARNTL2 was mainly involved in immune response processes such as positive regulation of cytokine production, regulation of innate immune response, and cellular responses to molecules of bacterial origin. High expression of ARNTL2 was positively correlated with activated CD4 memory T cells, activated mast cells, and neutrophil infiltration and the expression of markers of neutrophils (ITGAM), dendritic cells (HLA-DRA, HLA-DPA1, ITGAM), Th1 (IL1B, STAT1), Th2 (IL13), Th17 (STAT3) and mast cells (TPSB2, TPSAB1).</p><p><strong>Conclusion: </strong>ARNTL2 may be linked with the functional modulation of the tumour immune microenvironment and serve as a potential biomarker for predicting the prognosis of TNBC patients.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1425-1440"},"PeriodicalIF":1.9,"publicationDate":"2021-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9f/50/pgpm-14-1425.PMC8591114.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39896983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Relevance of Regenerating Gene 1a Polymorphisms to Radiation Sensitivity and Survival of Nasopharyngeal Carcinoma Receiving Radiotherapy in a Southern Chinese Population.","authors":"Hai-Jie Xing,&nbsp;Xiang-Dong Chen,&nbsp;Hong-Xia Sun,&nbsp;Yao-Zhang Dai,&nbsp;Yao-Feng Han,&nbsp;Hai-Bo Chen,&nbsp;Feng Liu","doi":"10.2147/PGPM.S328285","DOIUrl":"https://doi.org/10.2147/PGPM.S328285","url":null,"abstract":"<p><strong>Objective: </strong>Gene polymorphism is closely related to tumor development, therapeutic response and prognosis. The relationship between regenerating gene 1A (Reg1A) polymorphism and nasopharyngeal carcinoma (NPC) is unclear. This retrospective study aimed to analyze the association between Reg1a polymorphisms and metastasis, radiation sensitivity and survivals in patients with NPC.</p><p><strong>Methods: </strong>A total of 308 patients who had received radiotherapy at the Affiliated Xinhua Hospital, Hainan Medical College, between January 2010 and December 2018 with NPC, were enrolled for assessment of Reg1a polymorphisms through direct DNA sequencing.</p><p><strong>Results: </strong>In the polymorphism of gene REG1A, patients with rs10165462 20CC genotype had later T stages (OR = 4.051, 95% CI: 1.775-9.244, P = 0.001), whereas carriers with rs12072 2922CC genotype had earlier T stages (OR = 1.891, 95% CI: 1.018-3.514, P = 0.044) after adjustments for age and gender, respectively. Among rs10165462 20 C/T polymorphism, 20TT wild-type was associated with better radiation response (P = 0.0019), and multivariate analysis showed that it was the only genotype of polymorphism that was significantly associated with better radiation response (OR = 0.265, 95% CI: 0.096-0.727, P = 0.01). Patients with the 20TT wild-type had a better five-year overall survival (60.9%) rate and five-year progression-free survival (60.8%) than those with the 20CC genotype (41.8% and 39.4%, P = 0.01 and P = 0.004, respectively). Patients with variant alleles (CC + CT) had significantly poorer OS (45.2%) and PFS (41.8%) compared with wild-type (TT) carriers (60.9% and 60.8%; P = 0.037 and P = 0.015, respectively). As for rs12072, patients with variant alleles (TT + TC) had significantly adverse OS and PFS compared with wild-type (CC) carriers (62.5% vs 44.8% and 62.5% vs 42.9%; P = 0.024 and P = 0.027, respectively). Cox regression showed that rs10165462 20CT was the only prognostic factor for OS (HR = 1.642, 95% CI 1.038-2.598, P = 0.034) and PFS (HR = 1.705, 95% CI 1.080-2.692, P = 0.022).</p><p><strong>Conclusion: </strong>Reg1a polymorphisms may be a predictor of radiation response, local invasion, OS and PFS in patients with NPC who undergo radiotherapy treatment.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1403-1413"},"PeriodicalIF":1.9,"publicationDate":"2021-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e6/f3/pgpm-14-1403.PMC8579874.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39896981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variation of Genomic Sites Associated with Severe Covid-19 Across Populations: Global and National Patterns.","authors":"Oleg Balanovsky,&nbsp;Valeria Petrushenko,&nbsp;Karin Mirzaev,&nbsp;Sherzod Abdullaev,&nbsp;Igor Gorin,&nbsp;Denis Chernevskiy,&nbsp;Anastasiya Agdzhoyan,&nbsp;Elena Balanovska,&nbsp;Alexander Kryukov,&nbsp;Ilyas Temirbulatov,&nbsp;Dmitriy Sychev","doi":"10.2147/PGPM.S320609","DOIUrl":"https://doi.org/10.2147/PGPM.S320609","url":null,"abstract":"<p><strong>Background: </strong>Information about the distribution of clinically significant genetic markers in different populations may be helpful in elaborating personalized approaches to the clinical management of COVID-19 in the absence of consensus guidelines.</p><p><strong>Aim: </strong>Analyze frequencies and distribution patterns of two markers associated with severe COVID-19 (<i>rs11385942</i> and <i>rs657152</i>) and look for potential correlations between these markers and deaths from COVID-19 among populations in Russia and across the world.</p><p><strong>Methods: </strong>We genotyped 1883 samples from 91 ethnic groups pooled into 28 populations representing Russia and its neighbor states. We also compiled a dataset on 32 populations from other regions using genotypes extracted or imputed from the available databases. Geographic maps showing the frequency distribution of the analyzed markers were constructed using the obtained data.</p><p><strong>Results: </strong>The cartographic analysis revealed that <i>rs11385942</i> distribution follows the West Eurasian pattern: the marker is frequent among the populations of Europe, West Asia and South Asia but rare or absent in all other parts of the globe. Notably, the transition from high to low <i>rs11385942</i> frequencies across Eurasia is not abrupt but follows the clinal variation pattern instead. The distribution of <i>rs657152</i> is more homogeneous. The analysis of correlations between the frequencies of the studied markers and the epidemiological characteristics of COVID-19 in a population revealed that higher frequencies of both risk alleles correlated positively with mortality from this disease. For <i>rs657152</i>, the correlation was especially strong (r = 0.59, <i>p</i> = 0.02). These reasonable correlations were observed for the \"Russian\" dataset only: no such correlations were established for the \"world\" dataset. This could be attributed to the differences in methodology used to collect COVID-19 statistics in different countries.</p><p><strong>Conclusion: </strong>Our findings suggest that genetic differences between populations make a small yet tangible contribution to the heterogeneity of the pandemic worldwide.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1391-1402"},"PeriodicalIF":1.9,"publicationDate":"2021-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/95/pgpm-14-1391.PMC8575442.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39880179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of Combined Effect of CYP2C19 Genetic Polymorphism and Proton Pump Inhibitors Coadministration on Trough Concentration of Voriconazole.","authors":"Magesa Mafuru,&nbsp;Sanlan Wu,&nbsp;Henry Mayala,&nbsp;Zaituni Msengwa,&nbsp;Amani Phillip,&nbsp;Charles Mgone","doi":"10.2147/PGPM.S329662","DOIUrl":"https://doi.org/10.2147/PGPM.S329662","url":null,"abstract":"<p><strong>Purpose: </strong>To analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-C_trough) in Chinese patients with hematological disorders.</p><p><strong>Patients and methods: </strong>A prospective observational study involved 250 plasma samples from 114 adult patients receiving voriconazole with or without PPIs were analyzed. Demographics and clinical characteristics were obtained from patient's records. A validated LC-MS/MS was used to quantify the plasma VCZ-C_trough. Genotyping for CYP2C19*2 and CYP2C19*3 variant alleles was performed by PCR-RFLP followed by DNA sequencing. The combined total score (from 2 to 5) was calculated for each patient. The higher the score, the lesser the metabolism of the patient.</p><p><strong>Findings: </strong>Fifty percent of patients administered with voriconazole were coadministered with PPIs, predominantly omeprazole or esomeprazole. Patients exhibiting CYP2C19 poor metabolizer phenotype showed a significantly higher median VCZ-C_trough, (4.31µg/mL [IQR, 1.64µg/mL-7.36µg/mL]) than patients with normal metabolizer (1.38µg/mL, [IQR, 0.79µg/mL-2.14µg/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-C_trough (2.86µg/mL [IQR 1.33µg/mL-4.66µg/mL]), than PPIs non-users (1.71µg/mL, [IQR, 0.86µg/mL-3.48µg/mL], p = 0.001). However, we noted that the median VCZ-C_trough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5µg/mL-5µg/mL). But when the two factors were combined, the median VCZ-C_trough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-C_trough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83µg/mL [IQR, 2.19µg/mL-9.51µg/mL] versus 1.13µg/mL [IQR, 0.67µg/mL-1.82µg/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-C_trough to supra-therapeutic levels was largely contributed by omeprazole or esomeprazole compared to lansoprazole or pantoprazole.</p><p><strong>Conclusion: </strong>Coadministration with PPIs significantly increased voriconazole trough concentrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1379-1389"},"PeriodicalIF":1.9,"publicationDate":"2021-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4b/d9/pgpm-14-1379.PMC8572102.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39693467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Epigenetic Regulatory Role of m6A-Associated SNPs in Type 2 Diabetes Pathogenesis.","authors":"Miao Chen,&nbsp;Weimin Lin,&nbsp;Jianru Yi,&nbsp;Zhihe Zhao","doi":"10.2147/PGPM.S334346","DOIUrl":"https://doi.org/10.2147/PGPM.S334346","url":null,"abstract":"<p><strong>Purpose: </strong>Genetic factors in type 2 diabetes (T2D) pathogenesis have been widely explored by the genome-wide association studies (GWAS), identifying a great amount of susceptibility loci. With the development of high-resolution sequencing, the N(6)-methyladenosine (m6A) RNA modification has been proved to be affected by genetic variation. In this study, we identified the T2D-associated m6A-SNPs from T2D GWAS data and explored the underlying mechanism of the pathogenesis of T2D.</p><p><strong>Methods: </strong>We examined the association of m6A-SNPs with T2D among large-scale T2D GWAS summary statistics and further performed multi-omics integrated analysis to explore the potential role of the identified m6A-SNPs in T2D pathogenesis.</p><p><strong>Results: </strong>Among the 15,124 T2D-associated m6A-SNPs, 71 of them reach the genome-wide significant threshold (5.0e-05). The leading SNP rs4993986 (C>G), which is located near the m6A modification site at the 3' end of the <i>HLA-DQB1</i> transcript, is expected to participate in the pathogenesis of T2D by influencing m6A modification to regulate the <i>HLA-DQB1</i> expression.</p><p><strong>Conclusion: </strong>The current study has suggested a potential correlation between m6A-SNPs and T2D pathogenesis and also provided new insights into the pathogenic mechanism of the T2D susceptibility loci identified by GWAS.</p>","PeriodicalId":509088,"journal":{"name":"Pharmacogenomics and Personalized Medicine","volume":" ","pages":"1369-1378"},"PeriodicalIF":1.9,"publicationDate":"2021-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3c/07/pgpm-14-1369.PMC8558037.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39592199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}