Genomics Inform. 2021 Sep;19(3):e29. doi: 10.5808/gi.21034. Epub 2021 Sep 30.

ABSTRACT

In our previous studies, we have demonstrated the association of certain variants of the thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (TG) genes with congenital hypothyroidism. Herein, we explored the mechanistic basis for this association using different in silico tools. The mRNA 3'-untranslated region (3'-UTR) plays key roles in gene expression at the post-transcriptional level. In TSHR variants (rs2268477, rs7144481, and rs17630128), the binding affinity of microRNAs (miRs) (hsa-miR-154-5p, hsa-miR-376a-2-5p, hsa-miR-3935, hsa-miR-4280, and hsa-miR-6858-3p) to the 3'-UTR is disrupted, affecting post-transcriptional gene regulation. TPO and TG are the two key proteins necessary for the biosynthesis of thyroid hormones in the presence of iodide and H2O2. Reduced stability of these proteins leads to aberrant biosynthesis of thyroid hormones. Compared to the wild-type TPO protein, the p.S398T variant was found to exhibit less stability and significant rearrangements of intra-atomic bonds affecting the stoichiometry and substrate binding (binding energies, ΔG of wild-type vs. mutant: ‒15 vs. ‒13.8 kcal/mol; and dissociation constant, Kd of wild-type vs. mutant: 7.2E-12 vs. 7.0E-11 M). The missense mutations p.G653D and p.R1999W on the TG protein showed altered ΔG (0.24 kcal/mol and 0.79 kcal/mol, respectively). In conclusion, an in silico analysis of TSHR genetic variants in the 3'-UTR showed that they alter the binding affinities of different miRs. The TPO protein structure and mutant protein complex (p.S398T) are less stable, with potentially deleterious effects. A structural and energy analysis showed that TG mutations (p.G653D and p.R1999W) reduce the stability of the TG protein and affect its structure-functional relationship.

PMID:34638176 | DOI:10.5808/gi.21034

Life Sci. 2021 Oct 9:120037. doi: 10.1016/j.lfs.2021.120037. Online ahead of print.

ABSTRACT

AIMS: Median raphe region (MRR) is an important bottom-up regulatory center for various behaviors as well as vegetative functions, but detailed descriptions and links between the two are still largely unexplored.

METHODS: Pharmacogenetics was used to study the role of MRR in social (sociability, social interaction, resident intruder test) and emotional behavior (forced swim test) parallel with some vegetative changes (biotelemetry: core body temperature). Additionally, to validate pharmacogenetics, the effect of clozapine-N-oxide (CNO), the ligand of the artificial receptor, was studied by measuring (i) serum and brainstem concentrations of CNO and clozapine; (ii) MRR stimulation induced neurotransmitter release in hippocampus; (iii) CNO induced changes in body temperature and locomotor activity.

KEY FINDINGS: MRR stimulation decreased locomotion, increased friendly social behavior in the resident intruder test and enhanced depressive-like behavior. The latter was accompanied by diminished decrease in core body temperature. Thirty minutes after CNO injection clozapine was predominant in the brainstem. Nonetheless, peripheral CNO injection was able to induce glutamate release in the hippocampus. CNO had no immediate (<30 min) or chronic (repeated injections) effect on the body temperature or locomotion.

SIGNIFICANCE: We confirmed the role of MRR in locomotion, social and depressive-like behavior. Most interestingly, only depressive-like behavior was accompanied by changed body temperature regulation, which was also observed in human depressive disorders previously. This indicates clinical relevance of our findings. Despite low penetration, CNO acts centrally, but does not influence the examined basic parameters, being suitable for repeated behavioral testing.

PMID:34637795 | DOI:10.1016/j.lfs.2021.120037

J Cell Mol Med. 2021 Oct 12. doi: 10.1111/jcmm.16981. Online ahead of print.

ABSTRACT

In chemotherapy for childhood acute lymphoblastic leukaemia (ALL), maintenance therapy consisting of oral daily mercaptopurine and weekly methotrexate is important. NUDT15 variant genotype is reportedly highly associated with severe myelosuppression during maintenance therapy, particularly in Asian and Hispanic populations. It has also been demonstrated that acquired somatic mutations of the NT5C2 and PRPS1 genes, which are involved in thiopurine metabolism, are detectable in a portion of relapsed childhood ALL. To directly confirm the significance of the NUDT15 variant genotype and NT5C2 and PRPS1 mutations in thiopurine sensitivity of leukaemia cells in the intrinsic genes, we investigated 84 B-cell precursor-ALL (BCP-ALL) cell lines. Three and 14 cell lines had homozygous and heterozygous variant diplotypes of the NUDT15 gene, respectively, while 4 and 2 cell lines that were exclusively established from the samples at relapse had the NT5C2 and PRPS1 mutations, respectively. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with DNA-incorporated thioguanine levels after exposure to thioguanine at therapeutic concentration. Considering the continuous exposure during the maintenance therapy, we evaluated in vitro mercaptopurine sensitivity after 7-day exposure. Mercaptopurine concentrations lethal to 50% of the leukaemia cells were comparable to therapeutic serum concentration of mercaptopurine. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with mercaptopurine sensitivity in 83 BCP-ALL and 23 T-ALL cell lines. The present study provides direct evidence to support the general principle showing that both inherited genotype and somatically acquired mutation are crucially implicated in the drug sensitivity of leukaemia cells.

PMID:34636169 | DOI:10.1111/jcmm.16981

Neurology. 2021 Oct 11:10.1212/WNL.0000000000012919. doi: 10.1212/WNL.0000000000012919. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.

METHODS: We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women's Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (Ncase=54,552, Ncontrol=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713).

RESULTS: There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 (P=0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (P<0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues.

CONCLUSIONS: The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

PMID:34635557 | DOI:10.1212/WNL.0000000000012919

Bioorg Med Chem. 2021 Oct 4;50:116454. doi: 10.1016/j.bmc.2021.116454. Online ahead of print.

ABSTRACT

A series of phenylurea hydroxamic acids incorporating pharmacophores of inhibitors of HDAC inhibitors and VEGFR-2 has been designed. Most of the compounds show antiproliferative activity comparable to that of Vorinostat and Sorafenib, and better EPC inhibitory activity. Enzymatic assays and Western blotting results indicated that compound 14 not only inhibits HDAC but also has slight VEGFR-2 inhibitory activity. A docking study revealed that the polar hydroxamic acid retains the interaction with HDAC through a zinc ion and also interacts with some residues of the active site of VEGFR-2. Despite 14 displaying a weaker VEGFR-2 activity, a possible route to develop potent HDAC/VEGFR-2 inhibitors is suggested.

PMID:34634618 | DOI:10.1016/j.bmc.2021.116454

Front Genet. 2021 Sep 22;12:740216. doi: 10.3389/fgene.2021.740216. eCollection 2021.

ABSTRACT

In psychiatry, the selection of antipsychotics and antidepressants is generally led by a trial-and-error approach. The prescribing of these medications is complicated by sub-optimal efficacy and high rates of adverse drug reactions (ADRs). These both contribute to poor levels of adherence. Pharmacogenetics (PGx) considers how genetic variation can influence an individual's response to a drug. Pharmacogenetic testing is a tool that could aid clinicians when selecting psychotropic medications, as part of a more personalized approach to prescribing. This may improve the use of and adherence to these medications. Yet to date, the implementation of PGx in mental health environments in the United Kingdom has been slow. This review aims to identify the current barriers and enablers to the implementation of PGx in psychiatry and determine how this can be applied to the uptake of PGx by NHS mental health providers. A systematic searching strategy was developed, and searches were carried out on the PsychInfo, EmBase, and PubMed databases, yielding 11 appropriate papers. Common barriers to the implementation of PGx included cost, concerns over incorporation into current workflow and a lack of knowledge about PGx; whilst frequent enablers included optimism that PGx could lead to precision medicine, reduce ADRs and become a more routine part of psychiatric clinical care. The uptake of PGx in psychiatric care settings in the NHS should consider and overcome these barriers, while looking to capitalize on the enablers identified in this review.

PMID:34630531 | PMC:PMC8493030 | DOI:10.3389/fgene.2021.740216

Front Pharmacol. 2021 Sep 22;12:725565. doi: 10.3389/fphar.2021.725565. eCollection 2021.

NO ABSTRACT

PMID:34630101 | PMC:PMC8493803 | DOI:10.3389/fphar.2021.725565

Pharmgenomics Pers Med. 2021 Oct 2;14:1303-1313. doi: 10.2147/PGPM.S325813. eCollection 2021.

ABSTRACT

PURPOSE: Severe myelosuppression in patients with acute lymphoblastic leukemia (ALL) undergoing 6-MP-based maintenance therapy is attributed to TPMT gene polymorphisms, which is rare in Asian populations. This study aims to evaluate the role of selected polymorphisms in NUDT15, ITPA, and MRP4 genes in addition to TPMT in predicting 6-MP intolerance during ALL maintenance therapy.

PATIENTS AND METHODS: We screened for the presence of NUDT15*3 (c.415 C>T, rs116855232); MRP4 c.2269 C>T (rs3765534), ITPA c.94 C>A (rs1127354) polymorphisms in addition to TPMT *2 (rs1800462), *3A (*3B and *3C; rs1800460 and rs1142345) in ALL patients with documented severe neutropenia (cohort-1; n=42). These polymorphisms were then screened in a prospective cohort of ALL patients (cohort-2; n=133) and compared with 6-MP dose reduction, early/late myelotoxicity.

RESULTS: Nineteen (45%) patients in cohort-1 and 18 (14%) in cohort-2 had NUDT15 c.415 C>T variant while 4 (3%) patients in cohort-2 had TPMT*3C variant. Five (12%) in cohort-1 and 30 (24%) in cohort-2 had ITPA c.94 C>A variant while 9 (22%) and 15 (12%) had MRP4 c.2269 C>T variant in cohorts-1 and 2, respectively. All in cohort-1 and 36 (27%) in cohort-2 had severe myelotoxicity. Twenty-eight patients (66.6%) in cohort-1 and 40 (30%) patients in cohort-2 had significant 6-MP dose reduction. NUDT15 c.415 C>T variant explained severe myelotoxicity in 63% and 33% in cohort 1 and 2. TPMT*3C and ITPA c.94 C>A variants also explained myelotoxicity in cohort-2 (Median ANC: 376 vs 1014 mm3; p=0.04 and 776 vs 1023 mm3; p=0.04 respectively). NUDT15 c.415 C>T polymorphism explained significant myelotoxicity (507 vs 1298 mm3; p<0.0001) in the multivariate analysis as well (β=-0.314, p<0.0001).

CONCLUSION: NUDT15 c.415 C>T (15*3), TPMT*3C, as well as ITPA c.94 C>A and MRP4 c.2269 C>T polymorphisms explain hematotoxicities. Preemptive genotype-based (NUDT15*3, TPMT, ITPA c.94 C>A) 6-MP dosing could improve the outcome after maintenance therapy.

PMID:34629890 | PMC:PMC8495143 | DOI:10.2147/PGPM.S325813

Pharmgenomics Pers Med. 2021 Oct 1;14:1275-1289. doi: 10.2147/PGPM.S324410. eCollection 2021.

ABSTRACT

BACKGROUND: Genetic polymorphism, obviously, has a potential clinical role in determining differences in drug efficacy; however, there are no reports about the pharmacogenomic information of the Lahu population. Therefore, our research aimed to screen the genotypic frequencies of the very important pharmacogenomics (VIP) mutations and determined the differences between Lahu and the other 11 populations.

METHODS: Agena MassARRAY (AgenaMassARRAY) single nucleotide polymorphism (SNP) genotyping technique was used to detect 81 VIP mutations of pharmacogenomics genes in Lahu, and their genotypic frequencies were compared with the other major 11 populations. Chi-square tests were used to identify different loci among these populations. Finally, the genetic structure and pairwise Fst values of Lahu and the other 11 populations were analyzed.

RESULTS: We found that the distribution of allele frequencies within different pharmacogenes in Lahu showed significantly different with other populations. Additionally, the pairwise F-statistics (Fst) values and genetic structure revealed the variants in the Lahu population as well were mostly related to the Han Chinese in Beijing, China (CHB) and the Japanese population in Tokyo, Japan (JPT) genetically.

CONCLUSION: This study will provide a theoretical basis for safe drug use and help to establish the appropriate individualized treatment strategies in the Lahu population.

PMID:34629888 | PMC:PMC8493477 | DOI:10.2147/PGPM.S324410

J Thromb Haemost. 2021 Oct 8. doi: 10.1111/jth.15552. Online ahead of print.

ABSTRACT

BACKGROUND: Circulating dysfunctional factor IX (FIX) might modulate distribution of infused FIX in haemophilia B (HB) patients. Recurrent substitutions at FIX activation sites (R191-R226, >300 patients) are associated with variable FIX activity and antigen (FIXag) levels.

OBJECTIVES: To investigate i) expression of a complete panel of missense mutations at FIX activation sites and ii) contribution of F9 genotypes on the FIX pharmacokinetics (PK).

METHODS: FIXag and activity assays in plasma and after recombinant expression of FIX variants. Analysis of infused FIX PK parameters in patients (n=30), mostly enrolled in the F9 Genotype and PK HB Italian Study (GePKHIS; EudraCT ID2017-003902-42).

RESULTS: The variable FIXag amounts and good relation between biosynthesis and activity of multiple R191 variants result in graded moderate-to-mild severity of the R191C>L>P>H substitutions. Recombinant expression may predict the absence in the HB mutation database of the benign R191Q/W/K and R226K substitutions. Equivalent changes at R191/R226 produced higher FIXag levels for R226Q/W/P substitutions, as also observed in p.R226W female carrier plasma. PK analysis in patients suggested that infused FIX Alpha distribution and Beta elimination phases positively correlated with endogenous FIXag levels. Mean residence time was particularly prolonged (79.4 hrs, 95% CI 44.3-114.5) in patients (n=7) with the R191/R226 substitutions, which in regression analysis were independent predictors (β coefficient 0.699, p=0.004) of Beta half-life, potentially prolonged by the increasing over time ratio between endogenous and infused FIX.

CONCLUSIONS: FIXag levels and specific features of the dysfunctional R191/R226 variants may exert pleiotropic effects both on HB patients' phenotypes and substitutive treatment.

PMID:34626083 | DOI:10.1111/jth.15552

Ann Oncol. 2021 Oct 5:S0923-7534(21)04496-3. doi: 10.1016/j.annonc.2021.09.017. Online ahead of print.

ABSTRACT

BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small cell lung cancer (NSCLC). We aimed to evaluate in this investigator-initiated study the predictive utility of the mRNA expression levels of ERCC1 and TS as assessed in resected tumor.

METHODS: Seven hundred seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the 4 genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n=389) or tailored chemotherapy (T, n=384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary end point of the study was overall survival (OS).

RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. 5-year survival for patients in arms C and T was of 65.4% (95%CI: 58.5-71.4%) and 72.9% (95%CI: 66.5-78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95%CI: 0.56-1.06, p-value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95%CI: 0.69-1.14, p-value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T.

CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

PMID:34624497 | DOI:10.1016/j.annonc.2021.09.017

Clin Pharmacol Ther. 2021 Oct 8. doi: 10.1002/cpt.2440. Online ahead of print.

ABSTRACT

Preparations of plasma-derived small extracellular vesicles (sEV) were deployed as liquid biopsy to study cytochrome P450 (CYP) 3A4 (CYP3A4) induction following modafinil (MOD) 400 mg once daily x 14 days (young healthy volunteers, N = 10 subjects). Induction was confirmed using the 4β-hydroxycholesterol-to-cholesterol (4βHC/C) ratio, a plasma CYP3A4/5 biomarker, with a mean 2.1-fold increase [Day 15 versus Day 1; 90% confidence interval (CI) = 1.8-2.3; P-value = 0.0004]. Proteomic analysis revealed the induction [mean Day 15 versus Day 1 fold-increase (90% CI)] of both liver [1.3 (1.1-1.5), P-value = 0.014] and non-liver [1.9 (1.6-2.2), P-value = 0.04] sEV CYP3A4 protein expression. In CYP3A5 non-expresser subjects, the baseline (pre-dose) 4βHC/C plasma ratio was more highly correlated with liver sEV (r = 0.937, P = 0.001) than non-liver sEV (r = 0.619, P-value = 0.101) CYP3A4 protein expression. When CYP3A5 expressers (CYP3A5*1/*3) were included, the correlation with liver sEV (r = 0.761, P-value = 0.011) and non-liver sEV (r = 0.391, P-value = 0.264) CYP3A4 protein was weaker. Although MOD-induced changes in plasma 4βHC/C ratio did not correlate with sEV CYP3A4 protein expression, the individual subject sEV proteomic data were used successfully to predict victim drug (midazolam, triazolam, dextromethorphan, 17α-ethinylestradiol, and abemaciclib) AUC (area under the plasma concentration-time curve) ratios (AUCR) following MOD. Based on the AUCR values, MOD was classified as a weak-to-moderate CYP3A4 inducer (versus rifampicin). For the first time, it was possible to deploy plasma-derived sEV to study CYP3A4 induction beyond rifampicin, a more potent CYP3A4 inducer.

PMID:34623637 | DOI:10.1002/cpt.2440

Int Ophthalmol. 2021 Oct 8. doi: 10.1007/s10792-021-02055-x. Online ahead of print.

ABSTRACT

PURPOSE: Neonatal retinal hemorrhage (RH) is a frequently occurring neonatal fundus condition and a very common ocular abnormality in neonates. Some of the key factors that influence the rate of RH are the mode of delivery, examination techniques, and time of examination after birth. The prognostic markers of severe RH are poorly known, making it difficult for an efficient diagnosis, prognosis, and treatment. Hence, to better understand the mechanism of disease, its study at the molecular level is required. Prognostic biomarkers are an essential tool for understanding the pathogenesis of the disease. In this paper, we present a meta-analysis of biomarkers to understand disease pathogenesis and support better diagnosis, prognosis, and treatment of neonatal RH.

METHODS: The meta-analysis was carried out by following the recommendation of PRISMA. The relevant articles were crawled using a systematic keyword using MeSH terms from the MEDLINE, PubMed, and Scopus databases, which were subjected to manual screening for reported biomarkers by two independent reviewers. The obtained biomarkers were further analyzed for gene-disease association and functional enrichment analysis.

RESULTS: Our meta-analysis suggests that genes ABCC6, Beta-APP, COL2A1, COL4A1, DNM2, ENPP1, IKBKG, ITGB2, IL-6, SELE, TREX1, and VEGFA are potential prognostic biomarkers associated with the neonatal RH. The gene-disease association and functional enrichment analysis suggest that few genes are associated with disease class "Vision"; however, some genes in the list are associated with the disease class "Pharmacogenomic," "Immune," "Renal."

CONCLUSION: The identified prognostic gene biomarkers may help to understand disease pathogenesis and provide a better diagnosis, prognosis, and treatment of neonatal RH.

PMID:34623569 | DOI:10.1007/s10792-021-02055-x

J Pharm Pract. 2021 Oct 8:8971900211049589. doi: 10.1177/08971900211049589. Online ahead of print.

ABSTRACT

ObjectiveThe study objective was to examine provider acceptance and genotyping responses to a best practice advisory (BPA) concerning clopidogrel and CYP2C19 intermediate and poor metabolizers within the context of a new pharmacogenomics program at a Midwestern health system. Other secondary objectives analyzed included appropriate BPA firing, the distribution of alleles in study population, indications for clopidogrel use, and impact of indication on therapy change. Methods: In this study, the progress of this program was assessed by quantifying how providers respond to BPAs generated in the electronic medical record (EMR), in the context of a single representative gene-drug-outcome relationship. Patient data was pulled via reports yielding patients with genotyped information in the EMR and cross-referenced with a report evaluating BPA firing occurrences. Results: By capturing antiplatelet therapy changes in response to CYP2C19 genotyping results, 37 patients were found that had 73 BPAs fire. Nine of those patients had alternative antiplatelet therapy ordered. Of these, 6 alternative antiplatelet therapies were ordered from the BPA. Conclusion: Providers utilized BPAs, but responded differently based on individual knowledge of genotypes and indications. Information obtained from this study can be used for provider education and as reference for future design and wording of BPAs.

PMID:34622701 | DOI:10.1177/08971900211049589

Transl Clin Pharmacol. 2021 Sep;29(3):135-149. doi: 10.12793/tcp.2021.29.e14. Epub 2021 Sep 2.

ABSTRACT

Genetic polymorphisms of enzymes and transporters associated with the absorption, distribution, metabolism, and elimination (ADME) of drugs are one of the major factors that contribute to interindividual variations in drug response. In the present study, we aimed to elucidate the pharmacogenetic profiles of the Korean population using the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET™) platform. A total of 1,012 whole blood samples collected from Korean subjects were genotyped using the DMET™ plus microarray. In total, 1,785 single nucleotide polymorphism (SNP) markers for 231 ADME genes were identified. The genotype and phenotype of 13 clinically important ADME genes implemented in the Clinical Pharmacogenetics Implementation Consortium guidelines were compared among different ethnic groups. Overall, the genotype frequencies of the Korean population were similar to those of the East Asian population. Several genes, notably CYP2C19 and VKORC1, showed marked differences in Koreans compared to Europeans (EURs) or Africans (AFRs). The percentage of CYP2C19 poor metabolizers was 15% in Koreans and less than 3% in EURs or AFRs. The frequencies of causative SNPs of the VKORC1 gene for the low warfarin dose phenotype were 90%, 60%, and 10% in Koreans, EURs and AFRs, respectively. Our findings can be utilized for optimal pharmacotherapy in Korean patients.

PMID:34621706 | PMC:PMC8492395 | DOI:10.12793/tcp.2021.29.e14

Transl Psychiatry. 2021 Oct 7;11(1):512. doi: 10.1038/s41398-021-01520-6.

NO ABSTRACT

PMID:34620835 | DOI:10.1038/s41398-021-01520-6

Transl Psychiatry. 2021 Oct 7;11(1):513. doi: 10.1038/s41398-021-01632-z.

ABSTRACT

Combination antidepressant pharmacotherapies are frequently used to treat major depressive disorder (MDD). However, there is no evidence that machine learning approaches combining multi-omics measures (e.g., genomics and plasma metabolomics) can achieve clinically meaningful predictions of outcomes to combination pharmacotherapy. This study examined data from 264 MDD outpatients treated with citalopram or escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) and 111 MDD outpatients treated with combination pharmacotherapies in the Combined Medications to Enhance Outcomes of Antidepressant Therapy (CO-MED) study to predict response to combination antidepressant therapies. To assess whether metabolomics with functionally validated single-nucleotide polymorphisms (SNPs) improves predictability over metabolomics alone, models were trained/tested with and without SNPs. Models trained with PGRN-AMPS' and CO-MED's escitalopram/citalopram patients predicted response in CO-MED's combination pharmacotherapy patients with accuracies of 76.6% (p < 0.01; AUC: 0.85) without and 77.5% (p < 0.01; AUC: 0.86) with SNPs. Then, models trained solely with PGRN-AMPS' escitalopram/citalopram patients predicted response in CO-MED's combination pharmacotherapy patients with accuracies of 75.3% (p < 0.05; AUC: 0.84) without and 77.5% (p < 0.01; AUC: 0.86) with SNPs, demonstrating cross-trial replication of predictions. Plasma hydroxylated sphingomyelins were prominent predictors of treatment outcomes. To explore the relationship between SNPs and hydroxylated sphingomyelins, we conducted multi-omics integration network analysis. Sphingomyelins clustered with SNPs and metabolites related to monoamine neurotransmission, suggesting a potential functional relationship. These results suggest that integrating specific metabolites and SNPs achieves accurate predictions of treatment response across classes of antidepressants. Finally, these results motivate functional investigation into how sphingomyelins might influence MDD pathophysiology, antidepressant response, or both.

PMID:34620827 | DOI:10.1038/s41398-021-01632-z

Neuron. 2021 Sep 28:S0896-6273(21)00683-8. doi: 10.1016/j.neuron.2021.09.011. Online ahead of print.

ABSTRACT

Psychiatric genomics is providing insights into the nature of psychiatric conditions that in time should identify new drug targets and improve patient care. Less attention has been paid to psychiatric pharmacogenomics research, despite its potential to deliver more rapid change in clinical practice and patient outcomes. The pharmacogenomics of treatment response encapsulates both pharmacokinetic ("what the body does to a drug") and pharmacodynamic ("what the drug does to the body") effects. Despite early optimism and substantial research in both these areas, they have to date made little impact on clinical management in psychiatry. A number of bottlenecks have hampered progress, including a lack of large-scale replication studies, inconsistencies in defining valid treatment outcomes across experiments, a failure to routinely incorporate adverse drug reactions and serum metabolite monitoring in study designs, and inadequate investment in the longitudinal data collections required to demonstrate clinical utility. Nonetheless, advances in genomics and health informatics present distinct opportunities for psychiatric pharmacogenomics to enter a new and productive phase of research discovery and translation.

PMID:34619094 | DOI:10.1016/j.neuron.2021.09.011

Perfusion. 2021 Oct 7:2676591211050606. doi: 10.1177/02676591211050606. Online ahead of print.

ABSTRACT

Procainamide is a useful agent for management of ventricular arrhythmia, however its disposition and appropriate dosing during extracorporeal membrane oxygenation (ECMO) is unknown. We report experience with continuous procainamide infusion in a critically ill adult requiring venoarterial ECMO for incessant ventricular tachycardia. Pharmacokinetic analysis of procainamide and its metabolite, N-acetylprocainamide (NAPA), was performed using serum and urine specimens. Kidney function was preserved, and sequencing of the N-acetyltransferase 2 gene revealed the patient was a phenotypic slow acetylator. Procainamide volume of distribution and half-life were calculated and found to be similar to healthy individuals. However, despite elevated serum procainamide concentrations, NAPA concentrations remained far lower in the serum and urine. The magnitude of procainamide and NAPA discordance suggested alternative contributors to the deranged pharmacokinetic profile, and we hypothesized NAPA sequestration by the ECMO circuit. Ultimately, the patient received orthotopic cardiac transplantation and was discharged home in stable condition. Procainamide should be used cautiously during ECMO, with close therapeutic drug monitoring of serum procainamide and NAPA concentrations. The achievement of therapeutic NAPA concentrations while maintaining safe serum procainamide concentrations during ECMO support may be challenging.

PMID:34617854 | DOI:10.1177/02676591211050606

Pharmacol Res Perspect. 2021 Oct;9(5):e00872. doi: 10.1002/prp2.872.

ABSTRACT

Elevation of hypoxia-inducible factor 1 protein has been shown to be protective in acute kidney injury and HIF1α enhancing drug therapies are currently in clinical trials for the treatment of anemia of chronic kidney disease. Despite its benefits, long-term HIF1 elevation seems to be associated with additional effects in the kidneys such as tubulointerstitial fibrosis. To better understand the effects of prolonged HIF1 exposure, assessment of baseline and post-therapy levels of HIF1α and other related biomarkers is essential. In this study, we assessed the effect of HIF1α enhancement using prolyl hydroxylase inhibitor (PHD-I) DMOG, on a key profibrotic marker of kidney disease. In specific, we examined the change in expression of Collagen 4 subunit A2 in cultured urinary cells of CKD patients pre and post 24-hour exposure to 1mM DMOG. Our results show that besides HIF1α enhancement, COL4A2 protein is suppressed in presence of DMOG. To determine if this effect is mediated by HIF1, we used HIF1α gene silencing in HEK293 cells and examined the effect of DMOG on protein and gene expression of COL4A2 post 24-hour exposure. We showed that silencing HIF1α reverses and amplifies the expression of COL4A2 in HEK293 cells. Our data suggest that HIF1 directly regulates the expression of COL4A2 in kidney cells and that HIF1α enhancing therapy has suppressive effects on COL4A2 that may be clinically relevant and must be considered in determining the safety and efficacy of these drugs in the treatment of anemia.

PMID:34617686 | DOI:10.1002/prp2.872