Explor Res Clin Soc Pharm. 2022 Oct 13;8:100192. doi: 10.1016/j.rcsop.2022.100192. eCollection 2022 Dec.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is a rapidly growing field which promises to deliver personalized, more effective medications tailored to genetic information. Although the pharmacy profession is expected to lead the translation of pharmacogenomics into widespread clinical implementation, there is a reported lack of preparedness among its members. Assessing pharmacogenomic-related training in Australian pharmacy program curricula may highlight educational gaps and provide guidance for curricula revision.

OBJECTIVE: To examine pharmacogenomic content in Australian tertiary pharmacy program curricula.

METHODS: We reviewed the curriculum of 22 Australian registrable pharmacy degrees, including 16 Bachelors of Pharmacy programs (with or without honors) and six Masters of Pharmacy programs, for content related to pharmacogenomics and genetics. This was done by screening the publicly available electronic course profiles on each institution's website and searching for key terms such as "pharmacogenomics," "pharmacogenetics," "genes," and "genetics". Three mapping activities were completed to assess the breadth and depth of pharmacogenomic training according to; 1. Bloom's taxonomy, 2. Author-assigned domains comprising; Enabling science, Translational science and Clinical implementation, and 3. Pharmacogenomic competencies from the National Human Genome Research Institute (NHGRI).

RESULTS: A total of 18 (82%) pharmacy registrable degree programs incorporated pharmacogenomics and/or genetics in their curricula. Four programs (18%) offered standalone PGx courses and 10 (45%) contained integrated PGx content in other science-related courses (i.e. pharmaceutical biology, biochemistry, microbiology etc.). Mapping activities showed that most learning objectives related to the "Understand" level of Bloom's taxonomy (61%), the "Basic Genetic Concepts" domain of NHGRI's competencies (64%) and "Enabling science" (84%).

CONCLUSIONS: Most Australian pharmacy registrable degrees have incorporated pharmacogenomic content in their curricula however, the scope of training is limited. Revisions to course curricula should be made to incorporate additional education with a focus on application-based training of clinical pharmacogenomics.

PMID:36299640 | PMC:PMC9589202 | DOI:10.1016/j.rcsop.2022.100192

Vaccines (Basel). 2022 Oct 8;10(10):1676. doi: 10.3390/vaccines10101676.

ABSTRACT

(1) Background: The purpose of this study was to investigate the concerns and beliefs of Olympians and elite athletes toward COVID-19 vaccination. (2) Methods: The study was framed by a quantitative method and was conducted using the PAPI (pen and paper interview) technique among 895 Polish elite athletes representing 34 sports. (3) Results: Three-quarters (76.3%) of the athletes were vaccinated against COVID-19; statistically participants were more likely to be women, and athletes who participated in the Olympic Games. Four in ten (39.2%) were in favor of vaccination. Athletes were mainly concerned that COVID-19 would exclude them from training/competition (19.3%) and could have a long-term impact on their health (17.2%). Athletes who were vaccinated reported much higher confidence in the composition of the vaccine and the doctors who recommended vaccination than unvaccinated athletes. Athletes who competed at the Olympic level were more likely than others to disbelieve that vaccines were produced too quickly and were not well tested. National-level athletes showed the highest degree of distrust in the government regarding COVID-19 vaccination, with one in six respondents distrusting doctors with respect to COVID-19 vaccination. Four in ten respondents said they were in favor of vaccination. (4) Conclusions: Athletes' attitudes toward COVID-19 vaccination were significantly influenced by their environment-especially coaches and relatives. The power of social norms with respect to the decision to vaccinate against COVID-19 was very strong. Therefore, it is essential to build awareness about preventive policies among athletes and their social environment.

PMID:36298541 | DOI:10.3390/vaccines10101676

Vaccines (Basel). 2022 Sep 22;10(10):1592. doi: 10.3390/vaccines10101592.

ABSTRACT

Anti-drug vaccines previously failed clinical trials because they did not provide a sufficient titer or duration of antibodies (AB), but new adjuvants enhance both AB titers and efficacy duration. This clinical trial assessed AB titers after a single booster of commercial tetanus-diphtheria (Td) vaccine in 40 males randomized as 15 to Td alone and 25 to Td combined with the TLR5 adjuvant, Entolimod (Ent). Ent significantly increased ABs against diphtheria (DPT) (0.46 vs. 0.29 IU/mL increase; n = 40, p < 0.05), but against tetanus (TT) only if baseline TT AB was below 3 IU/mL (3.1 vs. 2.1 IU/mL; n = 20; p < 0.05). These 20 participants also showed a two-fold increase in anti-TT AB titer more often when given Ent than non-Ent (33% vs. 82%) (p < 0.03). Anti-Ent AB was low and appeared unlikely to reduce Ent efficacy after repeated Ent administration. Medical safety was excellent, and a TLR5 missense polymorphism reduced anti-DPT AB production, but Ent increased anti-DPT AB titers to levels induced in subjects with genetically "normal" TRL5 functioning. Further clinical testing of TLR5 adjuvants like Ent seems warranted for anti-drug vaccines.

PMID:36298456 | DOI:10.3390/vaccines10101592

Pharmaceutics. 2022 Oct 12;14(10):2177. doi: 10.3390/pharmaceutics14102177.

ABSTRACT

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

PMID:36297612 | DOI:10.3390/pharmaceutics14102177

Pharmaceutics. 2022 Sep 29;14(10):2082. doi: 10.3390/pharmaceutics14102082.

ABSTRACT

BACKGROUND: The variant rs34983651 (UGT1A1*28) and its genotyping are used to prevent irinotecan-induced toxicity. Several variants are in close linkage disequilibrium. Our objective was to evaluate the potential correlation of genotyping UGT1A1*80 instead of UGT1A1*28 in different populations.

METHODS: We studied SNPs in linkage disequilibrium with UGT1A1*28 in several populations and selected rs887829 to develop an inexpensive and rapid genotyping method and compare it with the one we currently use for UGT1A1*28 genotyping. Samples from cancer patients (n = 701) already tested using PCR and electrophoresis prior to treatment with irinotecan for rs34983651 (UGT1A1*28) in a Spanish hospital were genotyped for rs887829 (UGT1A1*80) using real-time PCR with a TaqMan probe.

RESULTS: We observed a complete match for both genotypes, except in one sample. This method was 100% efficient in correctly genotyping *28/*28 patients, 99.68% efficient for *1/*28, and 100% efficient for *1/*1. Linkage disequilibrium between populations showed the Iberian population to be the most suitable for the clinical use of UGT1A1*80. This method is less expensive and the time to decision is shorter.

CONCLUSION: Genotyping of rs887829 using the proposed method may be used to substitute genotyping of rs34983651 as a pharmacogenetics test in cancer patients prior to starting irinotecan-based treatments, mainly in the Iberian population. In addition, it is less expensive than other conventional methods and easy to implement, with a shorter time to decision than UGT1A1*28.

PMID:36297516 | DOI:10.3390/pharmaceutics14102082

Pharmaceutics. 2022 Sep 21;14(10):2001. doi: 10.3390/pharmaceutics14102001.

ABSTRACT

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson's disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.

PMID:36297437 | DOI:10.3390/pharmaceutics14102001

Pharmaceutics. 2022 Sep 21;14(10):1995. doi: 10.3390/pharmaceutics14101995.

ABSTRACT

Although some methods for measuring bioadhesion/mucoadhesion have been proposed, a standardized method is not yet available. This is expected to hinder systematic comparisons of results across studies. This study aimed to design a single/systematic in vitro method for measuring bioadhesion/mucoadhesion that is applicable to various pharmaceutical dosage forms. To this end, we measured the peak force and work of adhesion of minitablets, pellets, and a bioadhesive emulsion using a texture analyzer. Porcine tissue was used to simulate human stomach/skin conditions. The results of these formulations were then compared to those for formulations without the bioadhesive product. We conducted a case study to assess the stability of a bioadhesive emulsion. The results for the two parameters assessed were contact time = 60 s and contact force = 0.5 N at a detachment speed of 0.1 mm/s. Significant differences were observed between the bioadhesive and control formulations, thus demonstrating the adhesive capacity of the bioadhesive formulations. In this way, a systematic method for assessing the bioadhesive capacity of pharmaceutical dosage forms was developed. The method proposed here may enable comparisons of results across studies, i.e., results obtained using the same and different pharmaceutical formulations (in terms of their bioadhesion/mucoadhesion capacity). This method may also facilitate the selection of potentially suitable formulations and adhesive products (in terms of bioadhesive properties).

PMID:36297431 | DOI:10.3390/pharmaceutics14101995

Pharmaceuticals (Basel). 2022 Oct 21;15(10):1300. doi: 10.3390/ph15101300.

ABSTRACT

Prunus spinosa fruits (sloes), both fresh and dried, are underexplored dietary components and ethno-phytotherapeutic remedies applied to treat chronic oxidative-stress-related diseases, including diabetes. The present study aimed to evaluate drying-related changes in the antidiabetic potential of sloe extracts and some bioactivity mechanisms, which might be connected with their traditional application. The polyphenol-enriched extracts, prepared by fractionated extraction and phytochemically standardised, i.a., by LC-MS/MS, were tested in vitro using a set of biological and chemical models. The experiments revealed the significant extracts' ability to counteract the generation of advanced glycation end products (AGEs) and inhibit the activity of key glycolytic enzymes, i.e., α-glucosidase and α-amylase. Moreover, they were proved to effectively scavenge multiple oxidants of physiological importance (O2•-, HO•, H2O2, NO•, HOCl), increase the non-enzymatic antioxidant capacity of human plasma (NEAC) under oxidative stress conditions induced by peroxynitrite, and protect plasma proteins and lipids against peroxidation and nitration at in vivo-relevant levels (1-50 µg/mL, equivalent to 0.03-6.32 µg polyphenols/mL). In most cases, the activity of fresh fruit extracts surpassed that of dried-based products. The correlation studies and tests on model compounds proved polyphenols as dominant contributors to the observed effects. Furthermore, the co-occurring representatives of various polyphenolic classes were found to contribute to the biological activity of sloes through additive and synergistic effects. Considering the extraction yield and activity parameters, especially the superior outcomes compared to anti-diabetic drugs aminoguanidine and acarbose in the anti-glycation and α-glucosidase inhibition tests, the methanol-water (75:25, v/v) extract of fresh fruits and its phenolic-enriched fractions revealed the most advantageous potential for functional application.

PMID:36297412 | DOI:10.3390/ph15101300

Pathogens. 2022 Oct 1;11(10):1138. doi: 10.3390/pathogens11101138.

ABSTRACT

The GNAS gene encodes the alpha-subunit of the stimulatory G-protein (Gαs) in humans and mice. The single-nucleotide polymorphism of GNAS, c.393C>T, is associated with an elevated production of Gαs and an increased formation of cyclic adenosine monophosphate (cAMP). In the present study, we analyzed the effect of this GNAS polymorphism on a renal allograft outcome. We screened a cohort of 436 renal allograft recipients, who were retrospectively followed up for up to 5 years after transplant. GNAS genotypes were determined with polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays. The 393T allele was detected in 319 (73%) recipients (113 recipients with TT and 206 with CT genotype) and the CC genotype in 117 (27%). The CC genotype was associated with a significantly lower frequency of BK viremia (CC, 17 recipients (15%); T 84 (26%)); p = 0.01; TT, 27 vs. CC, 17, p = 0.07; TT, 27 vs. CT, 57, p = 0. 46; CT, 57 vs. CC, 17, p = 0.01) and BKV-associated nephropathy (CC, 3 recipients (3%); T, 27 (8%); p = 0.03; TT,10 vs. CC, 3, p = 0.04; TT, 10 vs. CT,17, p = 0.85; CT, 17 vs. CC,3, p = 0.04) after transplant. BKV-associated nephropathy-free survival was significantly better among CC genotype carriers than among T allele carriers (p = 0.043; TT vs. CC, p = 0.03; CT vs. CC, p = 0.04; TT vs. CT, p = 0.83). Multivariate analysis indicated an independent protective effect of the CC genotype against the development of both BK viremia (relative risk. 0.54; p = 0.04) and BKV-associated nephropathy after renal transplant (relative risk. 0.27; p = 0.036). The GNAS 393 CC genotype seems to protect renal allograft recipients against the development of BK viremia and BKV-associated nephropathy.

PMID:36297195 | DOI:10.3390/pathogens11101138

Metabolites. 2022 Oct 21;12(10):1006. doi: 10.3390/metabo12101006.

ABSTRACT

Nucleotide sugar-dependent glycosyltransferases (UGTs) are critical to the homeostasis of endogenous metabolites and the detoxification of xenobiotics. Their impact on the cell metabolome remains unknown. Cellular metabolic changes resulting from human UGT expression were profiled by untargeted metabolomics. The abundant UGT1A1 and UGT2B7 were studied as UGT prototypes along with their alternative (alt.) splicing-derived isoforms displaying structural differences. Nineteen biochemical routes were modified, beyond known UGT substrates. Significant variations in glycolysis and pyrimidine pathways, and precursors of the co-substrate UDP-glucuronic acid were observed. Bioactive lipids such as arachidonic acid and endocannabinoids were highly enriched by up to 13.3-fold (p < 0.01) in cells expressing the canonical enzymes. Alt. UGT2B7 induced drastic and unique metabolic perturbations, including higher glucose (18-fold) levels and tricarboxylic acid cycle (TCA) cycle metabolites and abrogated the effects of the UGT2B7 canonical enzyme when co-expressed. UGT1A1 proteins promoted the accumulation of branched-chain amino acids (BCAA) and TCA metabolites upstream of the mitochondrial oxoglutarate dehydrogenase complex (OGDC). Alt. UGT1A1 exacerbated these changes, likely through its interaction with the OGDC component oxoglutarate dehydrogenase-like (OGDHL). This study expands the breadth of biochemical pathways associated with UGT expression and establishes extensive connectivity between UGT enzymes, alt. proteins and other metabolic processes.

PMID:36295907 | DOI:10.3390/metabo12101006

Metabolites. 2022 Oct 4;12(10):942. doi: 10.3390/metabo12100942.

ABSTRACT

Mass spectrometry (MS) is increasingly used in clinical studies to obtain molecular evidence of chemical exposures, such as tobacco smoke, alcohol, and drugs. This evidence can help verify clinical data retrieved through anamnesis or questionnaires and may provide insights into unreported exposures, for example those classified as the same despite small but possibly relevant chemical differences or due to contaminants in reported exposure compounds. Here, we aimed to explore the potential of untargeted SWATH metabolomics to differentiate such closely related exposures. This data-independent acquisition MS-based profiling technique was applied to urine samples of 316 liver and 570 kidney transplant recipients from the TransplantLines Biobank and Cohort Study (NCT03272841), where we focused on the immunosuppressive drug mycophenolate, which is either supplied as a morpholino-ester prodrug or as an enteric-coated product, the illicit drug cocaine, which is usually supplied as an adulterated product, and the proton pump inhibitors omeprazole and esomeprazole. Based on these examples, we found that untargeted SWATH metabolomics has considerable potential to identify different (unreported) exposure or co-exposure metabolites and may determine variations in their abundances. We also found that these signals alone may sometimes be unable to distinguish closely related exposures, and enhancement of differentiation, for example by integration with pharmacogenomics data, is needed.

PMID:36295843 | DOI:10.3390/metabo12100942

J Pers Med. 2022 Oct 17;12(10):1728. doi: 10.3390/jpm12101728.

ABSTRACT

Antipsychotic-induced weight gain (AIWG) is a serious adverse effect. Studies have linked genetically-predicted CYP2D6 metabolic capacity to AIWG. The evidence, however, is ambiguous. We performed multiple regression analyses examining the association between genetic-predicted CYP2D6 metabolic capacity and AIWG. Analyses were based on previously unpublished data from an RCT investigating the clinical utility of routine genotyping of CYP2D6 and CYP2C19 in patients with schizophrenia. A total of 211 patients, corresponding to 71% of the original study population, were included. Our analyses indicated an effect of genetically predicted CYP2D6 metabolic capacity on AIWG with significant weight gain in both CYP2D6 poor metabolizers (PMs) (4.00 kg (95% CI: 0.80; 7.21)) and ultrarapid metabolizers (UMs) (6.50 kg (95% CI: 1.03; 12.0)). This finding remained stable after adjustment for covariates (PMs: 4.26 kg (0.88; 7.64), UMs: 7.26 kg (1.24; 13.3)). In addition to the CYP2D6 metabolic capacity, both baseline body mass index (-0.24 (95% CI: -0.44; -0.03)) and chlorpromazine equivalents per day (0.0041 (95% CI: 0.0005; 0.0077)) were statistically significantly associated with weight change in the adjusted analysis. Our results support that the genetically predicted CYP2D6 metabolic capacity matters for AIWG.

PMID:36294867 | DOI:10.3390/jpm12101728

J Pers Med. 2022 Sep 30;12(10):1615. doi: 10.3390/jpm12101615.

ABSTRACT

The clinical adoption and implementation of pharmacogenomics (PGx) beyond academic medical centers remains slow, restricting the general population from benefitting from this important component of personalized medicine. As an initial step in the statewide initiative of PGx implementation in Minnesota, we engaged community members and assessed attitudes towards PGx testing and acceptability of establishing a secure statewide PGx database for clinical and research use among Minnesota residents. Data was collected from 808 adult attendees at the 2021 Minnesota State Fair through an electronic survey. Eighty-four percent of respondents felt comfortable getting a PGx test for clinical care. Most respondents trusted health professionals (78.2%) and researchers (73.0%) to keep their PGx data private. The majority expressed their support and interest in participating in a statewide PGx database for clinical and research use (64-72%). Higher acceptability of the statewide PGx database was associated with younger age, higher education, higher health literacy, having health insurance, and prior genetic testing. The study sample representing Minnesota residents expressed high acceptability of receiving PGx testing and willingness to participate in PGx data sharing for clinical and research use. Community support and engagement are needed to advance PGx implementation and research on the state scale.

PMID:36294754 | DOI:10.3390/jpm12101615

J Pers Med. 2022 Sep 29;12(10):1607. doi: 10.3390/jpm12101607.

ABSTRACT

Most malignant hematological diseases are generally a consequence of acquired mutations or rearrangements in cell replication processes. Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease that results from acquired genetic and epigenetic alterations in hematopoietic progenitor cells. Despite the advances made in understanding the pathogenesis of this disease, the overall survival of patients remains very low due to the high relapse rate. Pharmacogenetics and massive sequencing studies have allowed the identification of new recurrent mutations with significant prognostic impact in AML; furthermore, it seems likely that whole genome sequencing will soon become a standard diagnostic test, which will allow the molecular diagnosis of patients. Therefore, it is necessary to develop molecular targets that open new therapeutic perspectives and allow individualized treatment of patients with this aggressive disease. Chronic myeloid leukemia (CML) is the first neoplastic disease for which a characteristic genetic alteration was described. It has, by definition, a genetic marker, the BCR::ABL1 rearrangement, as a consequence of the t9;22(q34;q11) translocation. Its study is essential for the diagnosis of this entity and also for monitoring the response to treatment. Drugs known as tyrosine kinase inhibitors (TKIs) that target the BCR::ABL1 protein (oral targeted therapy) are the conventional treatment of CML, representing a change of paradigm in the management of oncohematological patients.

PMID:36294746 | DOI:10.3390/jpm12101607

J Pers Med. 2022 Sep 25;12(10):1578. doi: 10.3390/jpm12101578.

ABSTRACT

Vitamin K antagonists (VKAs) are used in the prophylaxis and treatment of thromboembolic disorders. Despite a high efficacy, their narrow therapeutic window and high response variability hamper their management. Several patients experience fluctuations in dose-response and are at increased risk of over- or under-anticoagulation. Therefore, it is essential to monitor the prothrombin time/international normalized ratio to determine the so-called stable dose and to adjust the dosage accordingly. Three polymorphisms, CYP2C9∗2, CYP2C9∗3 and VKORC1-1639G>A, are associated with increased sensitivity to VKAs. Other polymorphisms are associated with a request for a higher dose and VKA resistance. We described the clinical cases of two patients who were referred to the Clinical Pharmacology and Pharmacogenetics Unit of the University Hospital of Salerno for pharmacological counseling. One of them showed hypersensitivity and the other one was resistant to VKAs. A systematic review was performed to identify randomized clinical trials investigating the impact of pharmacogenetic testing on increased sensitivity and resistance to VKAs. Although international guidelines are available and information on the genotype-guided dosing approach has been included in VKA drug labels, VKA pharmacogenetic testing is not commonly required. The clinical cases and the results of the systematically reviewed RCTs demonstrate that the pharmacogenetic-based VKA dosing model represents a valuable resource for reducing VKA-associated adverse events.

PMID:36294717 | DOI:10.3390/jpm12101578

J Pers Med. 2022 Sep 24;12(10):1575. doi: 10.3390/jpm12101575.

ABSTRACT

The CYP2D6 gene has been widely studied to characterize variants and/or star alleles, which account for a significant portion of variability in drug responses observed within and between populations. However, African populations remain under-represented in these studies. The increasing availability of high coverage genomes from African populations has provided the opportunity to fill this knowledge gap. In this study, we characterized computationally predicted novel CYP2D6 star alleles in 30 African subjects for whom DNA samples were available from the Coriell Institute. CYP2D6 genotyping and resequencing was performed using a variety of commercially available and laboratory-developed tests in a collaborative effort involving three laboratories. Fourteen novel CYP2D6 alleles and multiple novel suballeles were identified. This work adds to the growing catalogue of validated African ancestry CYP2D6 allelic variation in pharmacogenomic databases, thus laying the foundation for future functional studies and improving the accuracy of CYP2D6 genotyping, phenotype prediction, and the refinement of clinical pharmacogenomic implementation guidelines in African and global settings.

PMID:36294714 | DOI:10.3390/jpm12101575

Genes (Basel). 2022 Oct 16;13(10):1873. doi: 10.3390/genes13101873.

ABSTRACT

Vitamin D deficiency is related with susceptibility or progression of various autoimmune diseases. The aim of the study was to assess potential relations between single nucleotide polymorphisms (SNPs) in the vitamin D receptor-coding gene (VDR): rs1544410 (BsmI), rs2228570 (FokI), rs731236 (TaqI), rs7975232 (ApaI), and disease activity in patients with axial spondyloarthritis (axSpA) undergoing anti-TNF therapy. The VDR rs731236 CT genotype was statistically more common among female patients (p = 0.027). An improvement of CRP equal to or higher than 50% after 3 months of anti-TNF therapy was observed for rs2228570 T allele (p = 0.002). After 6 months, CRP improvement equal to or higher than 75% was related to presence of the rs1544410 AA genotype (p = 0.027) and the rs731236 CC homozygotes (p = 0.047). Baseline BASDAI values were lower in individuals with the rs2228570 TT genotype (p = 0.036) and rs7975232 C allele (p = 0.029). After 6 months of treatment, lower BASDAI values were observed in AC heterozygotes (p = 0.005). The same AC genotype was more frequently detected in patients with remission (BASDAI ≤ 2) (p = 0.001) and in those achieving BASDAI improvement equal to or higher than 75% (p = 0.006). In conclusion, VDR SNPs were found to relate to CRP and BASDAI values at different time points of anti-TNF therapy.

PMID:36292758 | DOI:10.3390/genes13101873

Genes (Basel). 2022 Oct 11;13(10):1832. doi: 10.3390/genes13101832.

ABSTRACT

BACKGROUND: The increase in the medical use of cannabis has revealed a number of beneficial effects, a variety of adverse side effects and great inter-individual variability. Association studies connecting consumption, addiction and side effects related to recreational cannabis use have led to the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis.

METHOD: In total, 600 patients treated with cannabis were genotyped for several candidate polymorphic genes (single-nucleotide polymorphism; SNP), encoding receptors CNR1 and TRPV1; for the ABCB1 transporter; for biotransformation, bioactivation and biosynthesis; and CYP3A4, COMT and UGT2B7 conjugation.

RESULTS: Three polymorphic genes (ABCB1, TRPV1 and UGT2B7) were identified as being significantly associated with decline in pain after treatment with cannabis. Patients simultaneously carrying the most favourable allele combinations showed a greater reduction (polygenic effect) in pain compared to those with a less favourable combination. Considering genotype combinations, we could group patients into good responders, intermediate responders and poor or non-responders. Results suggest that genetic makeup is, at the moment, a significant predictive factor of the variability in response to cannabis.

CONCLUSIONS: This study proves, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain management and side effects, including therapy dropout.

SIGNIFICANCE: Our attention to pharmacogenetics began in 2008, with the publication of a first study on the association between genetic polymorphisms and morphine action in pain relief. The study we are presenting is the first observational study conducted on a large number of patients involving several polymorphic candidate genes. The data obtained suggest that genetic makeup can be a predictive factor in the response to cannabis therapy and that more extensive and planned studies are needed for the opening of new scenarios for the personalization of cannabis therapy.

PMID:36292717 | DOI:10.3390/genes13101832

Biomolecules. 2022 Oct 9;12(10):1449. doi: 10.3390/biom12101449.

ABSTRACT

Much scientific work over the past few decades has linked health outcomes and disease risk to genomics, to derive a better understanding of disease mechanisms at the genetic and molecular level. However, genomics alone does not quite capture the full picture of one's overall health. Modern computational biomedical research is moving in the direction of including social/environmental factors that ultimately affect quality of life and health outcomes at both the population and individual level. The future of studying disease now lies at the hands of the social determinants of health (SDOH) to answer pressing clinical questions and address healthcare disparities across population groups through its integration into electronic health records (EHRs). In this perspective article, we argue that the SDOH are the future of disease risk and health outcomes studies due to their vast coverage of a patient's overall health. SDOH data availability in EHRs has improved tremendously over the years with EHR toolkits, diagnosis codes, wearable devices, and census tract information to study disease risk. We discuss the availability of SDOH data, challenges in SDOH implementation, its future in real-world evidence studies, and the next steps to report study outcomes in an equitable and actionable way.

PMID:36291658 | DOI:10.3390/biom12101449

Biomolecules. 2022 Sep 24;12(10):1365. doi: 10.3390/biom12101365.

ABSTRACT

Cisplatin (CDDP) is the drug of choice against different types of cancer. However, tumor cells can acquire resistance to the damage caused by cisplatin, generating genetic and epigenetic changes that lead to the generation of resistance and the activation of intrinsic resistance mechanisms in cancer cells. Among them, we can find mutations, alternative splicing, epigenetic-driven expression changes, and even post-translational modifications of proteins. However, the molecular mechanisms by which CDDP resistance develops are not clear but are believed to be multi-factorial. This article highlights a description of cisplatin, which includes action mechanism, resistance, and epigenetic factors involved in cisplatin resistance.

PMID:36291573 | DOI:10.3390/biom12101365