Pharmacogenomics
Pharmacological Effects of Ginseng: Multiple Constituents and Multiple Actions on Humans
Am J Chin Med. 2023 Jun 30:1-20. doi: 10.1142/S0192415X23500507. Online ahead of print.
ABSTRACT
Ginseng is a very commonly used natural product in the world, and its two main species are Asian ginseng and American ginseng. Ginseng is an adaptogenic botanical that reportedly protects the body against stress, stabilizes physiological processes, and restores homeostasis. Previously, different animal models and contemporary research methodologies have been used to reveal ginseng's biomedical activities in different body systems and the linked mechanisms of actions. However, human clinical observation data on ginseng effects have attracted more attention from the general public and medical community. In this paper, after an introduction of the phytochemistry of ginseng species, we review positive ginseng clinical studies, mainly conducted in developed countries, performed over the past 20 years. The reported effects of ginseng are presented in several sections, and conditions impacted by ginseng include diabetes; cardiovascular disorders; cognition, memory, and mood; the common cold and flu; cancer fatigue and well-being; quality of life and social functioning, etc. Administration of ginseng demonstrated a good safety record in humans. Although encouraging beneficial effects obtained from clinical data, using the study treatment regimen, the reported ginseng effects in general only ranged from mild to moderate. Nonetheless, these beneficial effects of ginseng could be a valuable add-on therapy for patients receiving standard drug treatments. Additionally, as a dietary supplement, ginseng possesses an important role in maintaining and promoting human health. We believe that the quality of future ginseng trials should be improved, particularly by providing detailed herbal phytochemistry and quality control information. With solid effectiveness data obtained from a well-designed, carefully executed ginseng clinical trial, this meritoriously herbal medicine will be widely used by consumers and patients.
PMID:37385964 | DOI:10.1142/S0192415X23500507
Data mining identifies novel RNA-binding proteins involved in colon and rectal carcinomas
Front Cell Dev Biol. 2023 Jun 13;11:1088057. doi: 10.3389/fcell.2023.1088057. eCollection 2023.
ABSTRACT
Colorectal adenocarcinoma (COREAD) is the second most deadly cancer and third most frequently encountered malignancy worldwide. Despite efforts in molecular subtyping and subsequent personalized COREAD treatments, multidisciplinary evidence suggests separating COREAD into colon cancer (COAD) and rectal cancer (READ). This new perspective could improve diagnosis and treatment of both carcinomas. RNA-binding proteins (RBPs), as critical regulators of every hallmark of cancer, could fulfill the need to identify sensitive biomarkers for COAD and READ separately. To detect new RBPs involved in COAD and READ progression, here we used a multidata integration strategy to prioritize tumorigenic RBPs. We analyzed and integrated 1) RBPs genomic and transcriptomic alterations from 488 COAD and 155 READ patients, 2) ∼ 10,000 raw associations between RBPs and cancer genes, 3) ∼ 15,000 immunostainings, and 4) loss-of-function screens performed in 102 COREAD cell lines. Thus, we unraveled new putative roles of NOP56, RBM12, NAT10, FKBP1A, EMG1, and CSE1L in COAD and READ progression. Interestingly, FKBP1A and EMG1 have never been related with any of these carcinomas but presented tumorigenic features in other cancer types. Subsequent survival analyses highlighted the clinical relevance of FKBP1A, NOP56, and NAT10 mRNA expression to predict poor prognosis in COREAD and COAD patients. Further research should be performed to validate their clinical potential and to elucidate their molecular mechanisms underlying these malignancies.
PMID:37384253 | PMC:PMC10293682 | DOI:10.3389/fcell.2023.1088057
Editorial: The utilization of bench-to-bedside approaches in pharmacogenomics
Front Pharmacol. 2023 Jun 13;14:1234219. doi: 10.3389/fphar.2023.1234219. eCollection 2023.
NO ABSTRACT
PMID:37383722 | PMC:PMC10299726 | DOI:10.3389/fphar.2023.1234219
A Pharmacogenetics-Based Approach to Managing Gastroesophageal Reflux Disease: Current Perspectives and Future Steps
Pharmgenomics Pers Med. 2023 Jun 23;16:645-664. doi: 10.2147/PGPM.S371994. eCollection 2023.
ABSTRACT
Proton pump inhibitors (PPIs) are commonly used medications to treat acid-related conditions, including gastro-esophageal reflux disease (GERD). Gastroenterology guidelines mention the importance of CYP2C19 in PPI metabolism and the influence of CYP2C19 genetic variations on variable responses to PPIs, but do not currently recommend the genotyping of CYP2C19 prior to prescribing PPIs. There are strong data to support the influence of CYP2C19 genetic variations on the pharmacokinetics of PPIs and clinical outcomes. Existing pharmacogenetic guideline recommendations for dose increases focus on H. pylori and erosive esophagitis indications, but PPIs are also the main therapy for treating GERD. Recent data suggest GERD patients being treated with a PPI may also benefit from genotype-guided dosing. We summarize the literature supporting this contention and highlight future directions for improved management of patients with GERD through precision medicine approaches.
PMID:37383676 | PMC:PMC10296543 | DOI:10.2147/PGPM.S371994
Current and future developments in the pharmacology of asthma and COPD: ERS seminar, Naples 2022
Breathe (Sheff). 2023 Jun;19(2):220267. doi: 10.1183/20734735.0267-2022. Epub 2023 Jun 13.
ABSTRACT
Pharmacological management of airway obstructive diseases is a fast-evolving field. Several advances in unravelling disease mechanisms as well as intracellular and molecular pathways of drug action have been accomplished. While the clinical translation and implementation of in vitro results to the bedside remains challenging, advances in comprehending the mechanisms of respiratory medication are expected to assist clinicians and scientists in identifying meaningful read-outs and designing clinical studies. This European Respiratory Society Research Seminar, held in Naples, Italy, 5-6 May 2022, focused on current and future developments of the drugs used to treat asthma and COPD; on mechanisms of drug action, steroid resistance, comorbidities and drug interactions; on prognostic and therapeutic biomarkers; on developing novel drug targets based on tissue remodelling and regeneration; and on pharmacogenomics and emerging biosimilars. Related European Medicines Agency regulations are also discussed, as well as the seminar's position on the above aspects.
PMID:37377851 | PMC:PMC10292790 | DOI:10.1183/20734735.0267-2022
A meta-analysis of the pooled impact of <em>CYP7A1</em> single nucleotide polymorphisms on serum lipid responses to statins
Front Genet. 2023 Jun 9;14:1199549. doi: 10.3389/fgene.2023.1199549. eCollection 2023.
ABSTRACT
Background and Aims: Various publications suggested that there is an association between CYP7A1 single nucleotide polymorphisms (SNP) and a reduced response to statin therapy, but the results were inconsistent. This study aimed to collectively review these publications to appraise the effect of statins on cholesterol control in carriers of CYP7A1 variant alleles. Methods: PUBMED, Cochrane and EMBASE were searched systematically to identify reported studies on the lipid responses to statin treatment between carriers of the variant allele versus the non-variant allele of CYP7A1 SNPs. The change from baseline in lipid responses for all included studies were calculated using weighted mean differences (WMD) (with 95% confidence interval (CI)). A meta-analysis was conducted to pool results using either the random-effects model or the fixed effects model. Results: A total of 6 publications comprising of 1,686 subjects for the assessment of total cholesterol, LDL-C and HDL-C and 1,156 subjects for the assessment of triglycerides were included in the meta-analyses. Subjects who were non-carriers of a CYP7A1 SNP (-204 A/C (rs3808607), -278 A/C (rs3808607) and rs8192875) had a greater reduction in total cholesterol (overall WMD -0.17, 95% CI -0.29, -0.06) and LDL-C levels (overall WMD -0.16, 95% CI -0.26, -0.05) as compared with subjects who borne the variant allele of CYP7A1 SNPs when administered a statin. Conclusion: The presence of variant allele of CYP7A1 SNPs may result in suboptimal control of total cholesterol and LDL-C levels as compared with individuals who do not carry the variant allele, when administered an equivalent dose of statin.
PMID:37377593 | PMC:PMC10292746 | DOI:10.3389/fgene.2023.1199549
Genetic Variants Associated with Drug Resistance of Cytomegalovirus in Hematopoietic Cell Transplantation Recipients
Viruses. 2023 May 30;15(6):1286. doi: 10.3390/v15061286.
ABSTRACT
Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A total of 123 patients with refractory CMV DNAemia out of 2271 HCT patients at the Catholic Hematology Hospital between April 2016 and November 2021 were analyzed, which accounted for 8.6% of the 1428 patients who received pre-emptive therapy. Real-time PCR was used to monitor CMV infection. Direct sequencing was performed to identify drug-resistant variants in UL97 and UL54. Resistance variants were found in 10 (8.1%) patients, and variants of uncertain significance (VUS) were found in 48 (39.0%) patients. Patients with resistance variants had a significantly higher peak CMV viral load than those without (p = 0.015). Patients with any variants had a higher risk of severe graft-versus-host disease and lower one-year survival rates than those without (p = 0.003 and p = 0.044, respectively). Interestingly, the presence of variants reduced the rate of CMV clearance, particularly in patients who did not modify their initial antiviral regimen. However, it had no apparent impact on individuals whose antiviral regimens were changed due to refractoriness. This study highlights the importance of identifying genetic variants associated with CMV drug resistance in HCT recipients for providing appropriate antiviral treatment and predicting patient outcomes.
PMID:37376586 | DOI:10.3390/v15061286
Pharmacogenetic Sex-Specific Effects of Methotrexate Response in Patients with Rheumatoid Arthritis
Pharmaceutics. 2023 Jun 5;15(6):1661. doi: 10.3390/pharmaceutics15061661.
ABSTRACT
Methotrexate (MTX) is a commonly used drug for the treatment of rheumatoid arthritis (RA), but its effectiveness can vary greatly among patients. Pharmacogenetics, the study of how genetic variations can affect drug response, has the potential to improve the personalized treatment of RA by identifying genetic markers that can predict a patient's response to MTX. However, the field of MTX pharmacogenetics is still in its early stages and there is a lack of consistency among studies. This study aimed to identify genetic markers associated with MTX efficacy and toxicity in a large sample of RA patients, and to investigate the role of clinical covariates and sex-specific effects. Our results have identified an association of ITPA rs1127354 and ABCB1 rs1045642 with response to MTX, polymorphisms of FPGS rs1544105, GGH rs1800909, and MTHFR genes with disease remission, GGH rs1800909 and MTHFR rs1801131 polymorphisms with all adverse events, and ADA rs244076 and MTHFR rs1801131 and rs1801133, However, clinical covariates were more important factors to consider when building predictive models. These findings highlight the potential of pharmacogenetics to improve personalized treatment of RA, but also emphasize the need for further research to fully understand the complex mechanisms involved.
PMID:37376109 | DOI:10.3390/pharmaceutics15061661
A Novel UHPLC-MS/MS Method for the Quantification of Seven Opioids in Different Human Tissues
Pharmaceuticals (Basel). 2023 Jun 19;16(6):903. doi: 10.3390/ph16060903.
ABSTRACT
BACKGROUND: Opioids are considered the cornerstone of pain management: they show good efficacy as a first-line therapy for moderate to severe cancer pain. Since pharmacokinetic/pharmacodynamic information about the tissue-specific effect and toxicity of opioids is still scarce, their quantification in post-mortem autoptic specimens could give interesting insights.
METHODS: We describe an ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method for the simultaneous quantification of methadone, morphine, oxycodone, hydrocodone, oxymorphone, hydromorphone and fentanyl in several tissues: liver, brain, kidney, abdominal adipose tissue, lung and blood plasma. The presented method has been applied on 28 autoptic samples from different organs obtained from four deceased PLWH who used opioids for palliative care during terminal disease.
RESULTS: Sample preparation was based on tissue weighing, disruption, sonication with drug extraction medium and a protein precipitation protocol. The extracts were then dried, reconstituted and injected onto the LX50 QSight 220 (Perkin Elmer, Milan, Italy) system. Separation was obtained by a 7 min gradient run at 40 °C with a Kinetex Biphenyl 2.6 µm, 2.1 × 100 mm. Concerning the analyzed samples, higher opioids concentrations were observed in tissues than in plasma. Particularly, O-MOR and O-COD showed higher concentrations in kidney and liver than other tissues (>15-20 times greater) and blood plasma (>100 times greater).
CONCLUSIONS: Results in terms of linearity, accuracy, precision, recovery and matrix effect fitted the recommendations of FDA and EMA guidelines, and the sensitivity was high enough to allow successful application on human autoptic specimens from an ethically approved clinical study, confirming its eligibility for post-mortem pharmacological/toxicological studies.
PMID:37375850 | DOI:10.3390/ph16060903
Pharmacogenetic Testing for the Pediatric Gastroenterologist: Actionable Drug-Gene Pairs to Know
Pharmaceuticals (Basel). 2023 Jun 16;16(6):889. doi: 10.3390/ph16060889.
ABSTRACT
Gastroenterologists represent some of the earlier adopters of precision medicine through pharmacogenetic testing by embracing upfront genotyping for thiopurine S-methyltransferase nucleotide diphosphatase (TPMT) before prescribing 6-mercaptopurine or azathioprine for the treatment of inflammatory bowel disease. Over the last two decades, pharmacogenetic testing has become more readily available for other genes relevant to drug dose individualization. Common medications prescribed by gastroenterologists for conditions other than inflammatory bowel disease now have actionable guidelines, which can improve medication efficacy and safety; however, a clear understanding of how to interpret the results remains a challenge for many clinicians, precluding wide implementation of genotype-guided dosing for drugs other than 6-mercaptopurine and azathioprine. Our goal is to provide a practical tutorial on the currently available pharmacogenetic testing options and a results interpretation for drug-gene pairs important to medications commonly used in pediatric gastroenterology. We focus on evidence-based clinical guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC®) to highlight relevant drug-gene pairs, including proton pump inhibitors and selective serotonin reuptake inhibitors and cytochrome P450 (CYP) 2C19, ondansetron and CYP2D6, 6-mercaptopurine and TMPT and Nudix hydrolase 15 (NUDT15), and budesonide and tacrolimus and CYP3A5.
PMID:37375836 | DOI:10.3390/ph16060889
Bioinformatics Tools for the Analysis of Active Compounds Identified in Ranunculaceae Species
Pharmaceuticals (Basel). 2023 Jun 5;16(6):842. doi: 10.3390/ph16060842.
ABSTRACT
The chemical compounds from extracts of three Ranunculaceae species, Aconitum toxicum Rchb., Anemone nemorosa L. and Helleborus odorus Waldst. & Kit. ex Willd., respectively, were isolated using the HPLC purification technique and analyzed from a bioinformatics point of view. The classes of compounds identified based on the proportion in the rhizomes/leaves/flowers used for microwave-assisted extraction and ultrasound-assisted extraction were alkaloids and phenols. Here, the quantifying of pharmacokinetics, pharmacogenomics and pharmacodynamics helps us to identify the actual biologically active compounds. Our results showed that (i) pharmacokinetically, the compounds show good absorption at the intestinal level and high permeability at the level of the central nervous system for alkaloids; (ii) regarding pharmacogenomics, alkaloids can influence tumor sensitivity and the effectiveness of some treatments; (iii) and pharmacodynamically, the compounds of these Ranunculaceae species bind to carbonic anhydrase and aldose reductase. The results obtained showed a high affinity of the compounds in the binding solution at the level of carbonic anhydrases. Carbonic anhydrase inhibitors extracted from natural sources can represent the path to new drugs useful both in the treatment of glaucoma, but also of some renal, neurological and even neoplastic diseases. The identification of natural compounds with the role of inhibitors can have a role in different types of pathologies, both associated with studied and known receptors such as carbonic anhydrase and aldose reductase, as well as new pathologies not yet addressed.
PMID:37375790 | DOI:10.3390/ph16060842
Advancing Precision Medicine in South Tyrol, Italy: A Public Health Development Proposal for a Bilingual, Autonomous Province
J Pers Med. 2023 Jun 9;13(6):972. doi: 10.3390/jpm13060972.
ABSTRACT
This paper presents a comprehensive development plan for advancing precision medicine in the autonomous province of South Tyrol, Italy, a region characterized by its bilingual population and unique healthcare challenges. This study highlights the need to address the shortage of healthcare professionals proficient in language for person-centered medicine, the lag in healthcare sector digitalization, and the absence of a local medical university, all within the context of an initiated pharmacogenomics program and a population-based precision medicine study known as the "Cooperative Health Research in South Tyrol" (CHRIS) study. The key strategies for addressing these challenges and integrating CHRIS study findings into a broader precision medicine development plan are discussed, including workforce development and training, investment in digital infrastructure, enhanced data management and analytic capabilities, collaboration with external academic and research institutions, education and capacity building, securing funding and resources, and promoting a patient-centered approach. This study emphasizes the potential benefits of implementing such a comprehensive development plan, including improved early detection, personal ized treatment, and prevention of chronic diseases, ultimately leading to better healthcare outcomes and overall well-being in the South Tyrolean population.
PMID:37373961 | DOI:10.3390/jpm13060972
Pharmacogenetics of Lethal Opioid Overdose: Review of Current Evidence and Preliminary Results from a Pilot Study
J Pers Med. 2023 May 30;13(6):918. doi: 10.3390/jpm13060918.
ABSTRACT
There has been a worldwide substantial increase in accidental opioid-overdose deaths. The aim of this review, along with preliminary results from our pilot study, is to highlight the use of pharmacogenetics as a tool to predict causes of accidental opioid-overdose death. For this review, a systematic literature search of PubMed® between the time period of January 2000 to March 2023 was carried out. We included study cohorts, case-controls, or case reports that investigated the frequency of genetic variants in opioid-related post-mortem samples and the association between these variants and opioid plasma concentrations. A total of 18 studies were included in our systematic review. The systematic review provides evidence of the use of CYP2D6, and to a lower extent, CYP2B6 and CYP3A4/5 genotyping in identifying unexpectedly high or low opioid and metabolite blood concentrations from post-mortem samples. Our own pilot study provides support for an enrichment of the CYP2B6*4-allele in our methadone-overdose sample (n = 41) compared to the anticipated frequency in the general population. The results from our systematic review and the pilot study highlight the potential of pharmacogenetics in determining vulnerability to overdose of opioids.
PMID:37373907 | DOI:10.3390/jpm13060918
Determination of the Duplicated <em>CYP2D6</em> Allele Using Real-Time PCR Signal: An Alternative Approach
J Pers Med. 2023 May 24;13(6):883. doi: 10.3390/jpm13060883.
ABSTRACT
CYP2D6 duplication has important pharmacogenomic implications. Reflex testing with long-range PCR (LR-PCR) can resolve the genotype when a duplication and alleles with differing activity scores are detected. We evaluated whether visual inspection of plots from real-time-PCR-based targeted genotyping with copy number variation (CNV) detection could reliably determine the duplicated CYP2D6 allele. Six reviewers evaluated QuantStudio OpenArray CYP2D6 genotyping results and the TaqMan Genotyper plots for seventy-three well-characterized cases with three copies of CYP2D6 and two different alleles. Reviewers blinded to the final genotype visually assessed the plots to determine the duplicated allele or opt for reflex sequencing. Reviewers achieved 100% accuracy for cases with three CYP2D6 copies that they opted to report. Reviewers did not request reflex sequencing in 49-67 (67-92%) cases (and correctly identified the duplicated allele in each case); all remaining cases (6-24) were marked by at least one reviewer for reflex sequencing. In most cases with three copies of CYP2D6, the duplicated allele can be determined using a combination of targeted genotyping using real-time PCR with CNV detection without need for reflex sequencing. In ambiguous cases and those with >3 copies, LR-PCR and Sanger sequencing may still be necessary for determination of the duplicated allele.
PMID:37373874 | DOI:10.3390/jpm13060883
Differences in Plasma Cannabidiol Concentrations in Women and Men: A Randomized, Placebo-Controlled, Crossover Study
Int J Mol Sci. 2023 Jun 17;24(12):10273. doi: 10.3390/ijms241210273.
ABSTRACT
The potential therapeutic benefits of cannabidiol (CBD) require further study. Here, we report a triple-blind (participant, investigator, and outcome assessor) placebo-controlled crossover study in which 62 hypertensive volunteers were randomly assigned to receive the recently developed DehydraTECH2.0 CBD formulation or a placebo. This is the first study to have been conducted using the DehydraTECH2.0 CBD formulation over a 12-week study duration. The new formulation's long-term effects on CBD concentrations in plasma and urine, as well as its metabolites 7-hydroxy-CBD and 7-carboxy-CBD, were analyzed. The results of the plasma concentration ratio for CBD/7-OH-CBD in the third timepoint (after 5 weeks of use) were significantly higher than in the second timepoint (after 2.5 weeks of use; p = 0.043). In the same timepoints in the urine, a significantly higher concentration of 7-COOH-CBD was observed p < 0.001. Differences in CBD concentration were found between men and women. Plasma levels of CBD were still detectable 50 days after the last consumption of the CBD preparations. Significantly higher plasma CBD concentrations occurred in females compared to males, which was potentially related to greater adipose tissue. More research is needed to optimize CBD doses to consider the differential therapeutic benefits in men and women.
PMID:37373421 | DOI:10.3390/ijms241210273
RNA Biomarkers in Bipolar Disorder and Response to Mood Stabilizers
Int J Mol Sci. 2023 Jun 13;24(12):10067. doi: 10.3390/ijms241210067.
ABSTRACT
Bipolar disorder (BD) is a severe chronic disorder that represents one of the main causes of disability among young people. To date, no reliable biomarkers are available to inform the diagnosis of BD or clinical response to pharmacological treatment. Studies focused on coding and noncoding transcripts may provide information complementary to genome-wide association studies, allowing to correlate the dynamic evolution of different types of RNAs based on specific cell types and developmental stage with disease development or clinical course. In this narrative review, we summarize findings from human studies that evaluated the potential utility of messenger RNAs and noncoding transcripts, such as microRNAs, circular RNAs and long noncoding RNAs, as peripheral markers of BD and/or response to lithium and other mood stabilizers. The majority of available studies investigated specific targets or pathways, with large heterogeneity in the included type of cells or biofluids. However, a growing number of studies are using hypothesis-free designs, with some studies also integrating data on coding and noncoding RNAs measured in the same participants. Finally, studies conducted in neurons derived from induced-pluripotent stem cells or in brain organoids provide promising preliminary findings supporting the power and utility of these cellular models to investigate the molecular determinants of BD and clinical response.
PMID:37373213 | DOI:10.3390/ijms241210067
Genetic Influence on Treatment Response in Psoriasis: New Insights into Personalized Medicine
Int J Mol Sci. 2023 Jun 7;24(12):9850. doi: 10.3390/ijms24129850.
ABSTRACT
Psoriasis is a chronic inflammatory disease with an established genetic background. The HLA-Cw*06 allele and different polymorphisms in genes involved in inflammatory responses and keratinocyte proliferation have been associated with the development of the disease. Despite the effectiveness and safety of psoriasis treatment, a significant percentage of patients still do not achieve adequate disease control. Pharmacogenetic and pharmacogenomic studies on how genetic variations affect drug efficacy and toxicity could provide important clues in this respect. This comprehensive review assessed the available evidence for the role that those different genetic variations may play in the response to psoriasis treatment. One hundred fourteen articles were included in this qualitative synthesis. VDR gene polymorphisms may influence the response to topical vitamin D analogs and phototherapy. Variations affecting the ABC transporter seem to play a role in methotrexate and cyclosporine outcomes. Several single-nucleotide polymorphisms affecting different genes are involved with anti-TNF-α response modulation (TNF-α, TNFRSF1A, TNFRSF1B, TNFAIP3, FCGR2A, FCGR3A, IL-17F, IL-17R, and IL-23R, among others) with conflicting results. HLA-Cw*06 has been the most extensively studied allele, although it has only been robustly related to the response to ustekinumab. However, further research is needed to firmly establish the usefulness of these genetic biomarkers in clinical practice.
PMID:37372997 | DOI:10.3390/ijms24129850
Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy
Int J Mol Sci. 2023 Jun 7;24(12):9843. doi: 10.3390/ijms24129843.
ABSTRACT
Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.
PMID:37372990 | DOI:10.3390/ijms24129843
Lipid-Associated GWAS Loci Predict Antiatherogenic Effects of Rosuvastatin in Patients with Coronary Artery Disease
Genes (Basel). 2023 Jun 13;14(6):1259. doi: 10.3390/genes14061259.
ABSTRACT
We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and p-values were calculated through adaptive permutation tests by the PLINK software, v1.9. Over one-year rosuvastatin therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm < 0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm < 0.05). In conclusion, polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients.
PMID:37372439 | DOI:10.3390/genes14061259
Cholecalciferol Supplementation Induced Up-Regulation of <em>SARAF</em> Gene and Down-Regulated miR-155-5p Expression in Slovenian Patients with Multiple Sclerosis
Genes (Basel). 2023 Jun 8;14(6):1237. doi: 10.3390/genes14061237.
ABSTRACT
Multiple sclerosis is a common immune-mediated inflammatory and demyelinating disease. Lower cholecalciferol levels are an established environmental risk factor in multiple sclerosis. Although cholecalciferol supplementation in multiple sclerosis is widely accepted, optimal serum levels are still debated. Moreover, how cholecalciferol affects pathogenic disease mechanisms is still unclear. In the present study, we enrolled 65 relapsing-remitting multiple sclerosis patients who were double-blindly divided into two groups with low and high cholecalciferol supplementation, respectively. In addition to clinical and environmental parameters, we obtained peripheral blood mononuclear cells to analyze DNA, RNA, and miRNA molecules. Importantly, we investigated miRNA-155-5p, a previously published pro-inflammatory miRNA in multiple sclerosis known to be correlated to cholecalciferol levels. Our results show a decrease in miR-155-5p expression after cholecalciferol supplementation in both dosage groups, consistent with previous observations. Subsequent genotyping, gene expression, and eQTL analyses reveal correlations between miR-155-5p and the SARAF gene, which plays a role in the regulation of calcium release-activated channels. As such, the present study is the first to explore and suggest that the SARAF miR-155-5p axis hypothesis might be another mechanism by which cholecalciferol supplementation might decrease miR-155 expression. This association highlights the importance of cholecalciferol supplementation in multiple sclerosis and encourages further investigation and functional cell studies.
PMID:37372417 | DOI:10.3390/genes14061237