Pharmacogenomics. 2022 Jun 8. doi: 10.2217/pgs-2022-0037. Online ahead of print.

ABSTRACT

Antidepressant medications are frequently used as the first line of treatment for depression. However, their effectiveness is highly variable and influenced by genetic factors. Recently, pharmacogenetic studies, including candidate-gene, genome-wide association studies or polygenic risk scores, have attempted to uncover the genetic architecture of antidepressant response. Genetic variants in at least 27 genes are linked to antidepressant treatment response in both coding and non-coding genomic regions, but evidence is largely inconclusive due to the high polygenicity of the trait and limited cohort sizes in published studies. Future studies should increase the number and diversity of participants to yield sufficient statistical power to characterize the genetic underpinnings and biological mechanisms of treatment response, improve results generalizability and reduce racial health-related inequities.

PMID:35673953 | DOI:10.2217/pgs-2022-0037

Rom J Morphol Embryol. 2021 Oct-Dec;62(4):897-906. doi: 10.47162/RJME.62.4.02.

ABSTRACT

Psoriasis is a chronic autoimmune disease affecting over 2% of the worldwide population. From an anatomopathological point of view, psoriasis is characterized by immune cells infiltration, epidermal hyperproliferation, and abnormal keratinocyte differentiation. Understanding the pathogenesis of psoriasis will allow clinicians to manage this complex disease. Under these conditions, the application of effective treatments requires a thorough knowledge of all the pathogenetic mechanisms that lead to psoriasis. Numerous immunopathological pathways play crucial roles in the development of new therapies, such as biological therapies, which have been a breakthrough in psoriasis's treatment. Pharmacogenetics is an essential factor in the patient's response to treatment. One important pathway targeted by modern treatments is the interleukin (IL)-23∕T-helper (Th)17 axis. Like IL-17 inhibitors, IL-23 blockers are a very effective therapy for this autoimmune disease. It is considered that micro-ribonucleic acids (microRNAs) are the starting point for any autoimmune disease. Studying certain microRNA (miR) involved in the inflammatory pathway in psoriasis can find direct targets to future treatments that can even be more specific than actual biological therapies. As such, miR-210 has proven to be up-regulated in psoriasis, also leading to the up-regulation of the Th1∕Th17 axis. On the other hand, miR-187 was found to be down-regulated, influencing the outcome of psoriasis by increasing the proliferation of IL-6 stimulated keratinocytes and consecutively generating epidermal thickening. In this review, we are aiming to do an up-to-date briefing of psoriasis histopathology and pharmacogenetic factors that are considered for the accurate evaluation of treatment response.

PMID:35673809 | DOI:10.47162/RJME.62.4.02

J Diabetes Metab Disord. 2022 Jan 11;21(1):133-139. doi: 10.1007/s40200-021-00947-4. eCollection 2022 Jun.

ABSTRACT

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a common chronic condition characterized by high blood glucose levels which is caused by genetic and environmental factors. Currently, pharmacogenomics (PGx) is anticipated to enable the development of personalized treatment in a wide range of health issues. Sulfonylureas (SFUs) are among the oral anti-diabetic drugs that are very popular due to their low cost. Genetic variants in transcription factor 7 like 2 (TCF7L2) and potassium voltage-gated channel subfamily Q member 1 (KCNQ1) have been reported for altered therapeutic response to sulfonylurea. The aim of the present study is to evaluate any association between common genetic variant of the TCF7L2 and KCNQ1 (rs7903146 and rs2237892, respectively) and the response to sulfonylurea in a group of Iranian patients for the first time.

METHODS: Genotyping was carried out in 30 T2DM patients who received sulfonylurea treatment for more than two months in addition to previous medication using the Sanger sequencing method.

RESULTS: In 30 T2DM patients who received SFUs treatment, 60%, 33.3% and 6.7% had CC, CT and TT genotypes, respectively. After treatment, adjusted fasting blood sugar (FBS) mean reduction level in CT and TT carriers was lower than CC carriers. Adjusted hemoglobin A1c (HbA1c) mean reduction level was also lower in CT and TT compared with CC carriers, but, none of these differences were statistically significant. Genotype frequencies of TT, CT and CC genotypes of rs2237892 variant of KCNQ1 gene were 0 (0%), 3 (10%) and 27 (90%) respectively. Patients with CT and CC genotypes of rs2237892 variant had also similar changes in FBS (P=0.200) and HbA1c (P=0.436) after treatment with SFUs.

CONCLUSIONS: Genotypes of TCF7L2 and KCNQ1 common variant did not show any impact on the treatment response among T2DM patients receiving SFUs.

PMID:35673510 | PMC:PMC9167329 | DOI:10.1007/s40200-021-00947-4

J Diabetes Metab Disord. 2021 Aug 24;21(1):853-861. doi: 10.1007/s40200-021-00880-6. eCollection 2022 Jun.

ABSTRACT

Genomic medicine has created a great deal of hope since the completion of the Human Genome Project (HGP). Genomic medicine promises disease prevention and early diagnosis in the context of precision medicine. Precision medicine as a scientific discipline has introduced as an evolution in medicine. The rapid growth of high-development technologies permits the assessment of biological systems. Study of the integrated profiles of omics, such as genome, transcriptome, proteome and other omics information lead to significant advances in personalized and precision medicine. In the context of precision medicine, pharmacogenomics can play an important role in order to discriminate responders and non-responders to medications and avoiding toxicity and achieving the optimum dose. So precision medicine in accordance with genomic medicine will transform medicine from conventional evidence-based medicine in the diagnosis and treatment towards precision based-medicine. In this review, we have summarized the related issues for genomic medicine and precision medicine.

PMID:35673457 | PMC:PMC9167337 | DOI:10.1007/s40200-021-00880-6

J Diabetes Metab Disord. 2021 Nov 24;21(1):881-888. doi: 10.1007/s40200-021-00913-0. eCollection 2022 Jun.

ABSTRACT

It has been well established that understanding the underlying heterogeneity of numerous complex disease process needs new strategies that present in precision medicine for prediction, prevention and personalized treatment strategies. This approach must be tailored for each individual's unique omics that lead to personalized management of disease. The correlation between different omics data should be considered in precision medicine approach. The interaction provides a hypothesis which is called domino effect in the present minireview. Here we review the various potentials of omics data including genomics, transcriptomics, proteomics, metabolomics, pharmacogenomics. We comprehensively summarize the impact of omics data and its major role in precision medicine and provide a description about the domino effect on the pathophysiology of diseases. Each constituent of the omics data typically provides different information in associated with disease. Current research, although inadequate, clearly indicate that the information of omics data can be applicable in the concept of precision medicine. Integration of different omics data type in domino effect hypothesis can explain the causative changes of disease as it is discussed in the system biology too. While most existing studies investigate the omics data separately, data integration is needed on the horizon of precision medicine by using machine learning.

PMID:35673436 | PMC:PMC9167178 | DOI:10.1007/s40200-021-00913-0

J Diabetes Metab Disord. 2021 Dec 1;21(1):863-879. doi: 10.1007/s40200-021-00908-x. eCollection 2022 Jun.

ABSTRACT

PURPOSE: Genetic factors have a role in response to a target medication (personalized medicine). This study aimed to review available evidence about the relationship between gene variants and therapeutic response to sulfonylureas in type 2 diabetes, systematically.

METHODS: An extensive search was done in Scopus, PubMed, and Web of Science with specific search strategy in the field from the beginning until the 1st of Jan. 2021. After sending records to endnote software and removing duplicate records remained documents were screened by title and abstract. Full texts of remained documents were assessed after removing un-related records. Required data was extracted from remained documents and records were categorized according to gene/SNP studied.

RESULTS: Finally, 26 studies with 9170 T2DM patients with a mean age of 59.47 ± 6.67 (49.7-75.2 years) remained. The most contribution was from China, Slovakia and Greece, respectively and the most genes studied were CYP2C9, KCNJ11, and both KCNQ1 and ABCC8 with 10, 7, and 4 articles, respectively. Also, rs1799853 and rs1057910 (each with seven studies), rs5219 with six studies and CYP2C9*1(with four articles), respectively were the most common variants investigated. Studies about each gene obtained different positive or negative results and were not consistent.

CONCLUSION: Considering heterogeneity between SFUs pharmacogenomic studies regarding the method, sample size, population, gene/variant studied, and outcome and findings, these studies are not conclusive and need further studies.

PMID:35673432 | PMC:PMC9167353 | DOI:10.1007/s40200-021-00908-x

Biotechnol Lett. 2022 Jun 7. doi: 10.1007/s10529-022-03266-7. Online ahead of print.

ABSTRACT

PURPOSE: Hepatocellular carcinoma (HCC) is the uncontrolled growth of hepatocytes which results in nearly 5 million deaths worldwide. Specific strategies have been developed to treat HCC, including surgery, chemotherapy and radiotherapy. But, the effective disease dealing requires synergistic collaboration with other approaches, which often results in moderate to severe side effects during and after the treatment period. Therefore, the focus is now shifting to explore and retrieve those plant-based products that could be utilized to treat HCC with maximum efficacy without causing any side effects. Strigolactones (SL) are compounds of plant origin derived from Striga lutea responsible for controlling the branching pattern of stem and have reported anti-cancerous activity by promoting apoptosis at micromolar concentrations. However, little work has been done concerning determining the pharmacogenomic effect of strigolactones on HCC.

METHODS: Current work focuses on comparing therapeutic efficiencies of SL analogs against core targets of HCC using network pharmacology approach, pharmacokinetics analysis, gene ontogeny, functional enrichment analysis, molecular docking and Molecular Dynamics simulation.

RESULTS: Drug-target prediction and functional enrichment analysis showed that HDAC1 and HDAC2 are the core proteins involved in hepatocellular carcinoma that strigolactone analogs can target. Consequently, results from molecular docking and MD simulation analyses report that among all the SL analogs strigol, epistrigol and nijmegen1 can turn out to be most effective in downregulating the expression of HDAC1, HDAC2 and CYP19A.

CONCLUSION: Strigol, epistrigol and nijmegen1 could be used as potential inhibitors against HCC and can be further validated through in vitro/in vivo studies.

PMID:35672528 | DOI:10.1007/s10529-022-03266-7

Semin Arthritis Rheum. 2022 May 28;55:152036. doi: 10.1016/j.semarthrit.2022.152036. Online ahead of print.

ABSTRACT

OBJECTIVE: To examine genetic influence on the risk of elevations in liver function tests (AST and ALT) among patients using low-dose methotrexate (LD-MTX).

METHODS: We examined data from the LD-MTX arm of a randomized double-blind placebo-controlled trial conducted among subjects without rheumatic disease. Genome wide association studies (GWAS) were performed in subjects of European ancestry to test the association between single nucleotide polymorphisms (SNPs) and the log transformed maximum values of AST, ALT, and dichotomized outcome with AST or ALT > 2 times upper limit of normal (ULN). The association between variants in MTX metabolism candidate genes and the outcomes was also tested. Furthermore, associations between a drug induced liver injury (DILI) weighted genetic risk score (wGRS) and the outcomes were tested, combining 10 SNPs and 11 classical HLA alleles associated with DILI.

RESULTS: In genome-wide genetic analyses among 1,429 subjects of European ancestry who were randomized to receive LD-MTX, two SNPs reached genome wide significance for association with log transformed maximum ALT. We observed associations between established candidate genes in MTX pharmacogenetics and log transformed maximum AST and ALT, as well as in dichotomized outcome with AST or ALT > 2 x ULN. There was no association between DILI wGRS or candidate variants and AST, ALT, or DILI response.

CONCLUSIONS: Modest evidence was observed that common variants affected AST and ALT levels in subjects of European ancestry on LD-MTX, but this genetic effect is not useful as a clinical predictor of MTX toxicity.

PMID:35671649 | DOI:10.1016/j.semarthrit.2022.152036

Eur J Cancer Prev. 2022 May 27. doi: 10.1097/CEJ.0000000000000757. Online ahead of print.

ABSTRACT

OBJECTIVE: To explore compliance with the smoke-free policy in hospitals in Catalonia, Spain, by exploring inpatients' perceptions.

METHODS: We conducted a cross-sectional study of a random sample of 1047 inpatients from 13 public hospitals. We collected data about: (a) type of information about the smoke-free policy provided by the hospital, (b) patients' knowledge about the policy, (c) general appreciation of the compliance with the policy, and (d) specific appreciation of such compliance by noticing any sign of tobacco consumption. We described the data by several patients' and hospitals' characteristics and assessed their association with the perceived noncompliance using prevalence ratios (PR) and their 95% confidence intervals (CIs).

RESULTS: Few patients were informed about the smoke-free policy (4.8% orally, 6.1% in writing, and 55.6% through sign postings). About 64% were aware of the regulation and 73.5% believed that it was properly obeyed. While 0.7% had never or rarely observed smoking indoors, 36.2% had seen someone smoking outdoors sometimes or many times. Signs of tobacco consumption were observed indoors and outdoors. Factors associated with the perception of noncompliance were: being less than 45 years old versus being more than 64 years old (adjusted PR, 2.33; 95% CI, 1.09-4.98) and currently smoking versus have never smoked (adjusted PR, 1.84; 95% CI, 1.02-3.34).

CONCLUSION: Compliance with the smoke-free policy in hospitals according to the patients' view is notable, although several infringements were reported, mainly outdoors. The smoke-free policy in hospitals should be reinforced by prompting continuous awareness campaigns and the exemplary role of hospital workers.

PMID:35671260 | DOI:10.1097/CEJ.0000000000000757

Pharmacogenomics. 2022 Jun 7. doi: 10.2217/pgs-2022-0056. Online ahead of print.

ABSTRACT

Implementation of personalized medicine in the clinic is a lengthy and multifaceted approach that is also dependent on the raising of the general public's awareness of genomics. The Festival of Genetics and Personalized Medicine aims to familiarize the general public with the principles and applications of genetics and personalized medicine using numerous approaches - namely, a theatrical performance; a roundtable discussion of emerging topics in the field, such as pharmacogenomics, clinical genetics, bioinformatics, bioethics and health economics; the 'Genome: Unlocking Life's Code' exhibition, with its do-it-yourself format; and a live demonstration of 2MoBiL, a portable molecular biology laboratory. This festival attracted more than 900 participants and helped disseminate to a broader audience the principles of genetics and personalized medicine.

PMID:35670264 | DOI:10.2217/pgs-2022-0056

Pharmacogenomics. 2022 Jun 7. doi: 10.2217/pgs-2022-0025. Online ahead of print.

ABSTRACT

Cystic fibrosis is a genetic, multiorgan system disease that involves the use of many medications to control symptoms associated with the underlying condition. Many of these medications have Clinical Pharmacogenetics Implementation Consortium evidence-based guidelines for pharmacogenomics that are available to guide dosing. The aim of this article is to review relevant literature and evaluate the utility of preemptive pharmacogenomics testing for persons with cystic fibrosis and propose a pharmacogenomics panel that could be considered standard of care for persons with cystic fibrosis.

PMID:35670256 | DOI:10.2217/pgs-2022-0025

Clin Transl Sci. 2022 Jun 6. doi: 10.1111/cts.13347. Online ahead of print.

ABSTRACT

Sertraline is a commonly used SSRI antidepressant drug, metabolised by CYP2C19 and CYP2B6, that exhibits a substantial interindividual variation in clinical response, of which only a part can be attributed to known genetic variants. In the current study we have examined the role of a newly discovered ultrarapid CYP2C:TG haplotype and CYP2B6 variants in order to identify the possible missing heritability for such variation in sertraline response in a large patient population (n=840). Compared to the reference group (CYP2C19*1/*1, n=160), sertraline exposure was increased by 128% in CYP2C19 PMs (n=29, p<0.001) but decreased by about 20% in CYP2C19 UMs (homozygous carriers of CYP2C19*17 and/or CYP2C:TG haplotype) with the diplotypes CYP2C19*17/*17, CYP2C:TG/TG or CYP2C19*17/CYP2C:TG (n=135, p<0.003, p=0.022, p<0.003, respectively). Interestingly, in patients carrying the increased function CYP2B6*4 allele, also carrying CYP2C19*17 and CYP2C:TG alleles (n=10), sertraline exposure was 35.4% lower compared to the reference group, whereas in subjects being PM in both the CYP2C19 and CYP2B6 gene, the sertraline concentrations were raised by 189%. In summary, the CYP2C19 variants including the CYP2C:TG haplotype, had a significant impact on sertraline metabolism, as well as the CYP2B6*4, *6 and *9 alleles. Knowing CYP2B6 and CYP2C19 genotype, including the CYP2C:TG haplotype status, can prospectively be useful to clinicians in making more appropriate sertraline dosing decisions.

PMID:35668575 | DOI:10.1111/cts.13347

Nat Commun. 2022 Jun 6;13(1):3124. doi: 10.1038/s41467-022-30875-7.

ABSTRACT

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

PMID:35668104 | DOI:10.1038/s41467-022-30875-7

Phytochem Anal. 2022 Jun 6. doi: 10.1002/pca.3147. Online ahead of print.

ABSTRACT

INTRODUCTION: Citri Reticulatae Pericarpium Viride (CRPV, Qing Pi in Chinese) has been widely used in traditional Chinese medicine. Polymethoxylated flavonoids (PMFs), which are a special group of flavonoids with strong antitumor activity, are broadly distributed in citrus peels. However, systematic investigation of antitumor PMFs in CRPV has received little attention to date.

OBJECTIVES: An MCF-7 cell biospecific extraction method integrated with neutral loss/diagnostic ion filtering-based HPLC-QTOF-MS/MS strategy was developed for rapid and specific profiling of antitumor PMFs and systematic identification of PMFs in CRPV.

METHODOLOGY: By incubating MCF-7 cells with CRPV extract, potential antitumor PMFs specifically bound to cells and were isolated. Then, by systematic investigation of fragmentation pathways, neutral loss and diagnostic ion filtering strategies were proposed to comprehensively and accurately identify PMFs.

RESULTS: Sixteen antitumor PMFs were unambiguously or tentatively identified. Among them, minor compound 15 (5-hydroxy-6,7,8,3',4'-pentamethoxyflavone with a free hydroxyl group at C-5) exhibited excellent antitumor activity, with an IC50 value of 2.81 ± 0.76 μg/mL, which is lower than that of 5-fluorouracil (IC50 , 4.92 ± 0.83 μg/mL). Nobiletin (12) and tangeretin (16), two major PMFs, presented moderate antitumor activities with IC50 values of 13.06 ± 1.85 and 17.07 ± 1.18 μg/mL, respectively, and their contents were sensitively and precisely determined.

CONCLUSIONS: To the best of our knowledge, this is the first report on the systematic investigation of antitumor PMFs in CRPV. The study will lay a foundation for the quality control and clinical application of CRPV.

PMID:35668040 | DOI:10.1002/pca.3147

Clin Colorectal Cancer. 2022 May 11:S1533-0028(22)00055-X. doi: 10.1016/j.clcc.2022.05.001. Online ahead of print.

ABSTRACT

BACKGROUND: Adjuvant fluoropyrimidine-based chemotherapy substantially reduces recurrence and mortality after resection of stage 3 colon cancer. While standard doses of 5-fluorouracil and capecitabine are safe for most patients, the risk of severe toxicity is increased for the approximately 6% of patients with dihydropyimidine dehydrogenase (DPD) deficiency caused by pathogenic DPYD gene variants. Pre-treatment screening for pathogenic DPYD gene variants reduces severe toxicity but has not been widely adopted in the United States.

METHODS: We conducted a cost-effectiveness analysis of DPYD genotyping prior to fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer, covering the c.1129-5923C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and c.2846A>T gene variants. We used a Markov model with a 5-year horizon, taking a United States healthcare perspective. Simulated patients with pathogenic DPYD gene variants received reduced-dose fluoropyrimidine chemotherapy. The primary outcome was the incremental cost-effectiveness ratio (ICER) for DPYD genotyping.

RESULTS: Compared with no screening for DPD deficiency, DPYD genotyping increased per-patient costs by $78 and improved survival by 0.0038 quality-adjusted life years (QALYs), leading to an ICER of $20,506/QALY. In 1-way sensitivity analyses, The ICER exceeded $50,000 per QALY when the cost of the DPYD genotyping assay was greater than $286. In probabilistic sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY DPYD genotyping was preferred to no screening in 96.2% of iterations.

CONCLUSION: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe and sometimes fatal toxicities of fluoropyrimidine chemotherapy.

PMID:35668003 | DOI:10.1016/j.clcc.2022.05.001

Phytomedicine. 2022 May 28;102:154218. doi: 10.1016/j.phymed.2022.154218. Online ahead of print.

ABSTRACT

BACKGROUND: Cannabis oils from FM2®, Bedica®, Bediol®, Bedrocan®, Bedrolite® and Pedanios 22/1® are largely used for medical purposes such as spasticity, chronic pain and appetite stimulating. Several studies showed cannabinoids action on CB1 and CB2 receptors reduces the hyperalgesic phase in inflammatory pain, leading to an improvement of conditions. The active compounds of these galenic preparations show a high variability making titration mandatory. For this reason, the exact oil composition knowledge is fundamental for personalizing therapy. This amis at adapting the correct dose to the patient, improving safety and efficacy of the galenic formulation, choosing the best preparation for each patient.

PURPOSE: The aim of this study was to investigate oil preparations variability among different galenic laboratories in order to highlight the importance of titration activity.

METHODS: Cannabis pharmacological active compounds titration has been performed in a large cohort of galenic laboratories in Italy. CBD, CBN, THC, THCA and CBDA quantification was carried out by a previous validated method in UHPLC-MS/MS.

RESULTS: A number of 4318 samples of Cannabis oil from 83 pharmacies between January 2021 and February 2022 were evaluated. All galenic preparation specialities showed statistically significant differences among galenic laboratories (p-value < 0.001). THCA and CBDA concentrations were investigated as percentage of the extration yelds for total THC and CBD: these compounds had different values in the same specialities among distinct galenic laboratories. Moreover, seasonal variability in analytes concentrations was observed.

CONCLUSION: This study described a wide range of oily samples from a large number of galenic laboratories, compared to published papers. In conclusion, knowledge of the exact oil composition is fundamental in the perspective of personalized therapy. Further studies aiming at the correlation between galenic composition and cannabinoids pharmacokinetics, clinical outcomes and toxic effects could be useful to improve our knowledge.

PMID:35665680 | DOI:10.1016/j.phymed.2022.154218

Front Genet. 2022 May 19;13:836970. doi: 10.3389/fgene.2022.836970. eCollection 2022.

ABSTRACT

Background: Statins are the most popular agents for the primary and secondary prevention of cardiovascular disease; however, the pharmacokinetic parameters and associated genetic factors in the Korean population have not been fully elucidated. This study explored the pharmacokinetic properties of atorvastatin and the association between genetic variations and atorvastatin pharmacokinetics in healthy Korean subjects. Methods: Atorvastatin (80 mg) was administered to 35 healthy Korean volunteers. Plasma levels of atorvastatin and its metabolites were measured sequentially using liquid chromatography-tandem mass spectrometry from 0 to 24 h after atorvastatin administration. Customized next-generation sequencing analysis was performed covering all coding exons of 15 genes, as well as 46 single-nucleotide variants in 29 genes related to statin pharmacokinetics. Results: The mean area under the concentration-time (AUC) and Cmax (maximum peak concentration) were 269.0 ng/ml∙h and 84.3 ng/ml, respectively, which were approximately two times higher than those reported in Caucasians. Genetic analysis revealed that eight genetic variants in ABCB1, ABCG2, APOA5, CETP, and CYP7A1 contributed to the AUC of atorvastatin. The atorvastatin AUC0-24 h prediction model was developed based on age and eight genetic variants using multivariate linear regression (adjusted R 2 = 0.878, p < 0.0001). Conclusion: This study shows that the pharmacokinetic properties of atorvastatin in Koreans are different from those in Caucasians and that atorvastatin AUC0-24 h could be predicted based on age and eight genetic variants of ABCB1, ABCG2, APOA5, CETP, and CYP7A1.

PMID:35664336 | PMC:PMC9160745 | DOI:10.3389/fgene.2022.836970

Front Genet. 2022 May 19;13:869160. doi: 10.3389/fgene.2022.869160. eCollection 2022.

ABSTRACT

Omeprazole is extensively used to manage gastroesophageal reflux disease (GERD). It is primarily metabolized by CYP2C19. The CYP2C19*17 (rs12248560) allele and the recently described CYP2C:TG haplotype (rs11188059 and rs2860840) are associated with increased enzymatic activity, and may reduce omeprazole exposure. This observational study aimed to investigate the association between these genetic variants and omeprazole treatment failure in GERD. We recruited predominantly New Zealand European GERD patients who either did not respond to omeprazole or experienced breakthrough heartburn symptoms despite at least 8 weeks of omeprazole (≥40 mg/day). The GerdQ score was used to gauge symptomatic severity. A total of 55 cases were recruited with a median age (range) of 56 years (19-82) and GerdQ score of 11 (5-17). Of these, 19 (34.5%) were CYP2C19*17 heterozygotes and two (3.6%) were CYP2C19*17 homozygotes. A total of 30 (27.3%) CYP2C:TG haplotypes was identified in our cohort, with seven (12.7%) CYP2C:TG homozygotes, and 16 (29%) CYP2C:TG heterozygotes. No significant differences were observed for overall CYP2C19*17 alleles, CYP2C19*17/*17, overall CYP2C:TG haplotypes, and CYP2C:TG heterozygotes (p > 0.05 for all comparisons). Gastroscopy and 24-h esophageal pH/impedance tests demonstrated objective evidence of GERD in a subgroup of 39 (71%) cases, in which the CYP2C:TG/TG was significantly enriched (p = 0.03) when compared with the haplotype frequencies in a predominantly (91%) New Zealand European reference population, but not the CYP2C19*17/*17 (p > 0.99), when compared with the allele frequencies for the non-Finnish European subset of gnomAD. We conclude that omeprazole treatment failure in GERD is associated with CYP2C:TG/TG, but not CYP2C19*17.

PMID:35664313 | PMC:PMC9160307 | DOI:10.3389/fgene.2022.869160

Front Pharmacol. 2022 May 18;13:885259. doi: 10.3389/fphar.2022.885259. eCollection 2022.

ABSTRACT

The implementation of pharmacogenetic testing into clinical practice has been a slow process so far. Here, we review the implementation of pre-treatment testing of dihydropyrimidine dehydrogenase gene (DPYD) risk variants to prevent early-onset fluoropyrimidine (FP)-related toxicity in cancer patients in Switzerland based on data of a large Swiss diagnostic center. In January 2017, the Swiss Federal Office of Public Health introduced the reimbursement of DPYD testing by the compulsory health insurance in Switzerland based on evidence for the clinical relevance of DPYD-risk variants and the cost-effectiveness of pre-treatment testing, and on the availability of international guidelines. However, we did not observe a strong increase in DPYD testing at our diagnostic center from 2017 to 2019. Only a low number of DPYD-testing requests (28-42 per year), concerning mostly retrospective investigations of suspected FP-toxicity, were received. In contrast, we observed a 14-fold increase in DPYD testing together with a strong shift from retrospective to pre-treatment test requests upon the release of recommendations for DPYD testing prior to FP-treatment in April 2020 by the European Medicines Agency. This increase was mainly driven by three geographic regions of Switzerland, where partner institutions of previous research collaborations regarding FP-related toxicity are located and who acted as early-adopting institutions of DPYD testing. Our data suggest the important role of early adopters as accelerators of clinical implementation of pharmacogenetic testing by introducing these policies to their working environment and educating health workers from their own and nearby institutions.

PMID:35662713 | PMC:PMC9159275 | DOI:10.3389/fphar.2022.885259

Contemp Clin Trials. 2022 Jun 1:106813. doi: 10.1016/j.cct.2022.106813. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVE: APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease.

STUDY DESIGN: Multicenter, pragmatic, randomized controlled clinical trial.

SETTING AND PARTICIPANTS: 6650 individuals with African ancestry and hypertension from 13 health systems.

INTERVENTION: APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use.

OUTCOMES: Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months.

RESULTS: To date, the trial has enrolled 3423 participants.

CONCLUSIONS: The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record.

TRIAL REGISTRATION: ClinicalTrials.govNCT04191824.

PMID:35660539 | DOI:10.1016/j.cct.2022.106813