Metabolism. 2022 Nov 11:155346. doi: 10.1016/j.metabol.2022.155346. Online ahead of print.

ABSTRACT

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes in response to GLP-1RA (liraglutide) therapy vs. placebo and in comparison to bariatric surgery.

METHODS: Three clinical studies were conducted: a bariatric surgery cohort study of participants with morbid obesity who underwent either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) studied over four and twelve weeks, and two randomized placebo-controlled, crossover double blind studies of liraglutide vs. placebo administration in participants with type 2 diabetes (T2D) and participants with obesity studied for three and five weeks, respectively. Nuclear magnetic resonance spectroscopy-derived metabolomic data were assessed in all eligible participants who completed all the scheduled in-clinic visits. The primary outcome of the study was to explore the changes of the metabolome among participants with obesity with and without T2D receiving the GLP-1RA liraglutide vs. placebo and participants with obesity undergoing bariatric surgery during the three to five-week study period. In addition, we assessed the bariatric surgery effects longitudinally over the twelve weeks of the study and the differences between the bariatric surgery subgroups on the metabolome. The trials are registered with ClinicalTrials.gov, numbers NCT03851874, NCT01562678 and NCT02944500.

RESULTS: Bariatric surgery had a more pronounced effect on weight and body mass index reduction (-14.19 ± 5.27 kg and - 5.19 ± 5.27, respectively, p < 0.001 for both) and resulted in more pronounced metabolomic and lipidomic changes compared to liraglutide therapy at four weeks postoperatively. Significant changes were observed in lipoprotein parameters, inflammatory markers, ketone bodies, citrate, and branched-chain amino acids after the first three to five weeks of intervention. After adjusting for the amount of weight loss, a significant difference among the study groups remained only for acetoacetate, β-hydroxybutyrate, and citrate (p < 0.05 after FDR correction). Glucose levels were significantly reduced in all intervention groups but mainly in the T2D group receiving GLP-1RA treatment. After adjusting for weight loss, only glucose levels remained significant (p = 0.001 after FDR correction), mainly due to the glucose change in the T2D group receiving GLP-1RA. Similar results with those observed at four weeks were observed in the surgical group when delta changes at twelve weeks were assessed. Comparing the two types of bariatric surgery, an intervention effect was more pronounced in the RYGB subgroup regarding total triglycerides, triglyceride-rich lipoprotein size, and trimethylamine-N-oxide (p for intervention: 0.031, 0.028, 0.036, respectively). However, after applying FDR correction, these changes deemed to be only suggestive; only time effects remained significant with no significant changes persisting in relation to the types of bariatric surgery.

CONCLUSIONS: The results of this study suggest that the early metabolomic, lipid and lipoprotein changes observed between liraglutide treatment and bariatric surgery are similar and result largely from the changes in patients' body weight. Specific changes observed in the short-term post-surgical period between bariatric vs. nonsurgical treated participants, i.e., acetoacetate, β-hydroxybutyrate, and citrate changes, may reflect changes in patient diets and calorie intake indicating potential calorie and diet-driven metabolomics/lipidomic effects in the short-term postoperatively. Significant differences observed between SG and RYGB need to be confirmed and extended by future studies.

PMID:36375643 | DOI:10.1016/j.metabol.2022.155346

Am J Manag Care. 2022 Nov;28(11):566-571. doi: 10.37765/ajmc.2022.89259.

ABSTRACT

OBJECTIVES: Drug-drug interactions (DDIs) are among the most common causes of adverse drug reactions and are further complicated by genetic variants of drug-metabolizing enzymes. The aim of this study is to quantify and describe potential DDIs, drug-gene interactions (DGIs), and drug-drug-gene interactions (DDGIs) in a community-based population.

STUDY DESIGN: This was an analysis of deidentified retail pharmacy prescription data for 4761 individuals.

METHODS: Data were first assessed for DDIs, and individuals were stratified to a risk category using the logic of a commercially available digital DDGI tool. To calculate the frequency of potential DGIs and DDGIs, genotypes were imputed and randomly allocated to the cohort 100 times via Monte Carlo simulation according to each variant's frequency in the general population.

RESULTS: The probability of a DDI of any impact was 26.0% and increased to 49.6% (95% CI, 48.4%-50.7%) when drug-metabolizing phenotypes were ascribed according to the distribution of variants of 11 genes as found in a Caucasian population. There was a 7.8% probability of major DDIs, which increased to a 10.1% (95% CI, 9.5%-10.8%) probability with the addition of genetic contributions. The probability of DDGIs of any impact was correlated with the number of medications. Antidepressants, antiemetics, blood products and modifiers, analgesics, and antipsychotics had the highest probability of DDGIs.

CONCLUSIONS: The probability of drug interaction risk increased when phenotypes associated with genetic polymorphisms were attributed to the population. These data suggest that pharmacogenomic assessment may be useful in predicting drug interactions and severity when evaluating patient medication profiles.

PMID:36374614 | DOI:10.37765/ajmc.2022.89259

J Urol. 2022 Nov 14:101097JU0000000000003049. doi: 10.1097/JU.0000000000003049. Online ahead of print.

ABSTRACT

PURPOSE: Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer (PCa) owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized PCa.

MATERIAL AND METHODS: We studied 1793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors (5-ARIs) in the prospective PROCURE cohort for which preoperative plasma samples were obtained prior to radical prostatectomy (RP). Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Circulating levels were evaluated in relation to prognostic factors, disease-free survival (DFS), and metastasis-free survival (MFS), using multivariable Cox proportional hazards models.

RESULTS: At a median follow-up time of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease and 168 diseased. Higher levels of 11-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT) were observed in men with prostatic specific antigen (PSA) >20 ng/ml and positive nodal status (P<.05). In multivariable analyses, no significant association between 11-oxygenated androgens and DFS was observed. Adrenal 11β-hydroxyandrostenedione (11OHA4), the predominant androgenic 11KT, and its metabolite 11-ketoandrosterone (11KAST), modeled as quartiles, were associated with MFS (P=.06, .03, and 0.008, respectively). A significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in 5-ARIs patients (P<.001).

CONCLUSIONS: Preoperative circulating 11-oxygenated androgen levels are associated with MFS in men with localized PCa undergoing RP and are affected by 5-ARI treatment.

PMID:36373402 | DOI:10.1097/JU.0000000000003049

Clin Pharmacol Ther. 2022 Nov 13. doi: 10.1002/cpt.2773. Online ahead of print.

ABSTRACT

Pharmacogenetic implementation programs are increasingly feasible due to the availability of clinical guidelines for implementation research. The utilization of these resources has been reported with selected drug-gene pairs; however, little is known about how prescribers respond to pharmacogenetic recommendations for statin therapy. We prospectively assessed prescriber interaction with point-of-care clinical decision support (CDS) to guide simvastatin therapy for a diverse cohort of primary care patients enrolled in a clinical pharmacogenetics program. Of the 1639 preemptively genotyped patients, 298 (18.2%) had an intermediate function (IF) OATP1B1 phenotype and 25 (1.53%) had a poor function (PF) phenotype, predicted by a common single nucleotide variant in the SLCO1B1 gene (c.521T>C; rs4149056). Clinicians were presented with CDS when simvastatin was prescribed for IF or PF patients through the Electronic Health Record. Importantly, 64.2% of the CDS deployed at the point-of-care was accepted by the prescribers and resulted in prescription changes. Statin intensity was found to significantly influence prescriber adoption of the pharmacogenetic-guided CDS, whereas patient gender or race, prescriber type, or pharmacogenetic training status did not significantly influence adoption. This study demonstrates that primary care providers readily adopt pharmacogenetic information to guide statin therapy for the majority of patients with preemptive genotype data.

PMID:36372942 | DOI:10.1002/cpt.2773

Biomed Pharmacother. 2022 Nov 10;157:114003. doi: 10.1016/j.biopha.2022.114003. Online ahead of print.

NO ABSTRACT

PMID:36371855 | DOI:10.1016/j.biopha.2022.114003

Med (N Y). 2022 Nov 11;3(11):740-759. doi: 10.1016/j.medj.2022.08.006.

ABSTRACT

Genome sequencing in the clinic often allows patients to receive a molecular diagnosis. However, variants are most often evaluated for pathogenicity, neglecting potential treatability and thus often yielding limited clinical benefit. Antisense oligonucleotides (ASOs), among others, offer attractive programmable and relatively safe platforms for customized therapy based upon the causative genetic variant. The landscape of ASO-treatable variants is largely uncharted, with new developments emerging for loss-of-function, haploinsufficient, and gain-of-function effects. ASOs can access the transcriptome to target splice-gain variants, poison exons, untranslated/regulatory regions, and naturally occurring antisense transcripts. Here we assess public variant databases and find that approximately half of pathogenic variants have one or more viable avenues for ASO therapy. The future might see medical teams considering "treatability" when interpreting genomic sequencing results to fully realize benefits for patients.

PMID:36370694 | DOI:10.1016/j.medj.2022.08.006

J Am Pharm Assoc (2003). 2022 Sep 28:S1544-3191(22)00320-X. doi: 10.1016/j.japh.2022.09.019. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenetic (PGx) testing is an evidence-based approach to finding effective medication therapies. While community pharmacists are ideally situated to provide PGx testing, the extent of its implementation is limited within community pharmacies.

OBJECTIVE: This study aimed to explore trends in the international peer-reviewed primary literature on community pharmacists' implementation of PGx and map the main findings on the Theoretical Domains Framework (TDF).

METHODS: A literature search and 2-step screening were conducted per PRISMA Extension for Scoping Reviews. Inclusion criteria were English language, community pharmacy setting, full papers, and empirical research. Data were collated in a data extraction form. The main findings were deductively mapped on the TDF with a content analysis approach.

RESULTS: Of 1176 identified documents screened, 39 were included in this scoping review. Four groups of research were identified: pre-implementation surveys, interviews, and focus groups (56%, n=22), PGx implementation: single cohort to assess feasibility (38%, n=15), PGx implementation: controlled study to assess feasibility (n=1, 2.5%), and efficacy of PGx (2.5%, n=1). Most studies throughout the 4 groups sought pharmacists' perceptions (46%, n=18) and used the quantitative paradigm (77%, n=30). TDF mapping documented positive beliefs about the benefits of PGx testing as a part of the pharmacists' role. Barriers to PGx use included pharmacists' awareness of knowledge gaps, low confidence in interpreting and communicating PGx results, concerns about cost, privacy, and integration into pharmacy workflow.

CONCLUSION: Research addressing PGx implementation within the community pharmacy evolved from assessing individuals' perceptions of PGx to determining the feasibility of PGx testing in pharmacies and evaluating the impact of PGx testing on patient outcomes in depression. Mapping the main findings on the TDF facilitates the development of multidimensional interventions, potentially targeting patients, pharmacists, and health policy.

PMID:36371398 | DOI:10.1016/j.japh.2022.09.019

Orphanet J Rare Dis. 2022 Nov 12;17(1):412. doi: 10.1186/s13023-022-02562-9.

ABSTRACT

BACKGROUND: X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies.

RESULTS: Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)2D increased dramatically under burosumab therapy.

CONCLUSION: To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.

PMID:36371259 | DOI:10.1186/s13023-022-02562-9

Clin Pharmacol Ther. 2022 Nov 12. doi: 10.1002/cpt.2794. Online ahead of print.

ABSTRACT

Intravenous (IV) busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplant (HCT) patients, all had samples collected immediately before to busulfan administration (preBU) and 96 had samples collected two weeks before busulfan (2-week-preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (<0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a Lasso penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least-squares. When the resulting linear prediction model was applied to the 2-week-preBU samples, it explained 40% of the variation in BuCL (adjusted R2 =0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by Steroid Biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses.

PMID:36369996 | DOI:10.1002/cpt.2794

Clin Lab Med. 2022 Dec;42(4):587-602. doi: 10.1016/j.cll.2022.09.012.

NO ABSTRACT

PMID:36368784 | DOI:10.1016/j.cll.2022.09.012

Clin Lab Med. 2022 Dec;42(4):533-546. doi: 10.1016/j.cll.2022.09.009.

NO ABSTRACT

PMID:36368780 | DOI:10.1016/j.cll.2022.09.009

Trends Pharmacol Sci. 2022 Dec;43(12):987-993. doi: 10.1016/j.tips.2022.10.001. Epub 2022 Oct 27.

NO ABSTRACT

PMID:36368301 | DOI:10.1016/j.tips.2022.10.001

Clin Pharmacol Ther. 2022 Nov 11. doi: 10.1002/cpt.2792. Online ahead of print.

ABSTRACT

Most pharmacogenetic research is conducted in adult, non-pregnant populations of European ancestry. Study of more diverse and special populations is necessary to validate findings and improve health equity. However, there are significant barriers to recruitment of diverse populations for genetic studies, such as mistrust of researchers due to a history of unethical research and ongoing social inequities. Engaging communities and understanding community members' perspectives may help to overcome these barriers and improve research quality. Here, we highlight one method for engaging communities, the Community Engagement Studio (CES), a consultative session that allows researchers to obtain guidance and feedback based on community members' lived experiences. We also provide an example of its use in pharmacogenetic studies. In designing a survey study of knowledge and attitudes around pharmacogenetic testing among children with chronic conditions and pregnant individuals, we sought input from diverse community stakeholders through CESs at Vanderbilt University Medical Center. We participated in two CESs with community stakeholders representing study target populations. Our goals were to learn specific concerns about pharmacogenetic testing and preferred recruitment strategies for these communities. Concerns were expressed about how genetic information would be used beyond the immediate study. Participants emphasized the importance of clarity and transparency in communication to overcome participation hesitancy and mistrust of the study team. Recruitment strategy recommendations ranged from informal notices posted in healthcare settings to provider referrals. The CES enabled us to modify our recruitment methods and research materials to better communicate with populations currently underrepresented in pharmacogenetics research.

PMID:36366911 | DOI:10.1002/cpt.2792

Br J Clin Pharmacol. 2022 Nov 10. doi: 10.1111/bcp.15591. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx), examining the effect of genetic variation on interpatient variation in drug disposition and response, has been widely studied for several decades. However, as cost, as well as turnaround time associated with PGx testing, have significantly improved, the use of PGx in the clinical setting has been gaining momentum. Nevertheless, challenges have emerged in the broader clinical implementation of PGx. In this review, we will outline current models of PGx delivery, methodologies of evaluation and discuss clinically relevant PGx tests and associated medications. Additionally, we will describe our approach for the broad implementation of pre-emptive DPYD genotyping in patients taking fluoropyrimidines, in Ontario, Canada, as an example of clinically actionable PGx testing with sufficient clinical evidence of patient benefit that can become a new standard of patient care. We will highlight challenges associated with PGx testing, including a lack of diversity in PGx studies as well as general limitations that impact the broad adaption of PGx testing. Lastly, this article will discuss the future of PGx, discussing new clinical targets, methodologies, and analysis approaches.

PMID:36366858 | DOI:10.1111/bcp.15591

Plants (Basel). 2022 Oct 27;11(21):2874. doi: 10.3390/plants11212874.

ABSTRACT

The Artemisia L. genus includes over five hundred species with great economic and medicinal properties. Our study aimed to provide a comprehensive metabolite and bioactivity profile of Artemisia campestris subsp. lednicensis (Spreng.) Greuter & Raab-Straube collected from north-eastern Romania. Liquid chromatography with tandem high-resolution mass spectrometry (LC-HRMS/MS) analysis of different polarity extracts obtained from the aerial parts led to the identification of twelve flavonoids, three phenolic acids, two sesquiterpene lactones, two fatty acids, one coumarin, and one lignan. The antioxidant and enzyme inhibitory properties were shown in the DPPH (0.71-213.68 mg TE/g) and ABTS (20.57-356.35 mg TE/g) radical scavenging, CUPRAC (38.56-311.21 mg TE/g), FRAP (121.68-202.34 mg TE/g), chelating (12.88-22.25 mg EDTAE/g), phosphomolybdenum (0.92-2.11 mmol TE/g), anti-acetylcholinesterase (0.15-3.64 mg GALAE/g), anti-butyrylcholinesterase (0-3.18 mg GALAE/g), anti-amylase (0.05-0.38 mmol ACAE/g), anti-glucosidase (0.43-2.21 mmol ACAE/g), and anti-tyrosinase (18.62-48.60 mg KAE/g) assays. At 100 μg/mL, Artemisia extracts downregulated the secretion of tumor necrosis factor (TNF)-α in a lipopolysaccharide (LPS)-stimulated human neutrophil model (29.05-53.08% of LPS+ control). Finally, the Artemisia samples showed moderate to weak activity (minimum inhibitory concentration (MIC) &gt; 625 mg/L) against the seventeen tested microbial strains (bacteria, yeasts, and dermatophytes). Overall, our study shows that A. campestris subsp. lednicensis is a promising source of bioactives with putative use as food, pharmaceutical and cosmetic ingredients.

PMID:36365326 | DOI:10.3390/plants11212874

Nutrients. 2022 Nov 4;14(21):4668. doi: 10.3390/nu14214668.

ABSTRACT

The pathogenesis of non-small-cell lung cancer (NSCLC) is complex, since many risk factors have been identified. Recent research indicates that polymorphisms in the metabolic pathway of vitamin D may be involved in both risk and survival of the disease. The objective of this study is to assess the effect of 13 genetic polymorphisms involved in the vitamin D metabolic pathway on the risk of suffering from NSCLC. We conducted an observational case-control study, which included 204 patients with NSCLC and 408 controls, of Caucasian origin, from southern Spain. The CYP27B1 (rs4646536, rs3782130, rs703842, rs10877012), CYP2R1 (rs10741657), GC (rs7041), CYP24A1, and VDR (BsmI, Cdx-2, FokI, ApaI, TaqI) gene polymorphisms were analyzed by real-time polymerase chain reaction. The logistic regression model, adjusted for smoking and family history of cancer, revealed that in the genotypic model, carriers of the VDR BsmI rs1544410-AA genotype were associated with a lower risk of developing NSCLC compared to the GG genotype (p = 0.0377; OR = 0.51; CI95% = 0.27-0.95; AA vs. GG). This association was maintained in the recessive model (p = 0.0140). Haplotype analysis revealed that the AACATGG and GACATGG haplotypes for the rs1544410, rs7975232, rs731236, rs4646536, rs703842, rs3782130, and rs10877012 polymorphisms were associated with a lower risk of NSCLC (p = 0.015 and p = 0.044 respectively). The remaining polymorphisms showed no effect on susceptibility to NSCLC. The BsmI rs1544410 polymorphism was significantly associated with lower risk of NSCLC and could be of considerable value as a predictive biomarker of the disease.

PMID:36364930 | DOI:10.3390/nu14214668

J Clin Med. 2022 Nov 6;11(21):6577. doi: 10.3390/jcm11216577.

ABSTRACT

Vitamin D has been traditionally seen to be mainly involved in the regulation of bone homeostasis. However, vitamin D has also been clinically linked to various diseases, including metabolic syndrome. The aim of this study was to examine the effect of low and high doses of a vitamin D supplement on the serum levels of 25(OH)D3 and insulin resistance. A total of 120 females were recruited in this study and supplemented weekly with 25,000 IU vitamin D or 50,000 IU vitamin D for three months. Anthropometric measurements were taken at the beginning of the study. Blood samples were collected at the beginning of the study to determine the baseline of the clinical variables and collected again after three months. Insulin resistance was measured using Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). After vitamin D supplementation, a non-significant increase was observed in the serum levels of 25(OH)D3 in the group treated with a low dose of vitamin D (LDVD) and a highly significant increase was seen in the group treated with a high dose of vitamin D (HDVD). In the group treated with a higher dose (HDVD), a significant improvement in insulin sensitivity was observed. The high dose of vitamin D (50,000 IU) supplementation was more effective in both correcting the blood levels of vitamin D and improving the sensitivity of insulin.

PMID:36362806 | DOI:10.3390/jcm11216577

Int J Mol Sci. 2022 Nov 3;23(21):13485. doi: 10.3390/ijms232113485.

ABSTRACT

The activity of cytochrome P450 enzymes is influenced by genetic and nongenetic factors; hence, the metabolism of exogenous psychotropic medications and potentially some endogenous neuropeptides is variably affected among different ethnic groups of psychiatric patients. The aim of this review is to highlight the most common cytochrome P450 isoenzymes associated with the metabolism of psychotropic medications (antidepressants, antipsychotics, and mood stabilizers), their variations among different populations, their impact on endogenous neurotransmitters (dopamine and serotonin), and the effect of nongenetic factors, particularly smoking, age, and pregnancy, on their metabolic activity. Furthermore, the adverse effects of psychiatric medications may be associated with certain human leukocytic antigen (HLA) genotypes. We also highlight the gene variants that may potentially increase susceptibility to obesity and metabolic syndrome, as the adverse effects of some psychiatry medications. Collectively, the literature revealed that variation of CYP450 activity is mostly investigated in relation to genetic polymorphism, and is directly correlated with individualized clinical outcomes; whereas adverse effects are associated with HLA variants, projecting the value of pharmacogenetics implementation in psychiatry clinics. Only a few previous studies have discussed the impact of such genetic variations on the metabolism of endogenous neuropeptides. In this review, we also report on the prevalence of key variants in different ethnicities, by demonstrating publicly available data from the 1000 Genomes Project and others. Finally, we highlight the future direction of further investigations to enhance the predictability of the individual gene variants to achieve precision therapies for psychiatric patients.

PMID:36362270 | DOI:10.3390/ijms232113485

Int J Mol Sci. 2022 Oct 29;23(21):13177. doi: 10.3390/ijms232113177.

ABSTRACT

Ankylosing spondylitis (AS) is an inflammatory disease that belongs to the spondyloarthritis family. IL-5 and IL-9 belong to the group of Th2 cytokines of anti-inflammatory nature. Polymorphisms in their coding genes have been so far associated with various inflammatory diseases, but there are no reports regarding their involvement in AS pathogenesis to date. The purpose of the study was to investigate relationships between IL5 and IL9 genetic variants with AS susceptibility, clinical parameters as well as response to therapy with TNF inhibitors. In total 170 patients receiving anti-TNF therapy and 218 healthy controls were enrolled in the study. The genotyping of IL5 rs2069812 (A &gt; G) and IL9 rs2069885 (G &gt; A) single nucleotide polymorphisms was performed using the Real-Time PCR method based on LightSNiP kits assays. The present study demonstrated significant relationships between IL5 rs2069812 and IL9 rs2069885 polymorphisms and response to anti-TNF therapy. Presence of the IL5 rs2069812 A allele in patients positively correlated with better response to treatment (p = 0.022). With regard to IL9 rs2069885, patients carrying the A allele displayed better outcomes in anti-TNF therapy (p = 0.046). In addition, IL5 rs2069812 A and IL9 rs2069885 A alleles were associated with lower CRP and VAS values. The obtained results may indicate a significant role for IL-5 and IL-9 in the course of AS and response to anti-TNF therapy.

PMID:36361964 | DOI:10.3390/ijms232113177

Biomedicines. 2022 Nov 10;10(11):2882. doi: 10.3390/biomedicines10112882.

ABSTRACT

Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography-mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (p = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; p = 0.001), and relative to the baseline IMPDH activity before transplantation (p = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.

PMID:36359401 | DOI:10.3390/biomedicines10112882