Pharmacogenomics

SNP rs11185644 in RXRA gene and SNP rs2235544 in DIO1 gene predict dosage requirements in a cross-sectional sample of hypothyroid patients

Thu, 2023-08-10 06:00

BMC Endocr Disord. 2023 Aug 10;23(1):167. doi: 10.1186/s12902-023-01425-z.

ABSTRACT

BACKGROUND AND PURPOSE: Primary hypothyroidism due to abnormality in the thyroid gland is the most common endocrine disease The recommended starting dose of levothyroxine replacement therapy is 1.6 µg/kg. This dose however is not optimal for every patient and dose adjustments are frequently done. Genetic polymorphisms in the absorption and metabolism pathway of levothyroxine are likely to influence its dose requirements. This study aimed to study the influence of genetic polymorphisms on levothyroxine replacement requirements.

METHODS: This was a cross-sectional study. Participants were recruited through a private nutrition clinic and through announcements distributed in the University of Petra in Amman, Jordan between September 2020 and February 2021. Hypothyroid patients had already been on stable doses of levothyroxine for the previous 3 months. A questionnaire was distributed to collect demographic and clinical information and a blood sample was taken for DNA extraction and clinical biochemistry analysis. rs11249460, rs2235544, rs225014, rs225015, rs3806596, rs11185644, rs4588, rs602662 were analyzed using Applied Biosystems TaqMan™ SNP Genotyping Assays on Rotor-Gene® Q and rs3064744 by direct sequencing. SPSS and Excel were used to perform analysis.

RESULTS: 76 patients were studied. The equation we calculated to find predicted daily dose of levothyroxine (mcg/kg) is 3.22+ (0.348 for CT genotype of rs11185644, 0 for other genotypes) + 0.027*disease duration (years) - 0.014*age (years) - 0.434*T3 (pmol/L) levels+ (0.296 for CC genotype of rs2235544, 0 for other genotypes).

CONCLUSION: SNP rs11185644 in RXRA gene and SNP rs2235544 in DIO1 affect dose requirement in hypothyroid patients and if confirmed in larger trials they can be used to individualize thyroxine starting doses.

PMID:37563580 | DOI:10.1186/s12902-023-01425-z

Categories: Literature Watch

The Use of Next-Generation Sequencing in Pharmacogenomics

Thu, 2023-08-10 06:00

Clin Lab. 2023 Aug 1;69(8). doi: 10.7754/Clin.Lab.2023.230103.

ABSTRACT

BACKGROUND: Next-generation sequencing (NGS) methods have become more commonly performed in clinical and research laboratories.

METHODS: This review summarizes the current laboratory NGS-based diagnostic approaches in pharmacogenomics including targeted multi-gene panel sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).

RESULTS: Clinical laboratories perform multiple non-uniform types of pharmacogenetic panels, which can reduce the overall number of single-gene tests to be more cost-efficient. Compared to the targeted multi-gene panels, which are not typically designed to detect novel variants, WES and WGS have a greater potential to identify secondary pharmacogenomic findings, which might be predictive for the pharmacotherapy outcome of different patient settings. WGS overcomes the limitations of WES enabling a more accurate exome-sequencing at appropriate coverage and the sequencing of non-coding regions. Different NGS-based study designs with different test strategies and study populations, varying sample sizes, and distinct analytical and interpretation procedures lead to different identification results of pharmacogenomic variants.

CONCLUSIONS: The rapid progress in gene sequencing technologies will overcome the clinical and laboratory challenges of WES and WGS. Further high throughput NGS-based pharmacogenomics studies in different populations and patient settings are necessary to expand knowledge about rare functional variants and to enhance translation in clinical practice.

PMID:37560847 | DOI:10.7754/Clin.Lab.2023.230103

Categories: Literature Watch

Genetic variations in idiopathic pulmonary fibrosis and patient response to pirfenidone

Thu, 2023-08-10 06:00

Heliyon. 2023 Jul 24;9(8):e18573. doi: 10.1016/j.heliyon.2023.e18573. eCollection 2023 Aug.

ABSTRACT

BACKGROUND: Genetic variations in Idiopathic Pulmonary Fibrosis (IPF) affect survival and outcomes. Current antifibrotic agents are managed based on the patient's reported side effects, although certain single nucleotide polymorphisms (SNPs) might alter treatment response and survival depending on the antifibrotic administered. This study investigated variations in response and outcomes to pirfenidone based on patients-specific genetic profiles.

METHODS: Retrospective clinical data were collected from 56 IPF patients and had blood drawn for DNA extraction between 7/2013 and 3/2016, with the last patient followed until 10/2018. Nine SNPs were selected for pharmacogenetic investigation based on prior associations with IPF treatment outcomes or implications for pirfenidone metabolism. Genetic variants were examined in relation to clinical data and treatment outcomes.

RESULTS: Of the 56 patients, 38 were males (67.85%). The average age of IPF at diagnosis was 66.88 years. At the initiation of pirfenidone, the average percent predicted FVC was 70.7%, and the average DLCO percent predicted was 50.02% (IQR 40-61%). Among the genetic variants tested, the TOLLIP rs5743890 risk allele was significantly associated with improved survival, with increasing pirfenidone duration. This finding was observed with CC or CT genotype carriers but not for those with the TT genotype (p = 0.0457). Similarly, the TGF-B1 rs1800470 risk allele was also significantly associated with improved survival with longer pirfenidone therapy (p = 0.0395), even though it was associated with disease progression.

CONCLUSION: This pilot study suggests that in IPF patients, the TOLLIP rs5743890 genotypes CC and CT, as well as TGF-B1 rs 1800470 may be associated with increased survival when treated with pirfenidone.

PMID:37560683 | PMC:PMC10407116 | DOI:10.1016/j.heliyon.2023.e18573

Categories: Literature Watch

Pharmaco-genetic analysis of <em>CYP1A1</em> and <em>RGS4</em> variants and its impact on response to olanzapine and risperidone in Indian schizophrenic cohort

Thu, 2023-08-10 06:00

Am J Transl Res. 2023 Jul 15;15(7):4763-4769. eCollection 2023.

ABSTRACT

OBJECTIVES: Genetic variations contribute significantly to inter-individual responses to drugs and side effects. Pharmacogenomics has the potential to be utilized as a tool in disorders like schizophrenia with a high degree of genetic inheritance, although data on pharmacogenomics of schizophrenia are limited. Olanzapine and risperidone are the frequently used anti-psychotic drugs used in clinics. Studies have observed the variability in the response of both drugs in schizophrenic individuals. Considering the pharmacogenomics importance of both drugs, we aim to examine the cytochrome P 4501A1 (CYP1A1) and regulator of G-protein signaling 4 (RGS4) variants and their metabolizing status in 94 schizophrenic individuals of Indian descent.

METHODS: The present study is retrospective observational study. The metabolizing status of schizophrenic individuals was examined using Axiom Precision Medicine Diversity Array (PMDA) and the data were analyzed with the help of SNP Axiom Analysis Suite v5.1 (Affymetrix). The pharmacogenomics annotation was performed using PharmGKB.

RESULTS: Genotype and allele frequencies were observed. The results reveal the high frequency of poor metabolizers of olanzapine and risperidone in the studied cohort. In lieu of the high distribution of poor metabolizers, we compare observed allele frequencies with global populations' data to understand the variability of the genetic pool attained by Indian schizophrenic individuals.

CONCLUSIONS: Interestingly, the Indian schizophrenic cohort forms a different cluster compared to global populations, suggesting that pharmacogenomics testing might play an important role in clinical decision making for schizophrenia drug management.

PMID:37560209 | PMC:PMC10408541

Categories: Literature Watch

Promises and challenges in pharmacoepigenetics

Thu, 2023-08-10 06:00

Camb Prism Precis Med. 2023 Feb 9;1:e18. doi: 10.1017/pcm.2023.6. eCollection 2023.

ABSTRACT

Pharmacogenetics, the study of how interindividual genetic differences affect drug response, does not explain all observed heritable variance in drug response. Epigenetic mechanisms, such as DNA methylation, and histone acetylation may account for some of the unexplained variances. Epigenetic mechanisms modulate gene expression and can be suitable drug targets and can impact the action of nonepigenetic drugs. Pharmacoepigenetics is the field that studies the relationship between epigenetic variability and drug response. Much of this research focuses on compounds targeting epigenetic mechanisms, called epigenetic drugs, which are used to treat cancers, immune disorders, and other diseases. Several studies also suggest an epigenetic role in classical drug response; however, we know little about this area. The amount of information correlating epigenetic biomarkers to molecular datasets has recently expanded due to technological advances, and novel computational approaches have emerged to better identify and predict epigenetic interactions. We propose that the relationship between epigenetics and classical drug response may be examined using data already available by (1) finding regions of epigenetic variance, (2) pinpointing key epigenetic biomarkers within these regions, and (3) mapping these biomarkers to a drug-response phenotype. This approach expands on existing knowledge to generate putative pharmacoepigenetic relationships, which can be tested experimentally. Epigenetic modifications are involved in disease and drug response. Therefore, understanding how epigenetic drivers impact the response to classical drugs is important for improving drug design and administration to better treat disease.

PMID:37560024 | PMC:PMC10406571 | DOI:10.1017/pcm.2023.6

Categories: Literature Watch

Association of lncRNA and transcriptome intersections with response to targeted therapy in metastatic renal cell carcinoma

Thu, 2023-08-10 06:00

Oncol Lett. 2023 Jul 11;26(3):365. doi: 10.3892/ol.2023.13951. eCollection 2023 Sep.

ABSTRACT

Long non-coding RNAs (lncRNAs) serve an important role in cancer progression and may be used as efficient molecular biomarkers. The present study aimed to identify lncRNAs associated with the response to the receptor tyrosine kinase inhibitor sunitinib and transcriptome profile and clinical features of metastatic renal cell carcinoma (mRCC). The gene expression of 84 cancer-associated lncRNAs in tumor and non-malignant tissue samples of 38 patients with mRCC was evaluated using quantitative PCR. In addition, the coding transcriptome was estimated using RNA sequencing in a subgroup of 20 patients and mRNA-lncRNA intersections were identified. In total, 37 and 13 lncRNAs were down- and upregulated, respectively, in tumor compared with non-malignant adjacent tissue samples. A total of 10 and 4 lncRNAs were up- and downregulated, respectively, in good responders to sunitinib compared with poor responders. High expression of HNF1A-AS1 and IPW lncRNAs was associated with prolonged progression-free survival of patients and a high expression of the TUSC7 lncRNA was associated with poor response and worse survival. Significant associations of dysregulated MEG3 and SNHG16 lncRNAs with expression of protein-coding genes representing various pathways, were identified. Furthermore, a significantly higher expression of CLIP4 gene was observed in good responders. The present study revealed promising candidates for predictive and prognostic biomarkers with further therapeutic potential.

PMID:37559591 | PMC:PMC10407709 | DOI:10.3892/ol.2023.13951

Categories: Literature Watch

Machine Learning and Pharmacogenomics at the Time of Precision Psychiatry

Thu, 2023-08-10 06:00

Curr Neuropharmacol. 2023 Aug 9. doi: 10.2174/1570159X21666230808170123. Online ahead of print.

ABSTRACT

Traditional medicine and biomedical sciences are reaching a turning point because of the constantly growing impact and volume of Big Data. Machine Learning (ML) techniques and related algorithms play a central role as diagnostic, prognostic, and decision-making tools in this field. Another promising area becoming part of everyday clinical practice is personalized therapy and pharmacogenomics. Applying ML to pharmacogenomics opens new frontiers to tailored therapeutical strategies to help clinicians choose drugs with the best response and fewer side effects, operating with genetic information and combining it with the clinical profile. This systematic review aims to draw up the state-of-the-art ML applied to pharmacogenomics in psychiatry. Our research yielded fourteen papers; most were published in the last three years. The sample comprises 9,180 patients diagnosed with mood disorders, psychoses, or autism spectrum disorders. Prediction of drug response and prediction of side effects are the most frequently considered domains with the supervised ML technique, which first requires training and then testing. The random forest is the most used algorithm; it comprises several decision trees, reduces the training set's overfitting, and makes precise predictions. ML proved effective and reliable, especially when genetic and biodemographic information were integrated into the algorithm. Even though ML and pharmacogenomics are not part of everyday clinical practice yet, they will gain a unique role in the next future in improving personalized treatments in psychiatry.

PMID:37559539 | DOI:10.2174/1570159X21666230808170123

Categories: Literature Watch

Lower Limb Muscle Fatigue Alters Spatiotemporal Gait Parameters and Turning Difficulty Characteristics in Parkinson's Disease

Wed, 2023-08-09 06:00

Ann Rehabil Med. 2023 Aug 9. doi: 10.5535/arm.23067. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine the effects of lower limb muscle fatigue on spatiotemporal gait parameters and turning difficulty characteristics during the extended Timed Up and Go (extended TUG) test in individuals with different severity stages of Parkinson's disease (PD).

METHODS: Forty individuals with PD, classified as Hoehn and Yahr (H&Y) stages 2 and 3 participated in this pre- and post-experimental study design. The participants performed a continuous sit-to-stand task from a chair based on 30 cycles/min set-up to induce lower limb muscle fatigue. They performed extended TUG test immediately before and after completing the fatigue protocol. Spatiotemporal gait parameters and turning difficulty characteristics were recorded using two GoPro® Hero 4 Silver cameras. Data were subjected to a repeated-measure ANOVA.

RESULTS: Individuals with PD experience significant changes in spatiotemporal gait parameters, specifically stride velocity and length, under conditions of lower limb muscle fatigue (p=0.001). These changes were more pronounced in individuals with PD in the H&Y stage 3 group. Additionally, both PD groups exhibited difficulty with turning, requiring more than five steps to complete a 180° turn and taking more than 3 seconds to accomplish it.

CONCLUSION: These findings highlight the impact of muscle fatigue on gait performance in PD and suggest that individuals in later stages of the disease may be particularly affected. Further research is needed to explore interventions that can mitigate these gait impairments and improve mobility in individuals with PD.

PMID:37558204 | DOI:10.5535/arm.23067

Categories: Literature Watch

ZNF671 methylation test in cervical scrapings for cervical intraepithelial neoplasia grade 3 and cervical cancer detection

Wed, 2023-08-09 06:00

Cell Rep Med. 2023 Aug 3:101143. doi: 10.1016/j.xcrm.2023.101143. Online ahead of print.

ABSTRACT

Effective triage of high-risk human papillomavirus (hrHPV)+ women is warranted to avoid unnecessary referral and overtreatment. Molecular triage tests have recently begun to impact cervical intraepithelial neoplasia grade 3 (CIN3) or cervical cancer (CC), termed CIN3+, detection. We find that zinc finger protein 671 methylation (ZNF671m) test has superior performance for CIN3+ detection in all single molecular triage tests, including HPV16/18 genotyping, paired box gene 1 methylation (PAX1m), and ZNF671m, in the training set. Using ZNF671m test instead of Thinprep cytologic test (TCT) as a single triage strategy or as a combined triage strategy with HPV16/18 genotyping has achieved comparable sensitivity but higher specificity for CIN3+ detection among 391 hrHPV+ women in the validation set. Little attention has been paid to the women with hrHPV- status but detected CIN3+. We find that the CIN3+ risk after a negative result could be reduced further by triage using ZNF671m in hrHPV- patients.

PMID:37557178 | DOI:10.1016/j.xcrm.2023.101143

Categories: Literature Watch

Loss of TAZ after YAP deletion severely impairs foregut development and worsens cholestatic hepatocellular injury

Wed, 2023-08-09 06:00

Hepatol Commun. 2023 Aug 9;7(9):e0220. doi: 10.1097/HC9.0000000000000220. eCollection 2023 Sep 1.

ABSTRACT

BACKGROUND: We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity.

METHODS: We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing.

RESULTS: DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.

CONCLUSIONS: YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.

PMID:37556373 | DOI:10.1097/HC9.0000000000000220

Categories: Literature Watch

The effect of chronic lithium treatment on hippocampal progenitor cells: Transcriptomic analysis and systems pharmacology

Wed, 2023-08-09 06:00

Brain Behav. 2023 Aug 8:e3215. doi: 10.1002/brb3.3215. Online ahead of print.

ABSTRACT

OBJECTIVE: To identify the genomics underpinning the increased volume of the hippocampus after long-term administration of lithium (Li) in bipolar disorder patients, hypothesizing the possible contribution of cell growth and differentiation pathways to this complication.

METHODS: RNA-seq profiles of four samples of hippocampal progenitor cells chronically treated with a high dose of Li and three samples chronically treated with the therapeutic dose were retrieved from NCBI-GEO. The raw data underwent filtration, quality control, expression fold change, adjusted significance, functional enrichment, and pharmacogenomic analyses.

RESULTS: CCND1, LOXL2, and PRNP were identified as the genes involved in the drug response and the chronic effects of Li in the hippocampal cells. GSK-3β was also a hub in the pharmacogenomic network of Li. In addition, ZMPSTE24 and DHX35 were identified as the important genes in lithium therapy.

CONCLUSIONS: As shown by gene ontology results, these findings conclude that lithium may increase the size of the hippocampus in bipolar patients by stimulating the generation of new neurons and promoting their differentiation into neuroblasts, neurons, or microglia.

PMID:37553827 | DOI:10.1002/brb3.3215

Categories: Literature Watch

Whole blood DNA methylation changes are associated with anti-TNF drug concentration in patients with Crohn's disease

Tue, 2023-08-08 06:00

J Crohns Colitis. 2023 Aug 8:jjad133. doi: 10.1093/ecco-jcc/jjad133. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Anti-TNF treatment failure in patients with inflammatory bowel disease (IBD) is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14.

METHODS: DNA methylation from 1,104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease (PANTS) study were assessed using the Illumina EPIC Beadchip (v1.0) at baseline, weeks 14, 30 and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 and if they were assessed at subsequent time points, were not in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 94), with patients who responded at week 14 and when assessed at subsequent time points, were in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 93).

RESULTS: Overall, between baseline and week 14, we observed 4,999 differentially methylated probes (DMPs) annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses.Epigenome-wide association (EWAS) analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at week 14. Of these, 125 DMPs demonstrated shared associations with other common traits (proportion of shared CpGs compared to DMPs) including body mass index (23.2%), followed by CRP (11.5%), smoking (7.4%), alcohol consumption per day (7.1%) and IBD type (6.8%). EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients (Spearman's rho = -0.94, p < 0.001).

CONCLUSION: Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy.

PMID:37551994 | DOI:10.1093/ecco-jcc/jjad133

Categories: Literature Watch

Genotype-guided dual antiplatelet therapy in cerebrovascular disease: assessing the risk and benefits for ethnic populations

Tue, 2023-08-08 06:00

Expert Rev Cardiovasc Ther. 2023 Aug 8. doi: 10.1080/14779072.2023.2245754. Online ahead of print.

ABSTRACT

INTRODUCTION: Cerebrovascular disease is a leading cause of morbidity and mortality in the world and antiplatelet therapy is a main pharmacologic means of secondary prevention. Clinical information has accumulated about benefit of dual antiplatelet therapy in certain clinical scenarios, genetic causes of antiplatelet resistance and its effect on clinical outcomes, and ethnic and geographic distributions of genetic polymorphisms.

AREAS COVERED: This review covers literature related to the pharmacogenomics of antiplatelet agents with a focus on ethnic variability, antiplatelet resistance, and dual antiplatelet therapy in cerebrovascular disease.

EXPERT OPINION: Selecting patients for dual antiplatelet therapy and specific agents require consideration of multiple factors. Ethnic factors should be considered in certain circumstances, but additional research is needed to determine the generalizability of the findings.

PMID:37551687 | DOI:10.1080/14779072.2023.2245754

Categories: Literature Watch

<em>MMP-3</em> -1171 5A/6A promoter polymorphism and cancer susceptibility: an updated meta-analysis and trial sequential analysis

Tue, 2023-08-08 06:00

Future Oncol. 2023 Aug 8. doi: 10.2217/fon-2022-1306. Online ahead of print.

ABSTRACT

Purpose: Previous studies of MMP-3 -1171 5A/6A in cancers have produced inconclusive outcomes. This updated meta-analysis was performed to clarify the link between this variant and cancer. Methods: Databases including PubMed, Google Scholar, EMBASE and Cochrane were searched for data collection. The associations were calculated by odds ratios with 95% CIs. Results: 63 eligible studies with 14,252 cases and 15,176 controls were included. The codominant 2, codominant 3, dominant, recessive and allele models were found to be significantly associated with 1.28-, 1.13-, 1.13-, 1.19- and 1.13-fold enhanced overall risk of cancer, respectively. Stratification analysis revealed a 1.28-times enhanced risk of esophageal cancer (codominant 1), 1.29- and 1.26-fold (codominant 3) and 1.18- and 1.28-fold (recessive model) enhanced risk in colorectal and gastrointestinal cancers, respectively, 1.30-, 1.35- and 1.22-times in codominant model 1, dominant and allele models for breast cancer, 1.56-fold (codominant 2) for gynecological cancer and 2.40-times in codominant model 2 for hepatocellular cancer. Conclusion: This meta-analysis suggests a significant association between the MMP-3 -1171 5A/6A variant and cancer. This meta-analysis was registered at INPLASY (registration number: INPLASY202280049).

PMID:37551683 | DOI:10.2217/fon-2022-1306

Categories: Literature Watch

Influence of genetic variants on the pharmacokinetics and pharmacodynamics of sirolimus: a systematic review

Tue, 2023-08-08 06:00

Pharmacogenomics. 2023 Aug 8. doi: 10.2217/pgs-2022-0147. Online ahead of print.

ABSTRACT

Sirolimus is an antiproliferative and immunosuppressive compound inhibiting the mTOR pathway, which is often activated in congenital low-flow vascular malformations. Studies have demonstrated the efficacy of sirolimus for this disease. Studies in kidney transplant patients suggest that genetic variants can influence these pharmacokinetic parameters. Therefore, a systematic literature search was performed to gain insight into pharmacogenetic studies with sirolimus. Most studies investigated CYP3A4 and CYP3A5, with inconsistent results. No pharmacogenetic studies focusing on sirolimus have been performed for low-flow vascular malformations. We analyzed two common variants of CYP3A4 and CYP3A5 (CYP3A4*22 and CYP3A5*3, respectively) in patients (n = 59) with congenital low-flow vascular malformations treated with sirolimus. No association with treatment outcome was identified in this small cohort of patients.

PMID:37551646 | DOI:10.2217/pgs-2022-0147

Categories: Literature Watch

Pharmacogenomic variation in the Malagasy population: implications for the antimalarial drug primaquine metabolism

Tue, 2023-08-08 06:00

Pharmacogenomics. 2023 Aug 8. doi: 10.2217/pgs-2023-0091. Online ahead of print.

ABSTRACT

Aim: Antimalarial primaquine (PQ) eliminates liver hypnozoites of Plasmodium vivax. CYP2D6 gene variation contributes to PQ therapeutic failure. Additional gene variation may contribute to PQ efficacy. Information on pharmacogenomic variation in Madagascar, with vivax malaria and a unique population admixture, is scanty. Methods: The authors performed genome-wide genotyping of 55 Malagasy samples and analyzed data with a focus on a set of 28 pharmacogenes most relevant to PQ. Results: Mainly, the study identified 110 coding or splicing variants, including those that, based on previous studies in other populations, may be implicated in PQ response and copy number variation, specifically in chromosomal regions that contain pharmacogenes. Conclusion: With this pilot information, larger genome-wide association analyses with PQ metabolism and response are substantially more feasible.

PMID:37551613 | DOI:10.2217/pgs-2023-0091

Categories: Literature Watch

Possible genetic biomarker associated with antipsychotic-induced amenorrhea in female patients with schizophrenia

Tue, 2023-08-08 06:00

Int Clin Psychopharmacol. 2023 Aug 7. doi: 10.1097/YIC.0000000000000501. Online ahead of print.

ABSTRACT

This study explored the association of pharmacogenomics with antipsychotic-induced amenorrhea in female patients with schizophrenia. A total of 89 female schizophrenia patients aged 18-40 receiving consistent antipsychotics at a consistent dose for more than 3 months were enrolled in this study. Amenorrhea was defined as the absence of menstrual period for 3 months or three periods in a row. Serum levels of prolactin, estradiol, follicle-stimulating hormone, luteinizing hormone, and thyroid-stimulating hormone were measured and Cytochrome P450 2D6, dopamine receptor D2 (DRD2) and estrogen receptor 1 were genotyped. Twenty-two patients with amenorrhea had higher prolactin levels and lower estradiol levels than those without amenorrhea (94.1 vs. 71.5 ng/ml for prolactin; P = 0.044 and 27.0 vs. 46.7 pg/ml for estradiol; P = 0.007, respectively). Multiple logistic regression analysis identified DRD2-141C deletion [odds ratio (OR) = 1.71, 95% confidence interval (CI) = 1.01-4.17; P = 0.049] and drugs increasing prolactin levels (OR = 6.17, 95% CI = 1.28-29.64; P = 0.023) as significant covariates for antipsychotic-induced amenorrhea. This study suggests that DRD2-141C deletion is associated with antipsychotic-induced amenorrhea although further studies are needed.

PMID:37551597 | DOI:10.1097/YIC.0000000000000501

Categories: Literature Watch

Association of <em>IL4RA</em> polymorphism in predicting susceptibility toward chronic obstructive pulmonary disease

Tue, 2023-08-08 06:00

Pharmacogenomics. 2023 Aug 8. doi: 10.2217/pgs-2023-0010. Online ahead of print.

ABSTRACT

Background: The cytokine IL-4 plays vital role in the intercellular signalling network during immune responses to allergen exposure. Methods: This cross-sectional study involved 202 chronic obstructive pulmonary disease (COPD) patients and 203 healthy individuals. The genotyping of IL4RAQ576R gene polymorphism was determined using polymerase chain reaction restriction fragment length polymorphism analysis. Results: Significant association between mutant genotype (GG) and combined (AA+AG) genotype for the risk of COPD was found (odds ratio [OR]: 4.32; p = 0.04). A significant protective effect was observed between the IL4RAQ576R polymorphism and Global Strategy for Obstructive Lung Disease (GOLD) stage four patients in a recessive model (AA+AG vs GG) (p = 0.002). In GOLD A, a substantial relationship was found between the AG and wild-type genotypes (AA) for COPD risk (OR: 2.38; p = 0.03). A strong association was found for COPD duration of 5-10 years (OR: 8.80; p = 0.01). Conclusion: IL4RAQ576R polymorphism is associated with COPD susceptibility.

PMID:37551548 | DOI:10.2217/pgs-2023-0010

Categories: Literature Watch

Pharmacogenomic testing for antidepressant treatment selection: lessons learned and roadmap forward

Mon, 2023-08-07 06:00

Neuropsychopharmacology. 2023 Aug 7. doi: 10.1038/s41386-023-01667-4. Online ahead of print.

ABSTRACT

Pharmacogenomic technology is a developing field with enthusiastic interest and broad application potential. Three large, controlled studies have been published exploring the benefit of pharmacogenomically guided antidepressant treatment selection. Though all three studies did not show significant benefit of using this technology, these studies laid the foundation for further research that should address the limitations of this previous research and currently available commercial platforms. Future research needs to include large scale pharmacogenomic trials with GWAS analytics across diverse groups with attention to cost-effectiveness models, particularly for cases of treatment resistance and polypharmacy. The application of results from these large scale pharmacogenomic trials must also include exploring optimal EHR user interface design.

PMID:37550439 | DOI:10.1038/s41386-023-01667-4

Categories: Literature Watch

The genetic, pharmacogenomic, and immune landscapes associated with protein expression across human cancers

Mon, 2023-08-07 06:00

Cancer Res. 2023 Aug 7:CAN-23-0758. doi: 10.1158/0008-5472.CAN-23-0758. Online ahead of print.

ABSTRACT

Proteomics is a powerful approach that can rapidly enhance our understanding of cancer development. Detailed characterization of the genetic, pharmacogenomic, and immune landscape in relation to protein expression in cancer patients could provide new insights into the functional roles of proteins in cancer. By taking advantage of the genotype data from The Cancer Genome Atlas (TCGA) and protein expression data from The Cancer Proteome Atlas (TCPA), we characterized the effects of genetic variants on protein expression across 31 cancer types and identified approximately 100,000 protein quantitative trait loci (pQTL). Among these, over 8000 pQTL were associated with patient overall survival. Furthermore, characterization of the impact of protein expression on more than 350 imputed anticancer drug responses in patients revealed nearly 230,000 significant associations. In addition, approximately 21,000 significant associations were identified between protein expression and immune cell abundance. Finally, a user-friendly data portal, GPIP (https://hanlaboratory.com/GPIP), was developed featuring multiple modules that enable researchers to explore, visualize, and browse multidimensional data. This detailed analysis reveals the associations between the proteomic landscape and genetic variation, patient outcome, the immune microenvironment, and drug response across cancer types, providing a resource that may offer valuable clinical insights and encourage further functional investigations of proteins in cancer.

PMID:37548539 | DOI:10.1158/0008-5472.CAN-23-0758

Categories: Literature Watch

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