Adv Gerontol. 2021;34(1):48-53.

ABSTRACT

We have analyzed influence of genetic variants CYP2D6*3 (2549delA) and CYP2D6*4 (1846G>A), as well as other factors on effects of bisoprolol in patients with acute coronary syndrome. The study included 97 patients with acute coronary syndrome. Mean age was 63±10 years; 60 men and 37 women. We have found association between carriage of CYP2D6*4 (1846G>A) and maximal heart rate at exertion (R-0,21; р<0,05). When the correction for potential confounders was made, age was the only significant predictor of maximal heart rate (β=0,6; SE=0,07; p<0,001). At the same time it was found that CYP2D6*4 was associated with more advanced age of the patients (r=0,2; p<0,05).

PMID:33993661

Rheumatology (Oxford). 2021 May 16:keab443. doi: 10.1093/rheumatology/keab443. Online ahead of print.

ABSTRACT

OBJECTIVES: Combination of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (kDa) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between both pediatric vasculitis.

METHODS: A total of 1,190 vasculitis patients and 11 302 healthy controls were analyzed. First, in the discovery phase, genome-wide data of 405 kDa patients and 6,252 controls and 215 IgAV patients and 1,324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3,726 controls). Polymorphisms with p-values ≤ 5x1 0 -8 in the global IgAV-kDa meta-analysis were considered as shared genetic risk loci.

RESULTS: A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (p= 8.06x10-10). Additionally, when IgAV was individually analyzed, a strong association between rs3743841 and this vasculitis was also evident (p= 1.25x10-7; OR (95% CI)=1.47 (1.27-1.69)). In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes.

CONCLUSION: We have identified a new risk locus with pleiotropic effects on the two vasculitis of childhood analyzed. This locus represents the strongest non-HLA signal described for IgAV to date.

PMID:33993232 | DOI:10.1093/rheumatology/keab443

Br J Clin Pharmacol. 2021 May 14. doi: 10.1111/bcp.14895. Online ahead of print.

ABSTRACT

Remdesivir is one of the most encouraging treatments against SARS-CoV-2 infection. After intravenous infusion, RDV is rapidly metabolized (T1/2 1h) within the cells to its active adenosine triphosphate analogue form (GS-443902) and, then, it can be found in plasma in its nucleoside analogue form (GS-441524). In this real life study we describe the Remdesivir and GS-441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC-MS/MS method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half-life of GS-441524. The mean Cmin , Cmax , AUC0-24 , were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS-441524. Three out of nine patients achieved a Cmax > 2610 ng/mL and 140 ng/mL and AUC0-24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean T1/2 value for GS-441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS-441524 concentrations in real-life ICU setting.

PMID:33990984 | DOI:10.1111/bcp.14895

Cell. 2021 May 13;184(10):2525-2531. doi: 10.1016/j.cell.2021.03.041.

ABSTRACT

Human cell lines (CLs) are key assets for biomedicine but lack ancestral diversity. Here, we explore why genetic diversity among cell-based models is essential for making preclinical research more equitable and widely translatable. We lay out practical actions that can be taken to improve inclusivity in study design.

PMID:33989545 | DOI:10.1016/j.cell.2021.03.041

Glob Med Genet. 2021 Jun;8(2):78-81. doi: 10.1055/s-0041-1726461. Epub 2021 Mar 22.

ABSTRACT

Novel coronavirus disease 2019 (COVID-19) is caused by a nonsegmented positive sense RNA, enveloped RNA virus that belongs to the family of β-coronaviridae. This virus shall cause acute respiratory distress syndrome (ARDS) which consequently leads to breathing difficulty and need to admit to intensive care units (ICUs). The current conventional treatment combination in most of the hospitals in Iran includes azithromycin 500 + naproxen 500 + vitamin C 1,000 + Zinc + vitamin D3 1,000. In this case reports ( n = 4), we would like to report significant findings in course of COVID-19 treatment reported to our clinic on August 8 and 9, 2020; patients presented as walk in and were advised house isolation and complete bed rest as there were no signs of lung involvement and their overall condition was stable. By the inclusion of cephalexin 500 in treatment combination, patients who received cephalexin 500 for 5 days along with other medicines did not develop any lung involvement and breathing complications. Cephalexin is the gold standard in upper and lower respiratory tract infections and here also shall play a vital role besides other conventional therapies. Azithromycin is a macrodial antibiotic working via the ABCB1 gene pathway. As of date, there is no clear evidence of pharmacogenomics data in COVID-19 patients. More research needs to be performed in COVID-19 before any sort of pharmacogenomics tests could be advised.

PMID:33987628 | PMC:PMC8110359 | DOI:10.1055/s-0041-1726461

Int J Gen Med. 2021 May 6;14:1751-1756. doi: 10.2147/IJGM.S305443. eCollection 2021.

ABSTRACT

PURPOSE: Tryptophan is the only precursor of serotonin, the hormone which helps regulate key human functions such as appetite, memory, mood, and sexual behavior. Connections have been identified between serotonin system dysfunction and the molecular etiology and treatment of mood disorders in a wide range of studies. Proposals have been put forward to co-administer tryptophan supplementation together with serotonin reuptake inhibitors in major depression patients, and also to exploit the sub-therapeutic depressive status in healthy populations. The reported responses, however, have been very dissimilar and this uneven effect may largely be explained by interindividual genetic differences.

MATERIALS AND METHODS: We studied mood change in 138 healthy subjects using both Goldberg's General Health Questionnaire and the Profile of Mood States Questionnaire to determine the effects of a daily supplementation of 1g of tryptophan or placebo. Buccal DNA samples were provided and TPH1 (rs1800532), MAOA (rs3788862 and rs979605), MAOB (rs3027452), and COMT (rs6269 and rs4680) variants were genotyped.

RESULTS: MAOB rs3027452 was equally associated with tryptophan supplementation efficacy in the depression subscales of both questionnaires (ΔT-Score.D; ΔT-Score.TMD and ΔPOMS.D p-values <0.01).

CONCLUSION: Here we provide evidence that tryptophan supplementation has an uneven effect on mood improvement in the general population.

PMID:33986613 | PMC:PMC8110250 | DOI:10.2147/IJGM.S305443

Pharmgenomics Pers Med. 2021 May 6;14:545-546. doi: 10.2147/PGPM.S316851. eCollection 2021.

NO ABSTRACT

PMID:33986611 | PMC:PMC8111333 | DOI:10.2147/PGPM.S316851

Ann Rheum Dis. 2021 May 13:annrheumdis-2021-220580. doi: 10.1136/annrheumdis-2021-220580. Online ahead of print.

NO ABSTRACT

PMID:33985939 | DOI:10.1136/annrheumdis-2021-220580

ESMO Open. 2021 May 10;6(3):100153. doi: 10.1016/j.esmoop.2021.100153. Online ahead of print.

ABSTRACT

Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the role of dose intensity in cancer treatment, and support full weight-based dosing, empirical dose capping often occurs in clinical practice in order to avoid toxicity. Thus a panel of experts of the Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD), Società Italiana Endocrinologia (SIE), and Società Italiana Farmacologia (SIF), provides here a consensus statement for appropriate cytotoxic chemotherapy and new biological cancer drug dosing in obese patients.

PMID:33984679 | DOI:10.1016/j.esmoop.2021.100153

Eur J Pharmacol. 2021 May 10:174169. doi: 10.1016/j.ejphar.2021.174169. Online ahead of print.

ABSTRACT

Diabetes, characterized by high glucose levels, has been listed to be one of the world's major causes of death. Around 1.6 million deaths are attributed to this disease each year. Persistent hyperglycemic conditions in diabetic patients affect various organs of the body leading to diabetic complications and worsen the disease condition. Current treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4(dipeptidyl peptidase-4) and GLP-1 (glucagon-like peptide) analogs. However, many side effects contributing to the devastation of the disease are associated with them. Sodium glucose co-tranporter-2 (SGLT2) inhibition has been reported to be new insulin-independent approach to diabetes therapy. It blocks glucose uptake in the kidneys by inhibiting SGLT2 transporters, thereby promoting glycosuria. Dapagliflozin, empagliflozin and canagliflozin are the most widely used SGLT2 inhibitors. They are effective in controlling blood glucose and HbA1c levels with no side effects including hypoglycemia or weight gain which makes them preferable to other anti-diabetic drugs. However, treatment is found to be associated with inter-individual drug response to SGLT2 inhibitors and adverse drug reactions which are also affected by genetic variations. There have been very few pharmacogenetics trials of these drugs. This review discusses the various SGLT2 inhibitors, their pharmacokinetics, pharmacodynamics and genetic variation influencing the inter-individual drug response.

PMID:33984301 | DOI:10.1016/j.ejphar.2021.174169

Adv Clin Exp Med. 2021 May 12. doi: 10.17219/acem/128764. Online ahead of print.

ABSTRACT

BACKGROUND: NF-κB is an essential player in cancer biology, especially in tumor development, due to its constitutive activation, and because a four-base deletion (ATTG) in the NF-κB1 promoter region at site -94, alters mRNA stability and regulates translation efficiency. This polymorphism is a good candidate risk marker and modulator of clinical course in chronic lymphocytic leukemia (CLL). As the effect of this NF-κB1 gene polymorphism has not been studied in patients with CLL so far, the present study was undertaken to find out whether the NF-κB1 promoter -94 ins/del ATTG polymorphism might be an essential genetic risk factor and/or modulatory disease player associated with CLL.

OBJECTIVES: The NF-κB1 -94 ins/del ATTG (rs28362491) polymorphism was investigated as a potential CLL susceptibility and progression factor, along with demonstration of potential modulation of the stage of clinical disease based on Rai classification.

MATERIAL AND METHODS: The associations of NF-κB1 -94 ins/del ATTG polymorphism with CLL and its clinical manifestation in 282 Polish individuals, including 156 CLL patients, were analyzed using polymerase chain reaction (PCR) with primers including a labeled forward primer, followed by capillary electrophoresis.

RESULTS: A higher occurrence of the del/del homozygosity was observed among patients when compared to controls, resulting in an increase in CLL risk of more than twofold in patients carrying this homozygous genotype (OR = 2.23, p = 0.02, 95% CI = 1.14-4.37). Moreover, the del/del-positive patients more frequently presented the less aggressive disease phenotype (Rai 0), suggesting a low probability of progression to more advanced disease.

CONCLUSIONS: The NF-κB1 -94 del/del genetic variant, although associated with increased risk of CLL disease, may be associated with maintenance of disease severity in the early, mildest stage. The likelihood of disease progression may increase as the frequency of wild-type (insertion) alleles for this polymorphism increases.

PMID:33982453 | DOI:10.17219/acem/128764

Heliyon. 2021 Apr 20;7(4):e06852. doi: 10.1016/j.heliyon.2021.e06852. eCollection 2021 Apr.

ABSTRACT

Antituberculosis drug-induced liver injury (ATDILI) is the common adverse reaction of antituberculosis drugs. Glutathione S-transferases (GSTs), which are phase II metabolizing enzymes for detoxification, are recognized as potential mediators of hepatotoxicity. However, role of GSTs polymorphisms in ATDILI pathogenesis has never been observed in Thais. This study aimed to investigate associations between GSTs and ATDILI susceptibility. This retrospective case-control multicentered study was conducted by the collaboration from ten secondary and tertiary care hospitals across Thailand, including Northern, Central, and Southern parts of Thailand. We enrolled 80 tuberculosis (TB) patients with ATDILI and 174 those without ATDILI into the study. Polymerase chain reaction (PCR) was used to determine genetic polymorphisms of GSTM1 and GSTT1 genes. CYP2E1 genotyping data were derived from microarray data. We illustrated that GSTT1 null and GSTM1/GSTT1 dual null genotypes were correlated with an increased risk of ATDILI with odds ratio (OR) at 1.83 (95% confidence interval (CI), 1.00 to 3.35; P = 0.049) and 2.12 (95%CI, 1.02 to 4.38; P = 0.044), respectively. Interestingly, GSTT1 null and GSTM1/GSTT1 dual null genotypes were found to be correlated with an increased risk of ATDILI in Thai TB patients who carried CYP2E1 wild type phenotype with OR 2.99 (95%CI, 1.07 to 8.39; P = 0.037) and 3.44 (95%CI, 1.01 to 11.71; P = 0.048), respectively. Collectively, GSTT1 null and GSTM1/GSTT1 dual null genotypes were associated with a higher risk of ATDILI in Thai TB patients, which may serve as alternative genetic biomarkers for ATDILI.

PMID:33981901 | PMC:PMC8082558 | DOI:10.1016/j.heliyon.2021.e06852

Front Oncol. 2021 Apr 26;11:628613. doi: 10.3389/fonc.2021.628613. eCollection 2021.

ABSTRACT

Gastric cancer has one of the highest mortality rate in the world, but the treatment is still limited. Building on previous studies, mechanistic studies on propranolol in gastric cancer mice models and gastric cancer patients were performed. Propranolol inhibited the in vitro proliferation of gastric cancer cells in a time- and concentration-dependent manner. Consistent findings were observed in MFC tumors engrafted 615 mice, which were treated with propranolol at 10 mg/kg daily for 14 days. Propranolol inhibited the phosphorylation of AKT, MEK, and ERK proteins than control in mice tumor tissues respectively (p-AKT 26.16 vs. 56.82, P = 0.0196, p-MEK 28.27 vs. 59.28, P = 0.1102, p-ERK 48.2 vs. 107.4, P = 0.0062). Propranolol had antiproliferative activity in gastric cancer patients receiving 60 mg daily for 7 days prior to surgery(ki67 44.8 vs 125.3 for placebo; P = 0.02). Phosphorylated AKT, MEK, and ERK did not differ between propranolol and placebo treatment in gastric cancer patients. The expression of molecules on CD8+ T cells was not changed both in mice model and patients nor was there a statistically significant difference in CD8+ T cell subsets in patients, although suggestion of an effect was evident. These results prove that propranolol may inhibit the growth of gastric cancer in mice model and patients and the possible mechanism was via inhibiting the AKT and MAPK pathways, but the frequency of tumor infiltration CD8+ T cells did not increase significantly.

PMID:33981600 | PMC:PMC8108985 | DOI:10.3389/fonc.2021.628613

Front Pharmacol. 2021 Apr 26;12:588063. doi: 10.3389/fphar.2021.588063. eCollection 2021.

ABSTRACT

Adverse drug reactions are a public health issue that draws widespread attention, especially for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which have high mortality and lack of efficacious treatment. Though T-cell-mediated HLA-interacted immune response has been extensively studied, our understanding of the mechanism is far from satisfactory. This review summarizes infection (virus, bacterial, and mycoplasma infection), an environmental risk factor, as a trigger for SJS/TEN. The mutations or polymorphisms of drug metabolic enzymes, transporters, receptors, the immune system genes, and T-cell-mediated apoptosis signaling pathways that contribute to SJS/TEN are discussed and summarized. Epigenetics, metabolites, and mobilization of regulatory T cells and tolerogenic myeloid precursors are emerged directions to study SJS/TEN. Ex vivo lymphocyte transformation test has been exploited to aid in identifying the causative drugs. Critical questions on the pathogenesis of SJS/TEN underlying gene polymorphisms and T cell cytotoxicity remain: why some of the patients carrying the risky genes tolerate the drug and do not develop SJS/TEN? What makes the skin and mucous membrane so special to be targeted? Do they relate to skin/mucous expression of transporters? What is the common machinery underlying different HLA-B alleles associated with SJS/TEN and common metabolites?

PMID:33981213 | PMC:PMC8107822 | DOI:10.3389/fphar.2021.588063

J Affect Disord. 2021 Apr 28;289:135-143. doi: 10.1016/j.jad.2021.04.040. Online ahead of print.

ABSTRACT

BACKGROUND: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD.

METHODS: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions.

RESULTS: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC.

LIMITATIONS: Cross-sectional design, modest sample size.

CONCLUSIONS: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.

PMID:33979723 | DOI:10.1016/j.jad.2021.04.040

World J Biol Psychiatry. 2021 May 12:1-68. doi: 10.1080/15622975.2021.1878427. Online ahead of print.

ABSTRACT

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

PMID:33977870 | DOI:10.1080/15622975.2021.1878427

Lakartidningen. 2021 May 11;118:21023.

ABSTRACT

The Genomic Medicine Sweden (GMS) initiative aims to strengthen precision medicine across the country. This will be accomplished through the implementation of large-scale sequencing techniques in Swedish healthcare. With a patient-centered view, initial efforts will focus on rare diseases, cancer, pharmacogenomics, and infectious diseases, and subsequently extend to complex diseases. GMS is being implemented as a broad collaborative project involving healthcare, universities with medical faculty, SciLifeLab, industry and patient organizations. To deliver top tier diagnostics, regional genomic medicine centers (GMC) are currently under establishment together with a national informatics infrastructure for data sharing. GMS will also offer a unique resource for research that could pave the way for the development of novel drugs, and enhance collaboration with industry. In summary, GMS provides Sweden with an opportunity to take an international forefront position in the field of precision medicine.

PMID:33977514

Indian J Pharmacol. 2021 Jan-Feb;53(1):19-24. doi: 10.4103/ijp.IJP_495_19.

ABSTRACT

INTRODUCTION: Pharmacogenomics is a growing field of science that explores the genetic contributions in an individual's response to the drug, so as to choose the right drug in the right doses tailored to a patient's genetic makeup. Although pharmacogenomics information is incorporated in chapters discussing relevant drugs, it has not been materialized into clinical practice yet and still, it remains a challenge due to limited knowledge and accessibility of the pharmacogenomic tests to diagnose these polymorphisms. With this background, the objective of the study was to assess the knowledge and perception of pharmacogenomics among second-year MBBS students and to sensitize them regarding pharmacogenomics.

MATERIALS AND METHODS: A cross-sectional study was done in which 138 medical students responded to a preformed semi-structured assessment tool. It comprised two main components (1) knowledge and (2) relevance of pharmacogenomics in medical education and clinical practice.

RESULTS: Ninety-five percent students defined pharmacogenomics correctly, but only 54% were aware of genetic variations in drug targets, metabolizing enzymes, and transporters affecting drug therapy. Only 15% knew about the availability of pharmacogenomics tests in India. Eighty-four percent of students felt that incorporating pharmacogenomics education in the MBBS curriculum is a must for precision medicine.

CONCLUSION: Second-year MBBS students had good knowledge of pharmacogenomics, but knowledge about the application in clinical practice and interpretation of pharmacogenomics was limited. Therefore, we recommend (1) basic pharmacogenomic education at all levels of medical curricula, (2) development of case-based knowledge application modules, (3) regular continuing medical education to update about available screening tools/biomarkers, and (4) patient and public awareness programs so that they receive personalized/precision medicine with optimum efficacy and reduced side effects and health-care costs.

PMID:33975995 | DOI:10.4103/ijp.IJP_495_19

J Clin Pharmacol. 2021 May 11. doi: 10.1002/jcph.1909. Online ahead of print.

ABSTRACT

Most patients experience severe hematological toxicities during treatment with gemcitabine; thus, preventing such toxicities would improve the treatment effects and patients' quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single-locus analysis showed that the SNPs RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia; hENT1 rs760370, hCNT3 rs7867504 and rs4877831 were associated with severe leucopenia; CDA rs2072671, DCTD rs7663494 and WEE1 rs3910384 were associated with severe anemia; and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P<0.0038). The gene-gene interaction analysis identified the overall best models, including a two-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leucopenia (P = 0.0022) and a three-locus model (CDA rs207671, DCTD rs7663494 and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = 0.0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, wherein the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggested that the gene-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we proposed a promising data mining analysis approach (generalized multifactor dimensionality reduction, GMDR) to detect and characterize gene-gene interactions. This article is protected by copyright. All rights reserved.

PMID:33974709 | DOI:10.1002/jcph.1909

Bosn J Basic Med Sci. 2021 Apr 20. doi: 10.17305/bjbms.2021.5646. Online ahead of print.

ABSTRACT

Type 2 diabetes (T2D) has a continuously rising prevalence worldwide. Pharmacogenetics has been recognized as a promising concept for pharmacological treatment of T2D, as antidiabetic drugs are not equally effective and safe for all patients, and the costs of diabetes treatment are increasing. The latest published guidelines on T2D treatment firmly endorse the use of newer antidiabetic drugs, sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-IVi), and glucagon-like peptide-1 receptor agonists (GLP-1RA), considering their satisfactory pharmacological effect and good safety profile. Furthermore, SGLT2i and GLP-1RA show protective effects in patients with established atherosclerotic cardiovascular disease and chronic kidney disease. However, there has been growing evidence that the effectiveness and safety of these drug classes could depend on genetic variability. Here, we summarized the results of the published studies on the pharmacogenetic biomarkers for the three drug classes. A number of genetic variations have been investigated so far. The explored candidate genes mostly encode drug targets, drug-metabolizing enzymes, and genes linked to T2D risk. Although many of the results are promising, it is still necessary to obtain more information from larger controlled studies to confirm their clinical significance. This approach may lead towards more personalized treatment for patients with T2D.

PMID:33974529 | DOI:10.17305/bjbms.2021.5646