Psychopharmacol Bull. 2021 Jan 12;51(1):69-80.

ABSTRACT

INTRODUCTION: Fluvoxamine is commonly administered to patients with recurrent depressive disorder. Some of these patients do not show adequate response to the therapy with fluvoxamine, whereas many of them experience dose-dependent adverse drug reactions. Previous research revealed that CYP2D6 is involved in the metabolism of fluvoxamine, the activity of which is highly dependent on the polymorphism of the gene encoding it.

OBJECTIVE: The objective of this study was to investigate the effect of polymorphisms of the CYP3A4, CYP2C9, CYP3A5, ABCB1, CYP2C19, SCL6A4, and 5-HTR2A genes on the concentration/dose indicator of fluvoxamine and on the CYP3A expression level obtained by measuring the miR-27b plasma concentration levels in patients suffering from a recurrent depressive disorder.

MATERIAL AND METHODS: Our study included 105 patients with recurrent depressive disorder (average age - 37.5 ± 13.2 years). The treatment regimen included fluvoxamine in an average daily dose of 117.6 ± 44.3 mg per week. Therapy efficacy was assessed using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels, we performed the real-time polymerase chain reaction. The activity of CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6b-HC/cortisol). Therapeutic drug monitoring has been performed using HPLC-MS/MS.

RESULTS: Our study didn't reveal any statistically significant results in terms of the treatment efficacy and safety of the therapy. We also didn't reveal a statistical significance for the concentration/dose indicator of fluvoxamine in patients with different genotypes. Analysis of the results of the pharmacotranscriptomic part of the study didn't demonstrate the statistically significant difference in the miR-27b plasma levels in patients with different genotypes. At the same time, correlation analysis didn't reveal a statistically significant relationship between the fluvoxamine efficacy profile evaluated by changes in HAMD scale scores and the miR-27b plasma concentration: rs = -0.012, p = 0.63. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = -0.175, p = 0.30. In addition, we didn't reveal the relationship between the CYP3A enzymatic activity and the miR-27b plasma concentration: rs = -0.197, p < 0.32. However, the difference in the CYP3A enzymatic activity in carriers of AG and GG genotypes of the 6986A > G polymorphism of CYP3A5 gene has been revealed: (AG) 4.72 [1.18; 8.45] vs (GG) 9.23 [5.12; 15.53], p-value = 0.23.

CONCLUSION: Thus, the effect of genetic polymorphism of the CYP3A4, CYP2C9, CYP2C9, CYP3A5, ABCB1, CYP2C19, CYP2C19, CYP2C19, SCL6A4, 5-HTR2A gene on the efficacy and safety profiles of fluvoxamine was not demonstrated in a group of 105 patients with depressive disorder and alcohol use disorder.

PMID:33897064 | PMC:PMC8063127

Expert Opin Drug Metab Toxicol. 2021 Apr 26. doi: 10.1080/17425255.2021.1922668. Online ahead of print.

ABSTRACT

INTRODUCTION: : Antipsychotic medications are used to treat a number of conditions in children and adolescents. While side effect profiles from second generation antipsychotics (SGAs) may differ from older antipsychotics, they do not come without risk. Knowing which children may be at higher risk for specific outcomes is important clinical information for prescribers. Common side effects and toxicities of SGAs in children include movement disorders, weight gain, and hormonal changes. There are also rare, but potentially dangerous adverse events including neuroleptic malignant syndrome, hypersensitivity and suicidal ideation.

AREAS COVERED: This review will summarize and comment on clinical, pharmacological, and genetic factors having evidence as predictors of SGA-associated side effects and toxicities in children.

EXPERT OPINION: : Observations across studies note that older children and those that do not respond early in treatment may be more at risk for movement disorders, while younger, antipsychotic naive children are at increased risk for weight gain. Relatively fewer studies have looked at pharmacogenetic relationships, although variations in pharmacokinetic and pharmacodynamic genes hold promise to advance drug dosing or selection strategies. Future efforts to assimilate multiple clinical, pharmacological, and genetic factors to facilitate predictive analytics and clinical decision support for prescribers will advance precision care to patients.

PMID:33896324 | DOI:10.1080/17425255.2021.1922668

Clin Pharmacol Ther. 2021 Apr 24. doi: 10.1002/cpt.2274. Online ahead of print.

ABSTRACT

Low- and middle-income countries (LMICs) have the highest rates of mortality and morbidity globally, but lag behind high-income countries in the number of clinical trials and trained researchers, as well as research data pertaining to their populations. Lack of local clinical pharmacology and pharmacometrics expertise, limited training opportunities, and lack of local genomic data may contribute to health inequalities and limit the application of precision medicine. Continuing to develop health care infrastructure, including well designed clinical pharmacology training and data collection in LMICs, can help address these challenges. International collaboration aimed at improving training and infrastructure and encouraging locally driven research and clinical trials will be of benefit. This review describes several examples where clinical pharmacology expertise could be leveraged, including opportunities for pharmacogenomics expertise that could drive improved recommendations for clinical guidelines. Also described are clinical pharmacology and pharmacometrics training programs in Africa, and the personal experience of a Tanzanian researcher currently on a training sabbatical in the United States, as illustrative examples of how training in clinical pharmacology can be effectively implemented in LMICs. These training efforts will benefit from advocacy for employment opportunities and career development pathways for clinical pharmacologists that are gradually being recognized and developed in LMICs. Clinical pharmacologists have a key role to play in global health, and development of training and research infrastructure to advance this expertise in LMICs will be of tremendous benefit.

PMID:33893656 | DOI:10.1002/cpt.2274

J Am Pharm Assoc (2003). 2021 Apr 5:S1544-3191(21)00156-4. doi: 10.1016/j.japh.2021.04.001. Online ahead of print.

ABSTRACT

BACKGROUND: Nearly 300 medications contain pharmacogenomic information in their labeling approved by the U.S. Food and Drug Administration. As this number continues to grow, community pharmacists will be called on to use available pharmacogenomic data at the point of dispensing.

OBJECTIVE: This qualitative study aimed to describe how pharmacists envision the integration of pharmacogenomic data into the current workflows of community pharmacy practice.

METHODS: Community pharmacists from a regional supermarket chain pharmacy in the greater Pittsburgh area were interviewed using a semistructured interview guide. Participating pharmacists were presented with 3 clinical scenarios, followed by questions, to gain insight into how they envisioned the integration of pharmacogenomic data into community pharmacy workflow. The interview transcriptions were transcribed and coded. The content was analyzed to deduce the final themes. Supporting quotes were selected to illustrate each theme.

RESULTS: Ten community pharmacists from 3 different pharmacy locations participated in the study. A thematic analysis produced 6 themes: (1) integrating pharmacogenomic data into the dispensing software, (2) receiving an alert for pharmacogenomic information within the dispensing software, (3) accessing pharmacogenomic clinical guidelines to guide drug-decision-making, (4) contacting the prescriber by adding a task to the call queue, (5) placing a mandatory counseling alert on medications that were adjusted using pharmacogenomic data, and (6) counseling the patient on the first refill of a medication that was adjusted using pharmacogenomic data.

CONCLUSION: This study describes how pharmacists envisioned the integration of pharmacogenomic data into community pharmacy workflow. The participants sought the integration of pharmacogenomic data into existing dispensing software, alerts for actionable prescribing changes using patient-specific pharmacogenomic data when available, and access to clinical decision support. In addition, the participants preferred to engage prescribers and receive alerts to counsel patients at prescription pick-up. These findings are key to integrating pharmacogenomic data into community pharmacy practice.

PMID:33893058 | DOI:10.1016/j.japh.2021.04.001

J Pharm Biomed Anal. 2021 Apr 14;200:114077. doi: 10.1016/j.jpba.2021.114077. Online ahead of print.

ABSTRACT

Drug resistance and adverse reactions to oxaliplatin remain a considerable issue in clinical practice. Emerging evidence has suggested that alterations in the lipid metabolism during drug therapy affect cancer cells. To gain insight into the important process of lipid metabolism, we investigated the lipid and gene expression profile changes in HT29 cells treated with oxaliplatin. A total of 1403 lipid species from 16 lipid classes were identified by UHPLC-MS. Interestingly, phospholipids, including phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylcholine (PC), and most of phosphatidylethanolamine (PE) with polyunsaturated fatty acid (PUFA) chains, were significantly higher due to oxaliplatin treatment, while triacylglycerols (TAGs) with a saturated fatty acid chain or monounsaturated fatty acid were significantly downregulated. Gene Set Enrichment Analysis (GSEA) based on RNA sequencing data suggested that neutral lipid metabolism was enriched in the control group, whereas the phospholipid metabolic process was enriched in the oxaliplatin-treated group. We observed that altered lipid metabolism enzyme genes were involved in the synthesis and lipolysis of TAGs and the Lands cycle pathway based on the network between the core lipid-related gene and lipid species, which was further verified by qRT-PCR. In summary, our findings revealed that oxaliplatin impressed a specific lipid profile signature and lipid transcriptional reprogramming in HT29 cells, which provides new insights into biomarker discovery and pathways for overcoming drug resistance and adverse reactions.

PMID:33892396 | DOI:10.1016/j.jpba.2021.114077

Drug Discov Today. 2021 Apr 20:S1359-6446(21)00203-8. doi: 10.1016/j.drudis.2021.04.015. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) has essential roles in identifying optimal drug responders, optimizing dosage regimens and avoiding adverse events. Population-specific therapeutic interventions that tackle the genetic root causes of clinical outcomes are an important precision medicine strategy. In this perspective, we discuss next-generation sequencing genotyping and its significance for population-specific PGx applications. We emphasize the potential of NGS for preemptive pharmacogenotyping, which is crucial to population-specific clinical studies and patient care. We also provide examples that use publicly available population-based genomics data for population-specific PGx studies. Last, we discuss the remaining challenges and regulatory efforts towards improvements in this field.

PMID:33892143 | DOI:10.1016/j.drudis.2021.04.015

Br J Clin Pharmacol. 2021 Apr 22. doi: 10.1111/bcp.14869. Online ahead of print.

ABSTRACT

AIM: People living with HIV (PLWH) have a high burden of comorbidities and concomitant medication use. Aim of this study was to analyze the prevalence, predictors and patterns of polypharmacy (PP) in a large therapeutic drug monitoring (TDM) registry.

METHODS: We searched our TDM registry and categorized co-medications into 26 drug classes. We included patients with at least one medication recorded: PP and severe PP (sPP) were defined as the concomitant use of ≥5 or ≥10 non-antiretroviral/non-antitubercular drugs. Multivariable binary logistic analysis were conducted for identifying PP/sPP predictors. A hierarchical average-linkage cluster analysis was performed among drug classes.

RESULTS: We included 2432 participants (1158 PLWH) aged 49.6 years (± 14.4) in the 2016-2020 period. A higher number of concomitant medications (4 vs. 3.1, p<0.001) and a higher prevalence of PP (26.1% vs. 21.8%, p=0.015) were recorded in controls. At multivariable binary logistic analysis older age, female gender and HIV-positive serostatus (p=0.015) were independent predictors of PP; older age and year of inclusion were independent predictors of sPP. Cluster analysis showed that patients receiving oral drug for type-2-diabetes have a high probability of receiving several other drugs; a cluster of co-medications was observed with opioids, diuretics and central nervous system affecting drugs.

CONCLUSION: We observed a moderately high prevalence of polypharmacy in middle-aged PLWH: advanced age and female gender were associated with the greatest prevalence. The observation of co-medication clusters suggests groups of comorbidities but also identifies groups of patients at risk of similar drug to drug interactions.

PMID:33890312 | DOI:10.1111/bcp.14869

Hum Reprod. 2021 Apr 23:deab068. doi: 10.1093/humrep/deab068. Online ahead of print.

ABSTRACT

STUDY QUESTION: Does the presence of single nucleotide polymorphisms (SNPs) in the FSH receptor gene (FSHR) and/or FSH beta subunit-encoding gene (FSHB) influence ovarian response in predicted normal responders treated with rFSH?

SUMMARY ANSWER: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) has a statistically significant impact in ovarian response, although this effect is of minimal clinical relevance in predicted normal responders treated with a fixed dose of 150 IU rFSH.

WHAT IS KNOWN ALREADY: Ovarian reserve markers have been a breakthrough in response prediction following ovarian stimulation. However, a significant percentage of patients show a disproportionate lower ovarian response, as compared with their actual ovarian reserve. Studies on pharmacogenetics have demonstrated a relationship between FSHR or FSHB genotyping and drug response, suggesting a potential effect of individual genetic variability on ovarian stimulation. However, evidence from these studies is inconsistent, due to the inclusion of patients with variable ovarian reserve, use of different starting gonadotropin doses, and allowance for dose adjustments during treatment. This highlights the necessity of a well-controlled prospective study in a homogenous population treated with the same fixed protocol.

STUDY DESIGN, SIZE, DURATION: We conducted a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia), from November 2016 until June 2019. All patients underwent ovarian stimulation followed by oocyte retrieval in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Blood sampling and DNA extraction was performed prior to oocyte retrieval, followed by genotyping of four SNPs from FSHR (rs6165, rs6166, rs1394205) and FSHB (rs10835638).

PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible were predicted normal responder women <38 years old undergoing their first or second ovarian stimulation cycle. Laboratory staff and clinicians were blinded to the clinical results and genotyping, respectively. The prevalence of hypo-responders, the number of oocytes retrieved, the follicular output rate (FORT), and the follicle to oocyte index (FOI) were compared between different FSHR and FSHB SNPs genotypes.

MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of derived allele homozygous SNPs in the FSHR was rs6166 (genotype G/G) 15.8%, rs6165 (genotype G/G) 34.8%, and rs1394205 (genotype A/A) 14.1%, with significant differences between Caucasian and Asian women (P < 0.001). FSHB variant rs10835638 (c.-211 G>T) was very rare (0.5%). Genetic model analysis revealed that the presence of the G allele in FSHR variant rs6166 resulted in less oocytes retrieved when compared to the AA genotype (13.54 ± 0.46 vs 14.81 ± 0.61, estimated mean difference (EMD) -1.47 (95% CI -2.82 to -0.11)). In FSHR variant rs1394205, a significantly lower number of oocytes was retrieved in patients with an A allele when compared to G/G (13.33 ± 0.41 vs 15.06 ± 0.68, EMD -1.69 (95% CI -3.06 to -0.31)). A significantly higher prevalence of hypo-responders was found in patients with the genotype A/G for FSHR variant rs6166 (55.9%, n = 57) when compared to A/A (28.4%, n = 29), ORadj 1.87 (95% CI 1.08-3.24). No significant differences were found regarding the FORT across the genotypes for FSHR variants rs6166, rs6165, or rs1394205. Regarding the FOI, the presence of the G allele for FSHR variant rs6166 resulted in a lower FOI when compared to the A/A genotype, EMD -13.47 (95% CI -22.69 to -4.24). Regarding FSHR variant rs6165, a lower FOI was reported for genotype A/G (79.75 ± 3.35) when compared to genotype A/A (92.08 ± 6.23), EMD -13.81 (95% CI -25.41 to -2.21).

LIMITATIONS, REASONS FOR CAUTION: The study was performed in relatively young women with normal ovarian reserve to eliminate biases related to age-related fertility decline; thus, caution is needed when extrapolating results to older populations. In addition, no analysis was performed for FSHB variant rs10835638 due to the very low prevalence of the genotype T/T (n = 2).

WIDER IMPLICATIONS OF THE FINDINGS: Based on our results, genotyping FSHR SNPs rs6165, rs6166, rs1394205, and FSHB SNP rs10835638 prior to initiating an ovarian stimulation with rFSH in predicted normal responders should not be recommended, taking into account the minimal clinical impact of such information in this population. Future research may focus on other populations and other genes related to folliculogenesis or steroidogenesis.

STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Theramex, and Institut Biochimique SA (IBSA). N.L.V. and M.T.H. report consultancy and conference fees from Merck, Ferring, and MSD, outside the submitted work. P.D. has received honoraria for lecturing and/or research grants from MSD, Ferring International, and Merck. D.S. reports grants and/or personal fees from MSD, Ferring International, Merck Serono, Cook, and Gedeon Richter. A.R.N., B.A.M., C.S., J.M., L.H.L., P.Q.M.M., H.T., and S.G. report no conflict of interests.

TRIAL REGISTRATION NUMBER: NCT03007043.

PMID:33889959 | DOI:10.1093/humrep/deab068

Pharmacogenomics. 2021 Apr 23. doi: 10.2217/pgs-2021-0019. Online ahead of print.

ABSTRACT

Aim: The aim of this study is to explore how SNPs may affect the response to anti-TNF-α therapy in the major autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases and Spondyloarthritis. Methodology: We conducted a systematic overview on the field, by assessing all studies that examined the association between polymorphisms and response to anti-TNF-α therapy in participants of European descent. Results: In total, six independent SNPs located in FCGR2A, FCGR3A, TNF-α and TNFRSF1B genes were significantly associated with response to TNF-α blockers, found mainly in disease-subgroup analyses. Conclusion: No common pharmacogenetic variant was identified for all autoimmune diseases under study, suggesting the requirement of more studies in the field in order to capture such predictive variants that will aid treatment selection.

PMID:33887993 | DOI:10.2217/pgs-2021-0019

Int J Cardiol. 2021 Apr 19:S0167-5273(21)00665-3. doi: 10.1016/j.ijcard.2021.04.029. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically.

METHODS: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding).

RESULTS: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77-1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66-1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62-1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively.

CONCLUSION: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

PMID:33887342 | DOI:10.1016/j.ijcard.2021.04.029

Expert Opin Drug Metab Toxicol. 2021 Apr 22. doi: 10.1080/17425255.2021.1921146. Online ahead of print.

ABSTRACT

INTRODUCTION: : Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane.

AREAS COVERED: : We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane.

EXPERT OPINION: : Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.

PMID:33886381 | DOI:10.1080/17425255.2021.1921146

Soc Stud Sci. 2021 Apr 22:3063127211005539. doi: 10.1177/03063127211005539. Online ahead of print.

ABSTRACT

Personalized medicine raises the stakes of pharmaceutical market regulation. Drawing on pragmatist valuation studies and science and technology studies literature on personalized medicine and pharmaceutical markets, this article demonstrates how complex negotiations about the value of a pharmaceutical can constitute a market in various ways, while also shaping the concerned patient populations. Tracing the path of a pharmacogenetic treatment, Spinraza, from its approval by the European Medicines Agency to its adoption in the publicly funded Danish healthcare system, we show how the market was formatted through particular stratifications of the patient population. We conceptualize these seemingly technical moves as strategies of stratification, that is, the application of techniques to assemble and divide data - and what data are meant to represent - into groups delineated by certain characteristics. We argue that stakeholders' use of strategies of stratification has important implications not only for market access, but also for the delineation of diseases and patient populations. Hence, it is crucial to make intelligible the mutual constitution of pharmaceutical markets and patient populations and the political efforts of delineating and connecting the two.

PMID:33885344 | DOI:10.1177/03063127211005539

J Genet Couns. 2021 Apr 21. doi: 10.1002/jgc4.1417. Online ahead of print.

ABSTRACT

The increasing number of genetic counselors participating directly in clinical pharmacogenomic post-test counseling prompted our evaluation of pharmacogenomic education across genetic counseling training programs in North America. Thirty-one program leadership participants from both the United States (U.S.) and Canada responded to a survey assessing pharmacogenomics education and the role of genetic counselors. Eighty-five percent of respondents agreed pharmacogenomics is currently within the scope of genetic counseling practice, and 96.3% indicated their training programs currently provide education on pharmacogenomics, with the majority reporting < 7 hr of education. Lectures on pharmacogenomics were the most common method for didactics; however, some programs also included practical modalities (e.g., case studies, clinical rotations) and online resources. Barriers to expanding pharmacogenomic education included the constrained timeline of training, and lack of resources and local expertise. Moreover, participants suggested that genetic counselors ideally should be able to order pharmacogenomic tests and counsel patients on pharmacogenomics, including result interpretation, as they believe pharmacogenomics does fall within the scope of practice of genetic counseling. Our novel results also confirm that training program leadership support a pharmacogenomic service delivery model that includes a combined effort between genetic counselors and pharmacists to utilize their synergistic expertise. However, this model likely still necessitates expanding pharmacogenomic didactics in genetic counseling training programs through more practical training and/or by leveraging online pharmacogenomic courses dedicated to supporting clinical implementation.

PMID:33882174 | DOI:10.1002/jgc4.1417

Clin Pharmacol Ther. 2021 Apr 20. doi: 10.1002/cpt.2270. Online ahead of print.

ABSTRACT

Pharmacogenetics (PGx) association studies are used to discover, replicate, and validate the association between an inherited genotype and a treatment outcome. The objective of this tutorial is to provide trainees and novice PGx researchers with an overview of the major decisions that need to be made when designing and conducting a PGx association study. The first critical decision is to determine whether the objective of the study is discovery, replication, or validation. Next, the researcher must identify a patient cohort that has all of the data necessary to conduct the intended analysis. Then, the investigator must select and define the treatment outcome, or phenotype, that will be analyzed. Next, the investigator must determine what genotyping approach and genetic data will be included in the analysis. Finally, the association between the genotype and phenotype is tested using some statistical analysis methodology. This tutorial is divided into 5 sections, each section describes commonly used approaches and provides suggestions and resources for designing and conducting a PGx association study. Successful PGx association studies are necessary to discover and validate associations between inherited genetic variation and treatment outcomes, which enable clinical translation to improve efficacy and reduce toxicity of treatment.

PMID:33880756 | DOI:10.1002/cpt.2270

Biol Res. 2021 Apr 20;54(1):13. doi: 10.1186/s40659-021-00336-4.

ABSTRACT

BACKGROUND: Helicobacter pylori is detected by pathogen recognition receptors including toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori.

RESULTS: A case-control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal-type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41-5.13, p = 0.0026). The association was not statistically significant in diffuse-type gastric cancer cases (OR = 1.26, 95% CI 0.63-2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80-3.36, p = 0.0019), in particular for intestinal-type gastric cancer cases (OR = 7.16, 95% CI 2.40-21.33, p = 4.1 × 10- 4) but not among diffuse-type gastric cancer cases (OR = 3.39, 95% CI 1.13-0.10, p = 0.03).

CONCLUSIONS: NOD1 rs2075820 increases the risk of intestinal-type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

PMID:33879265 | DOI:10.1186/s40659-021-00336-4

J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Apr 8;1173:122698. doi: 10.1016/j.jchromb.2021.122698. Online ahead of print.

ABSTRACT

Tacrolimus is the cornerstone of immunosuppressive therapy in solid organ transplantation and its blood concentrations are routinely monitored. Tacrolimus is extensively metabolized into metabolites that are supposed to be nephrotoxic. Yet, few analytical methods have been described to simultaneously quantify tacrolimus and its main metabolites. We developed and validated a simple liquid chromatography-mass spectrometry method for the quantification of tacrolimus and its three desmethylated metabolites, 13-O, 15-O, and 31-O-desmethylated tacrolimus (M-I, M-III, and M-II respectively) in human whole blood. Protein precipitation of 50 µL of whole blood with 100 µL methanol and zinc sulfate was used as a single-extraction procedure. Tacrolimus and its metabolites were quantified using electrospray ionization-triple quadrupole mass spectrometry in combination with selected reaction monitoring detection in the positive ionization mode. The method was validated following FDA recommendations. This method was precise (intra- and inter-assay coefficients of variation: 2.88-7.81% and 3.96-12.10% for low and high levels of internal quality controls, respectively) and accurate (intra- and inter-assay biases: -1.67-10.30%, and -0.77--9.36%, respectively). In adult kidney transplant patients who were treated with tacrolimus prolonged release formulation, the median (10th-90th percentiles) trough concentrations (n = 16) of tacrolimus, M-I, and M-III were 5.85 (3.37-7.09), 0.100 (0.037-0.168), 0.051 (0.03-0.104), respectively. M-II was measured in only 2 trough samples. The metabolic ratios M-I/tacrolimus and M-III/tacrolimus were 0.017 (0.009-0.027) and 0.009 (0.006-0.015) when measured on trough concentration and 0.022 (0.011-0.037) and 0.008 (0.006-0.015) when measured on area under the curves 0-24 h. This method is a suitable and easy-to-perform tool for future pharmacokinetic-pharmacodynamics studies investigating the importance of tacrolimus and its metabolites blood exposure for solid organ graft survival.

PMID:33878532 | DOI:10.1016/j.jchromb.2021.122698

Pharmacogenomics. 2021 Apr 20. doi: 10.2217/pgs-2020-0193. Online ahead of print.

ABSTRACT

Aim: To evaluate the variants in the genes coding for the proteins involved in thiopurine and folate metabolism with treatment related adverse effects (TRAEs). Materials & methods: Eleven variants in seven candidate genes were genotyped in 127 pediatric acute lymphoblastic leukemia patients under 6-mercaptopurine (6-MP) treatment to infer the association of selected genotypes with TRAEs. Results: Among the genotypes inspected, NUDT15 (c.415C>T) and SLC19A1 (c.80G>A) showed a significant association with the TRAEs (odds ratio = 4.01, p = 0.002 and odds ratio = 7.78, p = 0.002). Conclusion: SLC19A1 and NUDT15 play an important role in the metabolism of 6-MP and it is necessary to spot other variants in associated pathways and investigate the factors that can impact 6-MP metabolism.

PMID:33876659 | DOI:10.2217/pgs-2020-0193

J Genet Couns. 2021 Apr 19. doi: 10.1002/jgc4.1424. Online ahead of print.

ABSTRACT

Although genetic counseling is traditionally done through in-person, one-on-one visits, workforce shortages call for efficient result return mechanisms. Studies have shown that telephone and in-person return of cancer genetic results are equivalent for patient outcomes. Few studies have been conducted with other modes, result types or racially diverse participants. This study explored participants' perspectives on receiving pharmacogenomic results by mail. Two experienced moderators facilitated six focus groups with 49 individuals who self-identified primarily as African-American and consented to participate in a genome sequencing cohort study. Participants were given a hypothetical pharmacogenomic result report (positive for c.521T>C in SLCO1B1). An accompanying letter explained that the result was associated with statin intolerance along with a recommendation to share it with one's doctor and immediate relatives. Participants reacted to the idea of receiving this type of result by mail, discussing whether the letter's information was sufficient and what they predicted they would do with the result. Two researchers coded the focus group transcripts and identified themes. Many participants thought that it was appropriate to receive the result through the mail, but some suggested a phone call alerting the recipient to the letter. Others emphasized that although a letter was acceptable for disclosing pharmacogenomic results, it would be insufficient for what they perceived as life-threatening results. Most participants found the content sufficient. Some participants suggested resources about statin intolerance and warning signs be added. Most claimed they would share the result with their doctor, yet few participants offered they would share the result with their relatives. This exploratory study advances the evidence that African-American research participants are receptive to return of certain genetic results by approaches that do not involve direct contact with a genetic counselor and intend to share results with providers. ClinSeq: A Large-Scale Medical Sequencing Clinical Research Pilot Study (NCT00410241).

PMID:33876469 | DOI:10.1002/jgc4.1424

Sci Rep. 2021 Apr 19;11(1):8494. doi: 10.1038/s41598-021-87821-8.

ABSTRACT

Genetic risk analysis is increasingly in demand by participants. Hybrid genetic testing has the advantage over direct to consumer testing by involving a physician who guides the process and offers counseling after receiving the results. The objective of this study was to determine whether a structured physician moderated primary preventive, hybrid genetic risk assessment enhanced counseling program leads to improvement in lifestyle and does not impair quality of life. Risk genes for malignant, cardiovascular, coagulation, storage diseases and pharmacogenetics (> 100 genes) were tested. Screening, consultation and genetic counseling embedded in a primary/secondary prevention check-up program for executives of surrounding companies took place in a single center in Germany. Follow-up included established questionnaires for quality of life, nutrition and physical activity. Analysis included n = 244 participants. Median age at baseline was 49 years (interquartile range: 44-55), 93% were male, 3% (n = 7 of 136 responses) were smoker. Mean body mass index was 25.2 kg/m2. Follow-up response rate was 74% (n = 180), mean follow-up time was 6.8 months (standard deviation = 2.1). In 91 participants (37.8%, 91/241) at least one pathogenic variant was found, 60 thereof were clinically relevant (24.9%, 60/241). 238 participants (98%, 238/241) had > 1 pharmacogenetic variant, only 2 (0.8%, 2/241) took a correspondingly affected drug (56 participants took ≥ 1 drug/day). The energy expenditure significantly increased by ≈ 35% [median multiple of energy expenditure of 1.34 (confidence interval = 1.15-1.57, p < 0.001)] metabolic equivalents of task (MET)-min/week; participants spent on average 41 min (p < 0.001) less in sedentary activities per day and spent more time for lunch (≈ 2 additional minutes/day; p = 0.031). Indicators of the consumption of red meat and sweet pastries significantly decreased (both adjusted p = 0.049). Neither quality of life in general nor subgroup analysis of participants with at least one conspicuous genetic risk differed significantly over follow-up. Hybrid genetic testing and counseling exerted positive effects on health-related behavior and was not associated with major psychological adverse effects in the short-term follow-up. The approach seems to be feasible for use in preventive health care.

PMID:33875689 | DOI:10.1038/s41598-021-87821-8

Antimicrob Agents Chemother. 2021 Apr 19:AAC.00275-21. doi: 10.1128/AAC.00275-21. Online ahead of print.

ABSTRACT

Malaria remains one of the most deadly diseases in Africa, particularly for children. While successful in reducing morbidity and mortality, antimalarial treatments are also a major cause of adverse drug reactions (ADRs). Host genetic variation in genes involved in drug disposition or toxicity constitutes an important determinant of ADR risk and can prime for parasite drug resistance. Importantly however, the genetic diversity in Africa is substantial and thus genetic profiles in one population cannot be reliably extrapolated to other ethnogeographic groups. Gabon is considered a high-transmission country with more than 460,000 malaria cases per year. Yet, the pharmacogenetic landscape of the Gabonese population or its neighboring countries has not been analyzed. Using targeted sequencing, we here profiled 21 pharmacogenes with importance for antimalarial treatment in 48 Gabonese pediatric patients with severe Plasmodium falciparum malaria. Overall, we identified 347 genetic variants of which 18 were novel and each individual was found to carry 87.3±9.2 SD variants across all analyzed genes. Importantly, 16.7% of these variants were population-specific, highlighting the need for high-resolution pharmacogenomic profiling. Between one in three and one in six individuals harbored reduced activity alleles of CYP2A6, CYP2B6, CYP2D6 and CYP2C8 with important implications for artemisinin, chloroquine and amodiaquine therapy. Furthermore, one in three patients harbored at least one G6PD deficient allele, suggesting considerably increased risk of hemolytic anemia upon exposure to aminoquinolines. Combined, our results reveal the unique genetic landscape of the Gabonese population and pinpoint the genetic basis for inter-individual differences in antimalarial drug response and toxicity.

PMID:33875422 | DOI:10.1128/AAC.00275-21