While prior studies have focused on the clinical utility of pharmacogenetic (PGx) testing, less is known about factors that influence physicians' continued use of PGx testing in routine practice. Using data from the PGx-SParK trial, we examined whether the actionability of PGx test results from a physician's initial referral predicted subsequent PGx referral behavior. Youth aged 6-24 years referred for PGx testing in Western Canada between October 2020 and November 2025 were included. For each physician, an index PGx referral was identified and linked to patient characteristics, testing turnaround time, and CYP2B6, CYP2C19, and CYP2D6 results. Actionability for psychotropic prescribing was defined based on current PGx guidelines and categorized as current, future, or none. The number of subsequent referrals per physician was modeled using generalized linear models with a Poisson distribution corrected for overdispersion and adjusted for follow-up time and relevant covariates. Among 371 physician index referrals, 90% of tested youth had at least one current (22%) or future (68%) actionable result. Over a mean follow-up of 29 months, 52% of physicians made at least one subsequent PGx referral. Neither current nor future actionability of the initial PGx test results was associated with subsequent referral behavior. However, patient age (older) and physician speciality (psychiatrists) were associated with greater odds of a subsequent referral. These findings suggest that sustained physician engagement with PGx testing in youth mental healthcare may be driven more by implementation context and physician-level factors than by the clinical actionability of test results.

Posaconazole is used to treat and prevent invasive fungal infections. Posaconazole metabolism is mediated by the uridine 5'-diphopho-glucuronosyltransferase (UGT) 1A4 enzyme; prior studies have suggested UGT1A4*3 contributes to low posaconazole exposure, while the impact of UGT1A4*2 is unclear. This study aimed to further understand the relationship between posaconazole exposure and UGT1A4 genotypes. Steady-state posaconazole plasma concentrations (PPCs) and demographics of patients who received the oral tablet formulation of posaconazole were collected, retrospectively, regardless of the patient's underlying diagnoses. UGT1A4 genotypes were obtained from the institutional research biorepository. The patients' dose-controlled PPCs, PPCs, and clinical PPC categorizations by institutional prophylaxis and treatment targets were analyzed among UGT1A4 genotypes. Breakthrough infection data were also collected in patients receiving posaconazole prophylaxis. A total of 103 patients were included, with 21 (20.3%) UGT1A4 *1/*3, 76 (73.7%) UGT1A4 *1/*1, and 6 (5.8%) UGT1A4 *1/*2. The dose-controlled PPCs [(ng/ml)/(mg/day)] were 3.63 (2.45-6.92) for UGT1A4 *1/*3, 5.07 (3.04-7.11) for *1/*1, and 4.92 (2.89-6.12) for *1/*2 (P = 0.62). Additionally, no statistically significant differences in median PPC or clinical PPC prophylaxis and treatment classifications were found among UGT1A4 genotypes. One UGT1A4 *1/*3 and two *1/*1 patients experienced possible breakthrough fungal infections. This study did not confirm the previously reported association between UGT1A4*3 and reduced posaconazole exposure and found no association with UGT1A4*2. Further studies are needed to determine the impact of homozygous UGT1A4 variants on posaconazole exposure.

Pharmacogenomics (PGx) is a scientific field that aims to understand how an individual's genetic code regulates drug metabolism and response. The response to many anesthetic drugs varies widely among patients due to many factors including, but not limited to, age, gender, and comorbidities. However, PGx contributes to this variability, particularly regarding adverse drug reactions. This review explores the influence of PGx on five commonly used induction agents in anesthesia: propofol, midazolam, ketamine, etomidate, and thiopental. Propofol metabolism is significantly affected by polymorphisms in CYP2B6, CYP2C9, and UGT1A9, influencing both efficacy and toxicity. Midazolam's PGx is mainly mediated by variations in CYP3A4, CYP3A5, and UDP-glucuronosyltransferase enzymes, with implications for sedation depth and drug clearance. Ketamine response is modulated by polymorphisms in metabolic enzymes (e.g. CYP2B6), as well as neurobiological targets such as brain-derived neurotrophic factor and gamma-aminobutyric acid (GABA) receptors, particularly in psychiatric applications. Etomidate shows less studied but emerging PGx associations, including single-nucleotide polymorphisms in GABA receptor subunits and metabolic enzymes, which may affect both sedative depth and cardiovascular stability. Thiopental is a rapid-acting metabolite whose effect stems from GABA-A receptor potentiation; no studies have yet identified specific genetic polymorphisms influencing its action. Overall, PGx provides a promising avenue for tailoring anesthetic management to improve patient safety and outcomes. However, clinical integration remains limited due to practical and infrastructural barriers. This review highlights the potential and current limitations of pharmacogenomic-guided anesthesia, underscoring its relevance in the era of precision medicine.

Evaluate the feasibility of implementing a multigene pharmacogenetic (PGx) test and genotype-guided pharmacist recommendations into gynecologic perioperative workflows and fidelity to pharmacist genotype-guided postoperative analgesic recommendations. A randomized, prospective, open-label pilot study was conducted in gynecologic patients undergoing abdominal surgery. Participants received multigene PGx testing and were randomized to the PGx-guided group where results were returned to the electronic health record with pharmacist genotype-guided postoperative analgesic recommendations or usual care. Primary outcomes included the proportion of PGx results and pharmacist recommendations completed before surgery, the number of prescriptions in alignment with pharmacist recommendations, and the proportion of analgesics prescribed differing from usual care. Of the 101 participants analyzed, all were female, 50 ± 14 years old, 49% were Black, 48% were White, 60% were treated by gynecologic oncology, and 76% underwent minimally invasive surgery. PGx results were returned to the genomics results portal a median of 7 (interquartile range: 6-9) business days after ordering the test. A majority (85%) of results were returned before the participant's surgery. Pharmacist genotype-guided analgesic recommendations were completed for 35 (73%) of the 48 participants in the PGx-guided group. And, 32 (91%) of the prescribed nonsteroidal anti-inflammatory drugs and 23 (66%) of the prescribed opioids matched the pharmacist's recommendations. Barriers included missed pharmacist notes when surgery dates were moved and low use of study-specific order set. PGx test results were available before most surgeries, but the pharmacist recommendations were not always followed. Enhanced implementation strategies will need to be developed in future genotype-guided protocols.

Warfarin has a narrow therapeutic window and large variability in dosing that are affected by clinical and genetic factors. To help guide the dosing of warfarin, the Clinical Pharmacogenetics Implementation Consortium has recommended the use of pharmacogenetic algorithms, such as the ones developed by the International Warfarin Pharmacogenetics Consortium (IWPC) and by Gage et al. when genotype information is available. In this study, simulations were performed in Chinese cohorts to explore how dosing differences between Western (by IWPC and Gage et al.) and Chinese algorithms (by Miao et al.) would mean in terms of anticoagulation effect in clinical trials. We first tried to replicate a published clinical trial comparing genotype-guided dosing to routine clinical dosing in Chinese patients. We then made simulations where Chinese cohorts received daily doses recommended by Gage, IWPC, and Miao algorithms. We found that in simulation conditions where dosing specifications were strictly followed, genotype-guided dosing by IWPC and Lenzini formulae was more likely to overshoot the upper limit of the therapeutic window by day 15, and thus may have a lower % time in therapeutic range (%TTR) than that of clinical dosing group. Also, in comparing Gage, IWPC, and Miao algorithms, we found that the Miao dosing cohort has the highest %TTR and the lowest risk of over-anticoagulation by day 28. In summary, our results confirmed that algorithms developed based on data from local patients may be more suitable for achieving therapeutic international normalized ratio window in Chinese population.

Tenofovir is a component of preferred combination antiretroviral therapy (ART) regimens in Africa. Few pharmacogenetic studies have been conducted on tenofovir exposure in Africa, where genetic diversity is greatest. We characterized the pharmacogenetics of plasma tenofovir clearance in Southern Africans receiving tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). Adults randomized to TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262) were studied. Linear regression models stratified by study arm examined associations with unexplained variability in tenofovir clearance. We investigated genetic associations with polymorphisms selected a priori followed by genome-wide associations. A total of 268 participants (138 and 130 in the TAF and TDF arm, respectively) were evaluable for associations. Among polymorphisms previously associated with any drug-related phenotype, IFNL4 rs12979860 was associated with more rapid tenofovir clearance in both arms (TAF: P = 0.003; TDF: P = 0.003). Genome-wide, the lowest P values for tenofovir clearance in TAF and TDF arms were LINC01684 rs9305223 (P = 3.0 × 10-8) and intergenic rs142693425 (P = 1.4 × 10-8), respectively. Among Southern Africans randomized to TAF or TDF in ADVANCE, unexplained variability in tenofovir clearance was associated with a polymorphism in IFNL4, an immune-response gene. It is unclear how this gene would affect tenofovir disposition.

Aspirin-exacerbated respiratory disease (AERD), an asthma phenotype, often presents with severe manifestations and it remains widely underdiagnosed because of insufficient awareness of the relationship between the ingestion of nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid (ASA), and asthma exacerbation. Our previous genome-wide association study demonstrated an association between a single nucleotide polymorphism (SNP) of the ATP8B3 gene and the risk of AERD. This study examined AERD-related SNPs of the ATP8B3 gene in a large population. Twenty-five SNPs of ATP8B3 were genotyped with the GoldenGate assay using VeraCode microbeads in 141 asthmatics with AERD and 995 Aspirin-tolerant asthma (ATA). The genotype distribution was analyzed using logistic regression models. The declines in forced expiratory volume in 1 second (FEV1)following an ASA challenge were compared among the genotypes and haplotypes using a type III generalized linear model. The minor allele frequencies (MAFs) of rs10421558 A>G in the 5'UTR and rs10403288 G>A in the intron were significantly lower in the AERD than the ATA [34.0% vs. 43.8%, OR = 0.66 (0.62-0.92), Pcorr = 0.03 and 28.4% vs. 35.4%, OR = 0.62 (0.59-0.89), Pcorr = 0.016, respectively]. BL1ht5 was significantly higher in the AERD [7.6% vs. 1.6%, OR = 12.23 (0.2-0.51), P = 4.7 × 10 -4 , Pcorr = 0.001]. Among them, rs10421558 A>G and BL1ht5 were associated with the percent decline in FEV1 on the oral ASA challenge test. The minor allele of rs10421558 A>G in the 5'UTR may protect against the development of AERD via the increased production of ATP8B3.

The main objective of this study was to evaluate the effect of CYP2B6 and CYP3A4 polymorphisms on the virological and immunologic responses of HIV patients. A total of 153 HIV-positive patients were enlisted for the study. Viral load and median CD4 T cell counts were evaluated at baseline and month 6 (M6). Samples were identified using TaqMan genotyping assays. The AG in CYP2B6 rs2279343 was associated with VLS compared to homozygous AA. In the dominant model, the AG/GG genotypes were associated with VLS compared to the AA genotype. Moreover, in overdominant model, the AG genotype was associated with VLS compared to AA/GG. Regarding immunological response, only the AG in SNP rs2279343 CYP2B6 was associated with an increase in CD4 cell count between baseline and M6. In CYP2B6 rs3745274, the CD4 cell count at M6 was higher than that of baseline for GG carriers and for GT carriers. In CYP3A4 rs2740574, the TC carriers showed a higher median CD4 count at M6 compared to that of the baseline count, as well as for CC carriers. The best genotypes combination associated with CD4 cell count improvement were AA/AG in SNP rs2279343 and GG/GT in SNP rs3745274. Our findings support the fact that CYP2B6 rs2279343 could help in the prediction of VLS and both SNPs rs3745274 and rs2279343 in CYP2B6 and CYP3A4 rs2740574 were associated with immune recovery in Malian HIV-positive patients.

ObjectiveGut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria.MethodsFecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis.ResultsSignificantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor = -0.52, P = 8 × 10−5 for Megamonsa). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity.ConclusionsMicrobiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.