Adv Pharmacol. 2022;95:49-72. doi: 10.1016/bs.apha.2022.05.001. Epub 2022 Jul 20.

ABSTRACT

With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across almost all isoforms. This article is concerned mainly with 13 P450 isoforms of particular relevance to xenobiotic metabolism. After brief review of the extent of polymorphism in each, the relevance of selected P450 isoforms to both adverse drug reaction and disease susceptibility is considered in detail. Bleeding due to warfarin and other coumarin anticoagulants is considered as an example of a type A reaction with idiosyncratic adverse drug reactions affecting the liver and skin as type B. It is clear that CYP2C9 variants contribute significantly to warfarin dose requirement and also risk of bleeding, with a minor contribution from CYP4F2. In the case of idiosyncratic adverse drug reactions, CYP2B6 variants appear relevant to both liver and skin reactions to several drugs with CYP2C9 variants also relevant to phenytoin-related skin rash. The relevance of P450 genotype to disease susceptibility is also considered but detailed genetic studies now suggest that CYP2A6 is the only P450 relevant to risk of lung cancer with alleles associated with low or absent activity clearly protective against disease. Other cytochrome P450 genotypes are generally not predictors for risk of cancer or other complex disease development.

PMID:35953163 | DOI:10.1016/bs.apha.2022.05.001

Adv Pharmacol. 2022;95:393-416. doi: 10.1016/bs.apha.2022.04.004. Epub 2022 Jul 18.

ABSTRACT

The cytochromes P450s can be divided in two groups, those of high importance for endogenous functions being evolutionary quite stable and those participating in detoxification of drugs and other xenobiotics having less important endogenous functions. In the latter group extensive genetic diversity has been allowed and in addition this is of high importance for survival in different environments. The genetic polymorphisms in these genes have evolved to some extent based on dietary restrictions and environmental factors and have not been subject of conservation due to less importance for survival. In cases of high dietary selection events, gene multiplication and amplification events have been seen. The different variants in genes encoding drug metabolizing enzymes can be used as genetic biomarkers (pharmacogenomic labels) for adjustment of drug treatment leading to less adverse drug reactions and better response. Indeed, this has improved the use of personalized medicine, although the missing heredity seen based on twin studies indicates that there are indeed many more genetic variants to be discovered before one can achieve a satisfactory relationship between genotype and phenotype with respect to drug metabolism and toxicity.

PMID:35953162 | DOI:10.1016/bs.apha.2022.04.004

Adv Pharmacol. 2022;95:365-391. doi: 10.1016/bs.apha.2022.05.006. Epub 2022 Jul 19.

ABSTRACT

Cytochrome P450 enzymes play an important role in the pharmacokinetics, efficacy, and toxicity of drugs. Age-dependent changes in P450 enzyme expression have been studied based on several detection systems, as well as by deconvolution of in vivo pharmacokinetic data observed in pediatric populations. The age-dependent changes in P450 enzyme expression can be important determinants of drug disposition in childhood, in addition to the changes in body size and the other physiological parameters, and effects of pharmacogenetics and disease on organ functions. As a tool incorporating drug-specific and body-specific factors, physiologically-based pharmacokinetic (PBPK) models have become increasingly used to characterize and explore mechanistic insights into drug disposition. Thus, PBPK models can be a bridge between findings from basic science and utilization in predictive science. Pediatric PBPK models incorporate additional system specific information on developmental physiology and ontogeny and have been used to predict pharmacokinetic parameters from preterm neonates onwards. These models have been advocated by regulatory authorities in order to support pediatric clinical trials. The purpose of this chapter is to highlight accumulated knowledge and findings from basic research focusing on P450 enzymes, as well as the current status and future challenges of expanding the utilization of pediatric PBPK modeling.

PMID:35953161 | DOI:10.1016/bs.apha.2022.05.006

J Psychiatr Res. 2022 Jul 31;154:209-218. doi: 10.1016/j.jpsychires.2022.07.049. Online ahead of print.

ABSTRACT

OBJECTIVE: Canada exhibits one of highest lifetime prevalence for post-traumatic stress disorder (PTSD), but the etiology of this debilitating mental health condition still remains largely unknown. This study aims to examine the genetics of PTSD in the Canadian Longitudinal Study on Aging (CLSA) to identify potential genetic factors involved in the development of PTSD.

METHOD: The CLSA sample was screened for primary (PTSD status) and secondary outcomes (avoidance, detachment, guardedness, and nightmares) based on the Primary Care PTSD Screen Scale (PC-PTSD). After GWAS quality control and whole-genome imputation, single-marker, gene-based, and polygenic risk score (PRS) analyses were performed.

RESULTS: Based on available genotype and phenotype data, N = 16,535 individuals were selected for the analyses. While genome-wide analyses did not show significant findings for our primary and secondary outcomes, PRS analyses showed variable levels of association between PC-PTSD items with trauma, major depressive disorder, schizophrenia, bipolar disorder, educational attainment, and insomnia (p < 5e-4).

CONCLUSION: This is the first GWAS of PTSD status and individual PC-PTSD items in a population sample of older adults from Canada. This study was also able to replicate findings from previous studies. Genetic investigations into individual symptom components of PTSD may help untangle the complex genetic architecture of PTSD.

PMID:35952521 | DOI:10.1016/j.jpsychires.2022.07.049

Health Sci Rep. 2022 Aug 8;5(5):e762. doi: 10.1002/hsr2.762. eCollection 2022 Sep.

ABSTRACT

BACKGROUND AND AIMS: Vitamin C has been predicted to be effective as an antioxidant in treating various ailments, including viral infections such as pervasive coronavirus disease (COVID-19). With this meta-analysis, we looked to ascertain the relationship between high-dose vitamin C administration and mortality, severity, and length of hospitalization of COVID-19 patients.

METHODS: We collected articles from PubMed, Google Scholar, ScienceDirect, SAGE, and Cochrane databases between January 1, 2020, and May 30, 2022. Odds ratio (ORs) with corresponding 95% confidence interval (CI) and p value were calculated to assess the connection of high-dose vitamin C in COVID-19 patients' mortality and severity. The length of hospitalization was calculated and pooled with the mean difference (MD), 95% CI, and p value. Review manager 5.3 was used to carry out this meta-analysis.

RESULTS: This meta-analysis included 15 complete studies involving 2125 COVID-19 patients. Our study demonstrated a significant correlation between vitamin C consumption and death. Vitamin C consumption significantly reduces mortality risk with COVID-19 patients (OR = 0.54, 95% CI = 0.42-0.69, p < 0.00001). Furthermore, there was a link between the severity of COVID-19 and the intake of vitamin C. Patients who consumed vitamin C showed 0.63 times less severity than those who did not take vitamin C (OR = 0.63, 95% CI = 0.43-0.94, p = 0.02). Patients taking vitamin C spent slightly more time in hospital than those who did not take vitamin C (MD = 0.19, 95% CI = -1.57 to 1.96, p = 0.83).

CONCLUSIONS: During COVID-19, there was a substantial advantage in taking supplementary vitamin C, at least in terms of severity and mortality.

PMID:35949675 | PMC:PMC9358542 | DOI:10.1002/hsr2.762

Exp Ther Med. 2022 Jul 19;24(3):584. doi: 10.3892/etm.2022.11521. eCollection 2022 Sep.

ABSTRACT

Vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) have been investigated over the past years with the aim of identifying any association with the development of Alzheimer's disease (AD). However, information regarding the potential association of VDR SNP haplotypes with AD is limited. The aim of the present study was to provide additional knowledge on the effects of VDR haplotypes on the development of late-onset AD in a cohort of Southeastern European Caucasians (SECs). The study sample included 78 patients with late-onset AD and 103 healthy subjects as the control group. VDR SNPs that were analyzed were TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570). The CAC (TaqI, BsmI and FokI) haplotype was found to be associated with a 53% lower risk of developing the disease (OR, 0.47; 95% CI, 0.23-0.96; P=0.04) and the TAC (TaqI, BsmI and FokI) haplotype was associated with an ~6-fold greater risk of developing AD (OR, 6.19; 95% CI, 1.91-20.13; P=0.0028). Female subjects carrying the TAC haplotype had a ~9-fold greater risk of developing AD in comparison to female control subjects (OR, 9.27; 95% CI, 1.86-46.28; P<0.05). The TaqI and BsmI polymorphisms were in high linkage disequilibrium (D'=0.9717, r=0.8467) and produced a haplotype with a statistically significant different frequency between the control and AD group. The TA (TaqI and BsmI) haplotype was associated with an ~8-fold greater risk of developing AD (OR, 8.27; 95% CI, 2.70-25.28; P<0.05). Female TA carriers had an ~14-fold greater risk of developing the disease in comparison to female control subjects (OR, 13.93; 95% CI, 2.95-65.87; P<0.05). On the whole, the present study demonstrates that in the SEC population, TAC and TA are risk haplotypes for AD, while the CAC haplotype may act protectively. SEC women carrying the TAC or TA haplotype are at a greater risk of developing AD, thus suggesting that women are markedly affected by the poor utilization of vitamin D induced by the VDR haplotype.

PMID:35949319 | PMC:PMC9353461 | DOI:10.3892/etm.2022.11521

Pediatr Pulmonol. 2022 Aug 10. doi: 10.1002/ppul.26109. Online ahead of print.

ABSTRACT

BACKGROUND: Mannose binding lectin (MBL) is an important component of the innate immune system. Polymorphisms in the MBL2 gene and promoter region are directly associated with MBL-deficiency. We sought to determine the association between MBL genotype on the frequency of common childhood respiratory infections, respiratory symptoms, and atopic outcomes in early childhood.

METHODS: MBL2 gene variants were analysed in newborns recruited to the GO-CHILD multi-centre prospective cohort study. Follow-up for respiratory infection and atopy diagnoses and symptoms, healthcare utilisation and medication prescription were conducted by postal questionnaires at 12 and 24-months.

RESULTS: Genotyping and follow-up were completed in 1004 children. Genotypes associated with MBL-deficiency were associated with an increased risk of bronchiolitis (relative risk (RR) 1.95, 95%CI 1.33-2.85)) and pneumonia (RR 2.46, 95%CI 1.16-5.22). MBL-deficient genotypes were associated with an increased risk of wheeze with shortness of breath episodes (RR 1.22, 95%CI 1.04-1.43), emergency department attendance (RR 1.90 95%CI 1.13-3.19) and hospital admission (RR 2.01, 95%CI 1.04-3.89) for wheeze. MBL-deficient genotypes were associated with a reduced risk of developing atopic dermatitis (RR 0.72, 95%CI 0.53-0.98).

CONCLUSION: The positive association between MBL-deficient genotypes and bronchiolitis and pneumonia, as well as a severe wheeze phenotype in some young children, supports the hypothesis that MBL is an important component of innate immunity in the vulnerable period prior to the maturation of the adaptive immune system. Identification of disease modifying genotypes may help target preventative strategies in high-risk infants. This article is protected by copyright. All rights reserved.

PMID:35949104 | DOI:10.1002/ppul.26109

J Clin Pharmacol. 2022 Aug 9. doi: 10.1002/jcph.2138. Online ahead of print.

ABSTRACT

The susceptibility of different individuals to anesthetics varies widely, and sevoflurane is no exception. We hypothesized that polymorphisms in genes involved in pharmacokinetics and pharmacodynamics may explain this variation. One hundred fifty-one individuals undergoing otorhinolaryngology surgery were included. The influence of genetic polymorphisms on sevoflurane sensitivity were investigated through SNaPshot technology. Individuals carrying KCNK2 rs6686529 G > C, MTRR rs3733784 TT, rs2307116 GG, or rs1801394 AA polymorphisms had a higher sensitivity to the sedative effect of sevoflurane than those without those polymorphisms. The univariate linear regression analysis indicated that MTRR rs3733784 TT, rs2307116 GG and rs1801394 AA were potentially significant predictors of higher sensitivity to the sedative effect of sevoflurane. Moreover, CYP2E1 rs3813867 G > C and rs2031920 C > T, GABRG1 rs279858 T > C, KCNK3 rs1275988 CC, GRIN2B rs1806201 GG, MTRR rs2307116 G > A and rs1801394 A > G were associated with a higher sensitivity to the cardiovascular effect of sevoflurane. Our results suggested that nine SNPs in genes involved in metabolizing enzymes, transport proteins, target proteins of sevoflurane and folate metabolism may help to explain individual differences in the susceptibility to the sedative or cardiovascular effect of sevoflurane. This article is protected by copyright. All rights reserved.

PMID:35943164 | DOI:10.1002/jcph.2138

Br J Clin Pharmacol. 2022 Aug 9. doi: 10.1111/bcp.15485. Online ahead of print.

ABSTRACT

AIMS: The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.

METHODS: We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n=159) and a cohort of previously published studies (n=88).

RESULTS: In the genome-wide association meta-analysis of a prospective study and a cohort of previously published studies with rosuvastatin pharmacokinetic data, the SLCO1B1 c.521T>C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax ) of rosuvastatin (P=1.8×10-12 and P=3.2×10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C>A (rs2231142) SNV associates with increased rosuvastatin AUC (P=0.0079), while the SLCO1B1 c.388A>G (rs2306283) and SLCO2B1 c.1457C>T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P=0.0041 and P=0.0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased, and highly increased OATP1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P=4.69×10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16%-62%; P=0.019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P=2.6×10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P=0.01).

CONCLUSIONS: These data suggest roles for SLCO1B1, ABCG2, and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.

PMID:35942816 | DOI:10.1111/bcp.15485

Front Pharmacol. 2022 Jul 22;13:897951. doi: 10.3389/fphar.2022.897951. eCollection 2022.

ABSTRACT

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug-drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients' plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment.

PMID:35942220 | PMC:PMC9356076 | DOI:10.3389/fphar.2022.897951

Tuberculosis (Edinb). 2022 Jul 16;136:102233. doi: 10.1016/j.tube.2022.102233. Online ahead of print.

ABSTRACT

Single nucleotide polymorphisms (SNPs) in IRGM are reported to affect Mycobacterium tuberculosis (M.tb) degradation pathway. Here, we aim to screen promoter-region regulatory SNPs of IRGM in Pakistani population. DNA extracted from blood of cohort containing 70 TB patients (TB) and 30 controls subjects (Ctrl), was amplified for IRGM promoter region, followed by DNA sequencing. Group-specific variations were found in allelic frequencies at four loci. Allele T (p-value = 0.03) at -1161T/C, allele G (p-value = 0.027) at -1133G/A; allele C (p-value = 0.029) at -1049C/T; and allele G (p-value = 0.02) at -708G/A, showed higher associations with TB in our cohort. These SNPs display strong linkage disequilibrium (LD) in Pakistani population. Haplotype analysis showed a significant association of haplotype -1161T/-1133G/-1049C/-708G (p-value = 0.007) to TB. This 4-SNP haplotype also represents an expression quantitative trait locus (eQTL), associated with Crohn's disease and chronic inflammatory diseases. Our findings show that variants -1161T/C, -1133G/A, -1049C/T, and -708G/A are associated with IRGM expression and susceptibility to TB in a Pakistani population.

PMID:35939988 | DOI:10.1016/j.tube.2022.102233

ACS Chem Biol. 2022 Aug 8. doi: 10.1021/acschembio.2c00409. Online ahead of print.

ABSTRACT

Receptor tyrosine kinases are involved in essential signaling roles that impact cell growth, differentiation, and proliferation. The overexpression or mutation of these proteins can lead to aberrant signaling that has been directly linked to a number of diseases including cancer cell formation and progression. This has led to intense clinical focus on modulating RTK activity through direct targeting of signaling activity or cell types harboring aberrant RTK behavior. In particular, epidermal growth factor receptor (EGFR) has attracted intense clinical attention due to the impact of inhibiting this RTK on tumor growth. However, mutations incurred through targeting EGFR have led to therapeutic resistance that involves not only direct mutations to the EGFR protein but also the involvement of other RTKs, such as c-MET, that can overcome therapeutic-based EGFR inhibition effects. This has, not surprisingly, led to co-targeting strategies of RTKs such as EGFR and c-MET to overcome resistance mechanisms. While the ability to co-target these proteins has led to success in the clinic, a more comprehensive understanding of their proximal environments, particularly in the context of therapeutic modalities, could further enhance both our understanding of their signaling biology and provide additional avenues for targeting these surface proteins. Thus, to investigate EGFR and c-MET protein microenvironments, we utilized our recently developed iridium photocatalyst-based microenvironment mapping technology to catalog EGFR and c-MET surface environments on non-small cell lung cancer cell lines. Through this approach, we enriched EGFR and c-MET from the cell surface and identified known EGFR and c-MET associators as well as previously unidentified proximal proteins.

PMID:35939534 | DOI:10.1021/acschembio.2c00409

Br J Clin Pharmacol. 2022 Aug 8. doi: 10.1111/bcp.15480. Online ahead of print.

ABSTRACT

AIM: Propofol and opioids are commonly used in anaesthesia, but are highly susceptible to hemodynamic instability, thereby threatening the patient's surgical safety and prognosis. The purpose of this study was to investigate the predictors of haemodynamic instability and establish its predictive model.

METHODS: A total of 150 Chinese patients undergoing thyroid or breast surgery participated in the study, with target-controlled infusion concentrations of propofol, opioids dosage, heart rate (HR), mean arterial pressure (MAP), and Narcotrend Index recorded at key points throughout the procedure. The Agena MassARRAY system was used to genotype candidate single nucleotide polymorphisms (SNPs) related to pharmacodynamics and pharmacokinetics of propofol and opioids.

RESULTS: Among non-genetic factors, baseline HR (r=-0.579, P<0.001) and baseline MAP (r=-0.725, P<0.001) had a significant effect on the haemodynamic instability. Among genetic factors, the CT/CC genotype of GABRB1 rs4694846 (95%CI: -11.309 to -3.155), AA/AG of OPRM1 rs1799971 (95%CI: 0.773 to 10.290), AA of CES2 rs8192925 (95%CI: 1.842 to 9.090) were associated with higher HR instability; the AA/GG genotype of NR1I2 rs6438550 (95%CI: 0.351 to 7.761), AA of BDNF rs2049046 (95%CI: -9.039 to -0.640), and GG of GABBR2 rs1167768 (95%CI: -10.146 to -1.740) were associated with higher MAP instability. The predictive models of HR and MAP fluctuations were developed, accounting for 45.0% and 59.2% of variations, respectively.

CONCLUSION: We found that cardiovascular fundamentals and genetic variants of GABRB1, GABBR2, OPRM1, BDNF, CES2, NR1I2 are associated with cardiovascular susceptibility, which can provide a reference for haemodynamic management in clinical anaesthesia.

PMID:35939394 | DOI:10.1111/bcp.15480

Pharmacogenomics. 2022 Aug 8. doi: 10.2217/pgs-2022-0057. Online ahead of print.

ABSTRACT

Precision medicine is a medical model that proposes the customization of medical treatments to the individual patient, as opposed to a one-drug-fits-all model. Such a "personalized medicine" approach has been widely adopted in several medical fields, such as cancer medicine, but the implementation of precision medicine in cardiovascular medicine has not been similarly straightforward. Because pharmacogenomics plays an important role in the safety and efficacy of cardiovascular drug therapy, there has been a great interest in the use of tools aiming at personalizing antiplatelet therapy. Moreover, antiplatelet therapy is essential for the treatment of cardiovascular patients to reduce the risk of thrombotic complications, particularly those undergoing percutaneous coronary intervention, but it is inevitably associated with increased bleeding risk. In this review, the authors discuss the rationale, summarize the evidence and discuss the current and future directions for the personalization of antiplatelet treatment regimens in patients undergoing percutaneous coronary intervention.

PMID:35938534 | DOI:10.2217/pgs-2022-0057

Front Pharmacol. 2022 Jul 22;13:956397. doi: 10.3389/fphar.2022.956397. eCollection 2022.

ABSTRACT

Immunoglobulin A vasculitis (IgAV) nephritis, also known as Henoch-Schönlein purpura nephritis (HSPN), is a condition in which small blood vessel inflammation and perivascular IgA deposition in the kidney caused by neutrophil activation, which more often leads to chronic kidney disease and accounts for 1%-2% of children with end-stage renal disease (ESRD). The treatment principles recommended by the current management guidelines include general drug treatment, support measures and prevention of sequelae, among which the therapeutic drugs include corticosteroids, immunosuppressive agents and angiotensin system inhibitors. However, the concentration range of immunosuppressive therapy is narrow and the individualized difference is large, and the use of corticosteroids does not seem to improve the persistent nephropathy and prognosis of children with IgAV. Therefore, individualized maintenance treatment of the disease and stable renal prognosis are still difficult problems. Genetic information helps to predict drug response in advance. It has been proved that most gene polymorphisms of cytochrome oxidase P450 and drug transporter can affect drug efficacy and adverse reactions (ADR). Drug therapy based on genetics and pharmacogenomics is beneficial to providing safer and more effective treatment for children. Based on the pathogenesis of IgAV, this paper summarizes the current therapeutic drugs, explores potential therapeutic drugs, and focuses on the therapeutic significance of corticosteroids and immunosuppressants in children with IgAV nephritis at the level of pharmacogenomics. In addition, the individualized application of corticosteroids and immunosuppressants in children with different genotypes was analyzed, in order to provide a more comprehensive reference for the individualized treatment of IgAV nephritis in children.

PMID:35935867 | PMC:PMC9355498 | DOI:10.3389/fphar.2022.956397

Pharmacol Rep. 2022 Aug 6. doi: 10.1007/s43440-022-00400-0. Online ahead of print.

ABSTRACT

BACKGROUND: Nateglinide is a meglitinide used for the treatment of type 2 diabetes mellitus. Individual studies demonstrated the association of CYP2C9, SLCO1B1, and MTNR1B variants with the safety and efficacy of nateglinide. The current study aimed to develop a pharmacogenomic algorithm to optimize nateglinide therapy.

METHODS: Multiple linear regression (MLR) and classification and regression tree (CART) were used to develop a pharmacogenomic algorithm for nateglinide dosing based on the published nateglinide pharmacokinetic data on the area under the curve data (AUC) and Cmax (n = 143). CYP2C9 metabolizer phenotype, SLCO1B1, MTNR1B genotypes, and CYP2C9 inhibitor usage were used as the input variables. The results and associations were further confirmed by meta-analysis and in silico studies.

RESULTS: The MLR models of AUC and Cmax explain 87.4% and 59% variability in nateglinide pharmacokinetics. The Bland and Altman analysis of the nateglinide dose predicted by these two MLR models showed a bias of ± 26.28 mg/meal. The CART algorithm was proposed based on these findings. This model is further justified by the meta-analysis showing increased AUCs in CYP2C9 intermediate metabolizers and SLCOB1 TC and CC genotypes compared to the wild genotypes. The increased AUC in SLCO1B1 mutants is due to decreased binding affinity of nateglinide to the mutant affecting the influx of nateglinide into hepatocytes. MTNR1B rs10830963 G-allele-mediated poor response to nateglinide is attributed to increased transcriptional factor binding causing decreased insulin secretion.

CONCLUSION: CYP2C9, SLCO1B1, and MTNR1B genotyping help in optimizing nateglinide therapy based on this algorithm and ensuring safety and efficacy.

PMID:35932448 | DOI:10.1007/s43440-022-00400-0

Transl Psychiatry. 2022 Aug 5;12(1):316. doi: 10.1038/s41398-022-02091-w.

ABSTRACT

Given controversial findings of reduced depressive symptom severity and increased hippocampus volume in CYP2C19 poor metabolizers, we sought to provide empirical evidence from a large-scale single-center longitudinal cohort in the community-dwelling adult population-Colaus|PsyCoLaus in Lausanne, Switzerland (n = 4152). We looked for CYP2C19 genotype-related behavioral and brain anatomy patterns using a comprehensive set of psychometry, water diffusion- and relaxometry-based magnetic resonance imaging (MRI) data (BrainLaus, n = 1187). Our statistical models tested for differential associations between poor metabolizer and other metabolizer status with imaging-derived indices of brain volume and tissue properties that explain individuals' current and lifetime mood characteristics. The observed association between CYP2C19 genotype and lifetime affective status showing higher functioning scores in poor metabolizers, was mainly driven by female participants (ß = 3.9, p = 0.010). There was no difference in total hippocampus volume between poor metabolizer and other metabolizer, though there was higher subiculum volume in the right hippocampus of poor metabolizers (ß = 0.03, pFDRcorrected = 0.036). Our study supports the notion of association between mood phenotype and CYP2C19 genotype, however, finds no evidence for concomitant hippocampus volume differences, with the exception of the right subiculum.

PMID:35931695 | DOI:10.1038/s41398-022-02091-w

Trends Cell Biol. 2022 Aug 2:S0962-8924(22)00149-0. doi: 10.1016/j.tcb.2022.06.010. Online ahead of print.

ABSTRACT

Pharmacology-based methods that promote antitumor immunity have the potential to be highly efficacious while avoiding the systemic cytotoxicity associated with traditional chemotherapies. Activation of type I interferon (IFN) signaling in antigen-presenting cell types [e.g., macrophages and dendritic cells (DCs)] is critical, if not essential, for inducing a tumor-specific adaptive immune response, including the activation of cytolytic CD8 T cells. In the context of promoting antitumor immunity, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway has emerged as a principal regulator of essential type I IFN signaling. As such, STING represents a highly attractive target for developing a first-in-class immunotherapy, albeit one with a potential for significant cell type- and downstream pathway-dependent on-target toxicities, as well as conceivable pharmacogenomic liabilities.

PMID:35931610 | DOI:10.1016/j.tcb.2022.06.010

J Mol Diagn. 2022 Aug 2:S1525-1578(22)00194-5. doi: 10.1016/j.jmoldx.2022.06.007. Online ahead of print.

ABSTRACT

The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles ("Tier 1") and an extended panel of variant alleles ("Tier 2") that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document will focus on clinical TPMT and NUDT15 PGx testing that may be applied to all TPMT and NUDT15-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide.

PMID:35931343 | DOI:10.1016/j.jmoldx.2022.06.007

Clin Drug Investig. 2022 Aug 5. doi: 10.1007/s40261-022-01182-2. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Major depressive disorder (MDD) is a common and severe psychiatric disorder that has enormous economical and societal costs. As pharmacogenetics is one of the key tools of precision psychiatry, we analyze the cost-utility of test screening of CYP2C19 and CYP2D6 for patients suffering from major depressive disorder (MDD) and try to understand the main drivers that influence the cost-utility.

METHODS: We developed two pharmacoeconomic nonhomogeneous Markov models to test the cost-utility, from an Italian societal perspective, of pharmacogenetic testing genetic to characterize the metabolizing profiles of cytochrome P450 (CYP) 2C19 and CYP2D6 in a hypothetical case study of patients suffering from major depressive disorder (MDD). The model considers different scenarios of adjustment of antidepressant treatment according to the patient's metabolizing profile or treatment over a period of 18 weeks. The uncertainty of model parameters is tested through both a probabilistic sensitivity analysis and a one-way deterministic sensitivity analysis, and these results are used in a post-hoc analysis to understand the main drivers of three alternative cost-effectiveness levels ("poor," "standard," and "high"). These drivers are first evaluated from an exploratory multidimensional perspective and next from a predictive perspective as the probability that a patient belongs to a specific cost-effectiveness level is estimated on the basis of a restricted set of parameters used in the original pharmacoeconomic model.

RESULTS: The models for CYP2C19 and CYP2D6 indicate that screening has an incremental cost-effectiveness ratio of 60,000€ and 47,000€ per quality-adjusted life year (QALY), respectively. The probabilistic sensitivity analysis shows that the treatments are cost-effective for a 75,000€ willingness to pay (WTP) threshold in 58% and 63% of the Monte Carlo replications, respectively. The post-hoc analysis highlights the factors that allow us to clearly discriminates poor cost-effectiveness from high cost-effectiveness scenarios and demonstrates that it is possible to predict with reasonable accuracy the cost-effectiveness of a genetic test and the associated therapeutic pattern.

CONCLUSIONS: Our findings suggest that screenings for both CYP2C19 and CYP2D6 enzymes for patients with MDD are cost-effective for a WTP threshold of 75,000€ per QALY, and provide relevant suggestions about the most important aspects to be further explored in clinical studies aimed at addressing the cost-effectiveness of genetic testing for patients diagnosed with MDD.

PMID:35930170 | DOI:10.1007/s40261-022-01182-2