Cancers (Basel). 2021 Oct 14;13(20):5158. doi: 10.3390/cancers13205158.

ABSTRACT

Our understanding of metastatic prostate cancer (mPrCa) has dramatically advanced during the genomics era. Nonetheless, many aspects of the disease may still be uncovered through reanalysis of public datasets. We integrated the expression datasets for 209 PrCa tissues (metastasis, primary, normal) with expression, gene dependency (GD) (from CRISPR/cas9 screen), and drug viability data for hundreds of cancer lines (including PrCa). Comparative statistical and pathways analyses and functional annotations (available inhibitors, protein localization) revealed relevant pathways and potential (and previously reported) protein markers for minimally invasive mPrCa diagnostics. The transition from localized to mPrCa involved the upregulation of DNA replication, mitosis, and PLK1-mediated events. Genes highly upregulated in mPrCa and with very high average GD (~1) are potential therapeutic targets. We showed that fostamatinib (which can target PLK1 and other over-expressed serine/threonine kinases such as AURKA, MELK, NEK2, and TTK) is more active against cancer lines with more pronounced signatures of invasion (e.g., extracellular matrix organization/degradation). Furthermore, we identified surface-bound (e.g., ADAM15, CD276, ABCC5, CD36, NRP1, SCARB1) and likely secreted proteins (e.g., APLN, ANGPT2, CTHRC1, ADAM12) that are potential mPrCa diagnostic markers. Overall, we demonstrated that comprehensive analyses of public genomics data could reveal potentially clinically relevant information regarding mPrCa.

PMID:34680307 | PMC:PMC8534121 | DOI:10.3390/cancers13205158

Cancers (Basel). 2021 Oct 13;13(20):5128. doi: 10.3390/cancers13205128.

ABSTRACT

BACKGROUND: First-line decision making is the key to the successful care of mCRC patients and RAS/BRAF status is crucial to select the best targeted agent. In hub centers, a relevant proportion of patients referred from small volume centers may not have standard tissue-based (STB) molecular results available at the time of the first visit (T0). Liquid biopsy (LB) may help circumvent these hurdles.

METHODS: A monoinstitutional prospective head-to-head comparison of LB versus (vs.) STB testing was performed in a real-world setting. Selection criteria included: mCRC diagnosis with unknown RAS/BRAF status at T0, tumoral tissue archived in external centers, no previous treatment with anti-EGFR. At T0, patients underwent plasma sampling for LB testing and procedure for tissue recovery. RAS/BRAF genotyping was carried out by droplet digital PCR on circulating-tumoral (ct) DNA. The primary endpoint was the comparison of time to LB (T1) vs. STB (T2) results using the Mann-Whitney U test. Secondary endpoints were the concordance between LB and STB defined as overall percent agreement and the accuracy of LB in terms of specificity, sensitivity, positive and negative predictive value. We also performed an exploratory analysis on urinary (u) ctDNA.

RESULTS: A total of 33 mCRC patients were included. Mean T1 and T2 was 7 and 22 days (d), respectively (p < 0.00001). T2 included a mean time for archival tissue recovery of 17 d. The overall percent agreement between LB and STB analysis was 83%. Compared to STB testing, LB specificity and sensitivity were 90% and 80%, respectively, with a positive predictive value of 94% and negative one of 69%. In detail, at STB and LB testing, RAS mutation was found in 45% and 42% of patients, respectively; BRAF mutation in 15%. LB results included one false positive and four false negative. False negative cases showed a significantly lower tumor burden at basal CT scan. Concordance between STB and uctDNA testing was 89%.

CONCLUSIONS: Faster turnaround time, high concordance and accuracy are three key points supporting the adoption of LB in routinary mCRC care, in particular when decision on first-line therapy is urgent and tissue recovery from external centers may require a long time. Results should be interpreted with caution in LB wild-type cases with low tumor burden.

PMID:34680277 | PMC:PMC8533756 | DOI:10.3390/cancers13205128

Cancers (Basel). 2021 Oct 12;13(20):5112. doi: 10.3390/cancers13205112.

ABSTRACT

Recently, several panels using two representative targeting methods have been developed but they do not reflect racial specificity, especially for Asians. We have developed and analytically validated the Korean Pan-cancer Companion Diagnostic (CDX) Panel to apply targeted anticancer drugs to Korean patients based on the molecular characteristics of tumors using tumor samples without matched patient normal samples. The panel included 31 genes with reported single nucleotide variants, 9 genes with reported copy number variations, and 15 genes with predictive responses to targeted drugs under clinical testing, enabling the panel to be analyzed for the targets of 30 targeted anticancer drugs. It is cost-effective and optimized for cancer type-specific therapy in Korean cancer patients across solid cancer types while minimizing the limitations of existing approaches. In addition, the optimized filtering protocol for somatic variants from tumor-only samples enables researchers to use this panel without matched normal samples. To verify the panel, 241 frozen tumor tissues and 71 formalin-fixed paraffin-embedded (FFPE) samples from several institutes were registered. This gene screening method is expected to reduce test turnaround time and cost, making it a balanced approach to investigate solid cancer-related gene regions.

PMID:34680263 | PMC:PMC8534153 | DOI:10.3390/cancers13205112

Brain Sci. 2021 Sep 24;11(10):1265. doi: 10.3390/brainsci11101265.

ABSTRACT

Genetic analysis of the association between alcohol, cocaine, and opiate addiction and variable number tandem repeat (VNTR) polymorphisms in monoamine oxidase B (MAOB) and serotonergic 5-hydroxytryptamine (serotonin) receptor 1B and 2C (HTR1B 21 and HTR2C) pathway genes was performed in a sample of 302 polyconsumers. Our genetic association analysis revealed a significant association between a 184 base pair (bp) VNTR polymorphism in the MAOB gene and addiction to cocaine and opiates. This work highlights new genetic marker associations in cocaine and opiate polyconsumer addictions. These data help to clarify and quantify the complex role of genetics in addictive disorders, as well as their future contribution to the prevention (genetic counselling), diagnosis (genetic diagnosis of vulnerability), and treatment (pharmacogenomics) of these disorders.

PMID:34679329 | PMC:PMC8534042 | DOI:10.3390/brainsci11101265

Clin Pharmacol Ther. 2021 Oct 22. doi: 10.1002/cpt.2458. Online ahead of print.

ABSTRACT

Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the US. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (v19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval [CI]) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC0-∞ ), peak concentration (Cmax ), and time to reach peak concentration (Tmax ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS.

PMID:34679189 | DOI:10.1002/cpt.2458

Toxins (Basel). 2021 Sep 27;13(10):688. doi: 10.3390/toxins13100688.

ABSTRACT

P-cresyl sulfate and indoxyl sulfate are strongly associated with cardiovascular events and all-cause mortality in chronic kidney disease (CKD). This randomized controlled trial was conducted to compare the effects between sevelamer and calcium carbonate on protein-bound uremic toxins in pre-dialysis CKD patients with hyperphosphatemia. Forty pre-dialysis CKD patients with persistent hyperphosphatemia were randomly assigned to receive either 2400 mg of sevelamer daily or 1500 mg of calcium carbonate daily for 24 weeks. A significant decrease of total serum p-cresyl sulfate was observed in sevelamer therapy compared to calcium carbonate therapy (mean difference between two groups -5.61 mg/L; 95% CI -11.01 to -0.27 mg/L; p = 0.04). There was no significant difference in serum indoxyl sulfate levels (p = 0.36). Sevelamer had effects in terms of lowering fibroblast growth factor 23 (p = 0.01) and low-density lipoprotein cholesterol levels (p = 0.04). Sevelamer showed benefits in terms of retarding CKD progression. Changes in vascular stiffness were not found in this study.

PMID:34678981 | PMC:PMC8539528 | DOI:10.3390/toxins13100688

Psychiatry Res. 2021 Oct 12;305:114236. doi: 10.1016/j.psychres.2021.114236. Online ahead of print.

NO ABSTRACT

PMID:34678523 | DOI:10.1016/j.psychres.2021.114236

Eur J Pharmacol. 2021 Oct 19:174580. doi: 10.1016/j.ejphar.2021.174580. Online ahead of print.

ABSTRACT

Recent developments in pharmacogenomics have created opportunities for predicting temozolomide response in gliomas. Temozolomide is the main first-line alkylating chemotherapeutic drug together with radiotherapy as standard treatments of high-risk gliomas after surgery. However, there are great individual differences in temozolomide response. Besides the heterogeneity of gliomas, pharmacogenomics relevant genetic polymorphisms can not only affect pharmacokinetics of temozolomide but also change anti-tumor effects of temozolomide. This review will summarize pharmacogenomic studies of temozolomide in gliomas which can lay the foundation to personalized chemotherapy.

PMID:34678239 | DOI:10.1016/j.ejphar.2021.174580

OMICS. 2021 Oct 22. doi: 10.1089/omi.2021.0160. Online ahead of print.

ABSTRACT

Multiomics study designs have significantly increased understanding of complex biological systems. The multiomics literature is rapidly expanding and so is their heterogeneity. However, the intricacy and fragmentation of omics data are impeding further research. To examine current trends in multiomics field, we reviewed 52 articles from PubMed and Web of Science, which used an integrated omics approach, published between March 2006 and January 2021. From studies, data regarding investigated loci, species, omics type, and phenotype were extracted, curated, and streamlined according to standardized terminology, and summarized in a previously developed graphical summary. Evaluated studies included 21 omics types or applications of omics technology such as genomics, transcriptomics, metabolomics, epigenomics, environmental omics, and pharmacogenomics, species of various phyla including human, mouse, Arabidopsis thaliana, Saccharomyces cerevisiae, and various phenotypes, including cancer and COVID-19. In the analyzed studies, diverse methods, protocols, results, and terminology were used and accordingly, assessment of the studies was challenging. Adoption of standardized multiomics data presentation in the future will further buttress standardization of terminology and reporting of results in systems science. This shall catalyze, we suggest, innovation in both science communication and laboratory medicine by making available scientific knowledge that is easier to grasp, share, and harness toward medical breakthroughs.

PMID:34678084 | DOI:10.1089/omi.2021.0160

J Pain Res. 2021 Oct 8;14:3145-3161. doi: 10.2147/JPR.S320863. eCollection 2021.

ABSTRACT

PURPOSE: Precision pain medicine focuses on employing methods to assess each patient individually, identify their risk profile for disproportionate pain and/or the development of chronic pain, and optimize therapeutic strategies to target specific pathological processes underlying chronic pain. This review aims to provide a concise summary of the current body of knowledge regarding psychological, physiological, and genetic determinants of chronic pain related to precision pain medicine.

METHODS: Following the Scale for the Assessment of Narrative Review Articles (SANRA) criteria, we employed PubMed/Medline to identify relevant articles using primary database search terms to query articles such as: precision medicine, non-modifiable factors, pain, anesthesiology, quantitative sensory testing, genetics, pain medicine, and psychological.

RESULTS: Precision pain medicine provides an opportunity to identify populations at risk, develop personalized treatment strategies, and reduce side effects and cost through elimination of ineffective treatment strategies. As in other complex chronic health conditions, there are two broad categories that contribute to chronic pain risk: modifiable and non-modifiable patient factors. This review focuses on three primary determinants of health, representing both modifiable and non-modifiable factors, that may contribute to a patient's profile for risk of developing pain and most effective management strategies: psychological, physiological, and genetic factors.

CONCLUSION: Consideration of these three domains is already being integrated into patient care in other specialties, but by understanding the role they play in development and maintenance of chronic pain, we can begin to implement both precision and personalized treatment regimens.

PMID:34675643 | PMC:PMC8517910 | DOI:10.2147/JPR.S320863

BMC Biol. 2021 Oct 21;19(1):228. doi: 10.1186/s12915-021-01155-5.

ABSTRACT

BACKGROUND: Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane.

RESULTS: We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome.

CONCLUSIONS: These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.

PMID:34674701 | DOI:10.1186/s12915-021-01155-5

Pharmacogenomics. 2021 Oct 21. doi: 10.2217/pgs-2021-0072. Online ahead of print.

ABSTRACT

Aim: Renal cell carcinoma (RCC) is the most lethal urological cancer and up to 40% of patients submitted to surgery will relapse. Thus, the study aim was to analyze the associations of AGO2 SNPs with RCC patients' prognosis, and evaluate their effect on AGO2 mRNA levels. Materials & methods: The AGO2 rs4961280, rs3928672 and rs11996715 polymorphisms and the relative quantification of AGO2 mRNA levels were analyzed by real-time PCR. Results: We observed that AGO2 rs4961280 AC + AA genotypes carriers presented a higher cancer progression risk (OR= 3.13, p < 0.001), a reduced progression-free survival (log rank test, p = 0.003) and an increased risk of an early relapse (HR= 2.26, p = 0.008). In fact, these patients also presented higher circulating levels of AGO2 mRNA (p = 0.043), with the high levels being associated with more aggressive tumors. Conclusion: The AGO2 rs4961280 AA/AC genotypes are unfavorable RCC prognostic biomarkers, with the AGO2 levels being a useful RCC aggressive phenotype biomarker.

PMID:34672687 | DOI:10.2217/pgs-2021-0072

Int J Biol Sci. 2021 Sep 21;17(14):3936-3953. doi: 10.7150/ijbs.63732. eCollection 2021.

ABSTRACT

Background: Nonalcoholic fatty liver disease (NAFLD) is a serious threat to human health worldwide, with a high genetic susceptibility. Rs2302685, a functional germline variant of LRP6, has been recently found to associate with NAFLD risk. This study was aimed to clarify the underlying mechanism associated with rs2302685 risk and its impact on pharmacotherapy in treatment of NAFLD. Methods: Venous blood samples were collected from NAFLD and non-NAFLD patients for SNP genotyping by using mass spectrometry. The Lrp6-floxdel mouse (Lrp6 (+/-)) was generated to model the partial function associated with human rs2302685. The liver injury and therapeutic effects of silibinin were compared between Lrp6 (+/-) and Lrp6 (+/+) mice received a methionine-choline deficient (MCD) diet or normal diet. The effect of Lrp6 functional alteration on Wnt/β-catenin-Cyp2e1 signaling activities was evaluated by a series of cellular and molecular assays. Results: The T allele of LRP6 rs2302685 was confirmed to associate with a higher risk of NAFLD in human subjects. The carriers of rs2302685 had reduced level of AST and ALT as compared with the noncarriers. The Lrp6 (+/-) mice exhibited a less severe liver injury induced by MCD but a reduced response to the treatment of silibinin in comparison to the Lrp6 (+/+) mice, suggesting Lrp6 as a target of silibinin. Wnt/β-catenin-Cyp2e1 signaling together with ROS generation could be exacerbated by the overexpression of Lrp6, while decreased in response to Lrp6 siRNA or silibinin treatment under NAFLD modeling. Conclusions: The Lrp6 function affects individual susceptibility to NAFLD and the therapeutic effect of silibinin through the Wnt/β-catenin-Cyp2e1 signaling pathway. The present work has provided an underlying mechanism for human individual susceptibility to NAFLD associated with Lrp6 polymorphisms as well as a rationale for the effective use of silibinin in NAFLD patients.

PMID:34671210 | PMC:PMC8495406 | DOI:10.7150/ijbs.63732

Mucosal Immunol. 2021 Oct 20. doi: 10.1038/s41385-021-00462-y. Online ahead of print.

ABSTRACT

Itaconate is produced from the mitochondrial TCA cycle enzyme aconitase decarboxylase (encoded by immune responsive gene1; Irg1) that exerts immunomodulatory function in myeloid cells. However, the role of the Irg1/itaconate pathway in dendritic cells (DC)-mediated airway inflammation and adaptive immunity to inhaled allergens, which are the primary antigen-presenting cells in allergic asthma, remains largely unknown. House dust mite (HDM)-challenged Irg1-/- mice displayed increases in eosinophilic airway inflammation, mucous cell metaplasia, and Th2 cytokine production with a mechanism involving impaired mite antigen presentations by DC. Adoptive transfer of HDM-pulsed DC from Irg1-deficient mice into naïve WT mice induced a similar phenotype of elevated type 2 airway inflammation and allergic sensitization. Untargeted metabolite analysis of HDM-pulsed DC revealed itaconate as one of the most abundant polar metabolites that potentially suppress mitochondrial oxidative damage. Furthermore, the immunomodulatory effect of itaconate was translated in vivo, where intranasal administration of 4-octyl itaconate 4-OI following antigen priming attenuated the manifestations of HDM-induced airway disease and Th2 immune response. Taken together, these data demonstrated for the first time a direct regulatory role of the Irg1/itaconate pathway in DC for the development of type 2 airway inflammation and suggest a possible therapeutic target in modulating allergic asthma.

PMID:34671116 | DOI:10.1038/s41385-021-00462-y

Pharmacogenomics J. 2021 Oct 20. doi: 10.1038/s41397-021-00258-0. Online ahead of print.

ABSTRACT

PURPOSE: The Pharmacogenomics (PGx) Profile Service was a proof-of-concept project to implement PGx in patient care at Mayo Clinic.

METHODS: Eighty-two healthy individuals aged 18 and older underwent genotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, HLA-B*58:01, and VKORC1. A PGx pharmacist was involved in ordering, meeting with patients, interpreting, reviewing, and documenting results.

RESULTS: Ninety three percent were CYP1A2 rapid metabolizers, 92% CYP3A4 normal metabolizers, and 88% CYP3A5 poor metabolizers; phenotype frequencies for CYP2C19 and CYP2D6 varied. Seventy-three percent had normal functioning SLCO1B1 transporter, 4% carried the HLA-B*58:01 risk variant, and 35% carried VKORC1 and CYP2C9 variants that increased warfarin sensitivity.

CONCLUSION: Pre-emptive PGx testing offered medication improvement opportunity in 56% of participants for commonly used medications. A collaborative approach involving a PGx pharmacist integrated within a clinical practice with regards to utility of PGx results allowed for implementation of the PGx Profile Service.

KEY POINTS: The Mayo Clinic PGx (PGx) Profile Service was a proof-of-concept project to utilize PGx testing as another clinical tool to enhance medication selection and decrease serious adverse reactions or medication failures. Over one-half of participants in the pilot using the PGx Profile Service were predicted to benefit from pre-emptive PGx testing to guide pharmacotherapy. PGx pharmacists played a crucial role in the PGx Profile Service by educating participants, identifying medication-gene interactions, and providing evidence-based (CPIC and DPWG) PGx recommendations for past, current, and future medication us.

PMID:34671112 | DOI:10.1038/s41397-021-00258-0

J Hum Genet. 2021 Oct 21. doi: 10.1038/s10038-021-00980-4. Online ahead of print.

ABSTRACT

No genome-wide association studies (GWAS) were reported for colorectal polyps and the overlap in polygenic backgrounds conferring risk of colorectal cancer and polyps remains unclear. We performed GWAS on subjects with colorectal polyps using the BioBank Japan data with 4447 cases and 157,226 controls. We evaluated genetic correlations between colorectal polyps and cancer, and effects on colorectal polyps of single nucleotide polymorphisms (SNPs) known to be associated with colorectal cancer. We identified CUX2, a known genetic locus to colorectal cancer, as a susceptibility locus to colorectal polyps (p value = 1.1 × 10-15). Subsequent fine-mapping analysis indicated that rs11065828 in CUX2 is the causal variant for colorectal polyps. We found that known colorectal cancer-susceptible SNPs were also associated with colorectal polyps. The genetic correlation between colorectal cancer and polyps is very high (r = 0.98 and p value = 0.0006). We additionally identified 14 significant loci of colorectal polyps and three significant loci of colorectal cancer by applying the multi-trait analysis of GWAS of colorectal cancer and colorectal polyps. We showed very similar germline polygenic features, which gives us the additional insight into potential cancers at polygenic levels for patients with polyps who are followed up at outpatients' clinic; thus, close observation and polypectomy is critical to prevent colorectal cancers.

PMID:34671089 | DOI:10.1038/s10038-021-00980-4

Pediatr Allergy Immunol. 2021 Oct 20. doi: 10.1111/pai.13682. Online ahead of print.

ABSTRACT

Peanut allergy is a common food allergy and the main cause of anaphylaxis among children1 . In recent years, oral immunotherapy has emerged as a promising treatment for children with different IgE-mediated food allergies, although safety issues must be considered2 . The main aim of immunotherapy is to induce tolerance or desensitization to an allergen which otherwise causes an allergic reaction. For oral immunotherapy this means ingesting the allergen in a controlled manner with gradually increasing dosages.

PMID:34669990 | DOI:10.1111/pai.13682

Mol Neurobiol. 2021 Oct 20. doi: 10.1007/s12035-021-02591-8. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk human brain RNA sequencing studies have revealed sex differences in dysregulated molecular pathways related to energy production, neuronal function, and immune response; however, the sex differences in disease mechanisms are yet to be examined comprehensively on a single-cell level. We leveraged nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to perform a case versus control sex-stratified differential gene expression analysis and pathway network enrichment in a cell type-specific manner for each brain region. Our examination at the single-cell level revealed sex differences in AD prominently in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and networks to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology.

PMID:34669146 | DOI:10.1007/s12035-021-02591-8

Eur J Clin Pharmacol. 2021 Oct 19. doi: 10.1007/s00228-021-03233-7. Online ahead of print.

ABSTRACT

PURPOSE: The study aims to evaluate relationship between polymorphisms associated with a reduced function of two transporter proteins resulting in increased exposure to rosuvastatin - organic anion transporter 1B1 (OATP1B1) (SLCO1B1 c.521T>C) and ATP binding cassette subfamily G member 2 (ABCG2) (ABCG2 c.421C>A) and occurrence of rosuvastatin related myotoxicity/hepatotoxicity.

METHODS: In a case-control study, cases (rosuvastatin treated patients developing myotoxicity or hepatotoxicity) and controls (concurrent rosuvastatin treated patients free of adverse events) were prospectively recruited over a 2 year period in a single tertiary center specialized in treatment of metabolic disorders. Subjects were evaluated for clinical, comorbidity, and comedication characteristics and for genotype predicted metabolizing phenotypes regarding cytochrome P450 enzymes CYP2C9 and CYP2C19. Standard regression analysis and analysis in matched sets of cases and controls (optimal full matching) were undertaken by fitting frequentist and Bayesian models (covariates/matching variables: age, sex, diabetes, liver/renal disease, hypertension, CYP2C9 and C19 phenotype, use of CYP or transporter inhibitors, non evaluated transporter genotype).

RESULTS: A total of 88 cases (81 with myotoxicity, 6 with hepatotoxicity, 1 with both) and 129 controls were recruited. Odds of variant SLCO1B1 c.521T>C allele were 2.2-2.5 times higher in cases than in controls (OR = 2.45, 95% CI 1.34-4.48; Bayesian OR = 2.59, 95% CrI 1.42-4.90 in regression analysis; OR = 2.20, 1.10-4.42; Bayesian OR = 2.26, 1.28-4.41 in matched analysis). Odds of variant ABCG2 c.421C>A allele were 2.1-2.3 times higher in cases than in controls (OR = 2.24, 1.04-4.83; Bayesian OR = 2.35, 1.09-4.31 in regression analysis; OR = 2.10, 0.83-5.31; Bayesian OR = 2.17, 1.07-4.35 in matched analysis).

CONCLUSION: Loss of function polymorphisms in SLCO1B1 c.521T>C and ABCG2 c.421C>A genes are associated with the presence of rosuvastatin related myotoxicity and/or hepatotoxicity.

PMID:34668025 | DOI:10.1007/s00228-021-03233-7

Anesth Essays Res. 2021 Jan-Mar;15(1):4-7. doi: 10.4103/aer.aer_94_21. Epub 2021 Aug 30.

ABSTRACT

Opioid-related respiratory depression is a serious clinical problem as it can cause multiple deaths and anoxic brain injury. Genetic variations influence the safety and clinical efficacy of fentanyl. Pharmacogenetic studies help in identifying single-nucleotide polymorphisms (SNPs) associated with fentanyl causing respiratory depression and aid clinician in personalized pain medicine. This narrative review gives an insight of the common SNPs associated with fentanyl.

PMID:34667340 | PMC:PMC8462425 | DOI:10.4103/aer.aer_94_21