Polymorphism on chromosome 20p13 near the IDH3B gene is associated with uterine prolapse.

Eur J Obstet Gynecol Reprod Biol. 2020 Jun 25;252:155-159

Authors: Bizjak T, Gorenjak M, Potočnik U, But I

Abstract
OBJECTIVES: Previous studies have found evidence for a genetic basis for pelvic organ prolapse (POP), but no genetic studies have differentiated between types of POP. This study investigated whether genetic variants in six previously suggested candidate loci for POP modify the risk of uterine prolapse (UP).
STUDY DESIGN: One hundred patients, aged 30-55 years, who had undergone surgery due to total UP and 105 healthy controls were included in this study. After extracting the genomic DNA from peripheral blood, six single nucleotide polymorphisms (SNPs) previously identified for POP were genotyped, and association analysis was performed for contributing risk factors. RNA expression was determined from sacrouterine ligaments of patients and controls using quantitative reverse transcription polymerase chain reaction.
RESULTS: The dominant genotype model for the T allele for SNP rs6051098 at the chromosome 20p13 locus was significant, and this remained significant with the risk factor regression model (p=0.046; odds ratio 1.93, 95 % confidence interval 1.01-3.66). The isocitrate dehydrogenase 3 beta (IDH3B) gene was the only potential candidate gene in the 20p13 locus that was significantly upregulated in sacrouterine biopsies in women with UP compared with controls (p = 0.034).
CONCLUSION: To the best of the authors' knowledge, this is the first study to show that genetic risk factors contribute to UP, and suggested rs6051098 as the best candidate risk factor associated with UP. According to expression data in sacrouterine tissue, this study suggests that the IDH3B gene plays a role in the pathogenesis of UP.

PMID: 32619879 [PubMed - as supplied by publisher]

Precision medicine for rheumatologists: lessons from the pharmacogenomics of azathioprine.

Clin Rheumatol. 2020 Jul 02;:

Authors: Daniel LL, Dickson AL, Chung CP

Abstract
Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.

PMID: 32617765 [PubMed - as supplied by publisher]

Response to: 'Cutaneous adverse events with febuxostat after previous reactions to allopurinol: comment on the artcile by Singh and Clevland' by Quills et al.

Ann Rheum Dis. 2020 Jul 02;:

Authors: Singh JA

PMID: 32616606 [PubMed - as supplied by publisher]

PreMetabo: An in silico phase I and II drug metabolism prediction platform.

Drug Metab Pharmacokinet. 2020 May 31;:

Authors: Hwang S, Shin HK, Shin SE, Seo M, Jeon HN, Yim DE, Kim DH, No KT

Abstract
This study aimed to develop a drug metabolism prediction platform using knowledge-based prediction models. Site of Metabolism (SOM) prediction models for four cytochrome P450 (CYP) subtypes were developed along with uridine 5'-diphosphoglucuronosyltransferase (UGT) and sulfotransferase (SULT) substrate classification models. The SOM substrate for a certain CYP was determined using the sum of the activation energy required for the reaction at the reaction site of the substrate and the binding energy of the substrate to the CYP enzyme. Activation energy was calculated using the EaMEAD model and binding energy was calculated by docking simulation. Phase II prediction models were developed to predict whether a molecule is the substrate of a certain phase II conjugate protein, i.e., UGT or SULT. Using SOM prediction models, the predictability of the major metabolite in the top-3 was obtained as 72.5-84.5% for four CYPs, respectively. For internal validation, the accuracy of the UGT and SULT substrate classification model was obtained as 93.94% and 80.68%, respectively. Additionally, for external validation, the accuracy of the UGT substrate classification model was obtained as 81% in the case of 11 FDA-approved drugs. PreMetabo is implemented in a web environment and is available at https://premetabo.bmdrc.kr/.

PMID: 32616370 [PubMed - as supplied by publisher]

Panax notoginseng saponins prevent colitis-associated colorectal cancer development: the role of gut microbiota.

Chin J Nat Med. 2020 Jul;18(7):500-507

Authors: Chen L, Chen MY, Shao L, Zhang W, Rao T, Zhou HH, Huang WH

Abstract
Gut microbiota dysbiosis is a risk factor for colorectal cancer (CRC) in inflammatory bowel disease (IBD). In this study, the effects of Panax notoginseng saponins (PNS) on colitis-associated CRC progression were evaluated on an azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model. In vivo, PNS significantly relieved AOM/DSS-induced colon tumorigenesis and development by reducing the disease activity index (DAI) scores and colon tumor load. The 16S rRNA data of fecal samples showed that the microbiome community was obviously destructed, while PNS could recover the richness and diversity of gut microbiota. Especially, PNS could increase the abundance of Akkermansia spp. which was significantly decreased in model group and negatively correlated with the progression of CRC. Moreover, ginsenoside compound K (GC-K) was evaluated on the effects of human CRC cells, which was the main bio-transformed metabolite of PNS by gut microbiota. Our data showed that PNS played important role in the prevention of the progression of CRC, due to their regulation on the microbiome balance and microbial bio-converted product with anti-CRC activity.

PMID: 32616190 [PubMed - in process]

High levels of tumor-infiltrating lymphocytes showed better clinical outcomes in FOLFOX-treated gastric cancer patients.

Pharmacogenomics. 2020 Jul 03;:

Authors: Li W, Wang W, Liao P, Song K, Zhu Z, Wang K, Liu Z, Zhang W, Xie S, He Y, Mcleod HL, Chen L

Abstract
Background: Tumor-infiltrating lymphocytes (TILs) and postoperative chemotherapeutics interact in the tumor micro-environment. This interaction has not been well investigated in gastric cancer. Materials & methods: A total of 129 patients were divided into high or low TILs based on the median number of positive CD3+ and FoxP3+ T cells, which was assessed by immunocytochemistry. Results: Cox regression analysis showed that the stage III disease with shorter overall survival was significant. The analysis showed that high numbers of CD3+ or FoxP3+ T cells have better clinical outcomes in FOLFOX-treated patients. Conclusion: High CD3+ and FoxP3+ T-cell infiltration was associated with better clinical outcomes in patients with gastric cancer treated with FOLFOX, suggesting TILs incorporated into algorithms to improve the therapeutic efficacy of optimal chemotherapy.

PMID: 32615909 [PubMed - as supplied by publisher]

The influence of coffee intake and genetics on adenosine pathway in rheumatoid arthritis.

Pharmacogenomics. 2020 Jul 03;:

Authors: Soukup T, Hloch K, Doseděl M, Tebbens JD, Nekvindová J, Šembera Š, Veleta T, Pávek P, Barvík I

Abstract
Aim: We studied the influence of coffee consumption on the therapeutic effect of methotrexate (MTX) in patients with rheumatoid arthritis (RA) sorted according to ADORA2A genotypes. Patients & methods: 82 RA patients were dichotomized according to caffeine intake with a threshold of 700 mg/week. Disease activity score 28 (DAS28) was applied (>3.2 - high; <3.2 - low or remission). Patients were genotyped using quantitative PCR allelic discrimination. Results: We found significantly higher risk of RA in patients with higher caffeine intake and the CT genotype of ADOARA2A rs2298383, rs3761422 and rs2267076 SNPs. The CC genotype of ADORA2A rs2236624 SNP in patients with lower caffeine intake treated with MTX is significantly protective. Conclusion: ADORA2A genotypes and coffee intake influence risk of RA and efficacy of it MTX treatment.

PMID: 32615857 [PubMed - as supplied by publisher]

Considerations for Implementing Precision Therapeutics for Children.

Clin Transl Sci. 2019 03;12(2):140-150

Authors: McLaughlin MJ, Wagner J, Shakhnovich V, Carleton B, Leeder JS

Abstract
Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contributes to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. With significant improvements in characterizing both the ontogeny and genetic contributions of drug metabolizing enzymes, the time is right to begin placing more emphasis on response rather than only the dose-exposure relationship. The amount of drug target receptors and the relative affinity for binding at that target site may require different levels of systemic exposure to achieve a desired response. Concentration-controlled studies can identify the needed exposure for a response at the drug target, the level of expression of the target site in an individual patient, and the tools required to individualize response. Although pediatrics represents a large spectrum of growth and development, developing tools to improve drug delivery for each individual patient across the spectrum of the ages treated by clinicians remains valuable.

PMID: 30516322 [PubMed - indexed for MEDLINE]

Pharmacologic Management of Severe Bronchopulmonary Dysplasia.

Neoreviews. 2020 Jul;21(7):e454-e468

Authors: Truog WE, Lewis TR, Bamat NA

Abstract
Few medications are available and well tested to treat infants who already have developed or inevitably will develop severe bronchopulmonary dysplasia (sBPD). Infants who develop sBPD clearly have not benefited from decades of research efforts to identify clinically meaningful preventive therapies for very preterm infants in the first days and weeks of their postnatal lives. This review addresses challenges to individualized approaches to medication use for sBPD. Specific challenges include understanding the combination of an individual infant's postmenstrual and postnatal age and the developmental status of drug-metabolizing enzymes and receptor expression. This review will also explore the reasons for the variable responsiveness of infants to specific therapies, based on current understanding of developmental pharmacology and pharmacogenetics. Data demonstrating the remarkable variability in the use of commonly prescribed drugs for sBPD are presented, and a discussion about the current use of some of these medications is provided. Finally, the potential use of antifibrotic medications in late-stage sBPD, which is characterized by a profibrotic state, is addressed.

PMID: 32611563 [PubMed - in process]

Inhibition of Hepatic CYP2D6 by the Active N-Oxide Metabolite of Sorafenib.

AAPS J. 2019 10 21;21(6):107

Authors: Murray M, Gillani TB, Rawling T, Nair PC

Abstract
The multikinase inhibitor sorafenib (SOR) is used to treat patients with hepatocellular and renal carcinomas. SOR undergoes CYP-mediated biotransformation to a pharmacologically active N-oxide metabolite (SNO) that has been shown to accumulate to varying extents in individuals. Kinase inhibitors like SOR are frequently coadministered with a range of other drugs to improve the efficacy of anticancer drug therapy and to treat comorbidities. Recent evidence has suggested that SNO is more effective than SOR as an inhibitor of CYP3A4-mediated midazolam 1'-hydroxylation. CYP2D6 is also reportedly inhibited by SOR. The present study assessed the possibility that SNO might contribute to CYP2D6 inhibition. The inhibition kinetics of CYP2D6-mediated dextromethorphan O-demethylation were analyzed in human hepatic microsomes, with SNO found to be ~ 19-fold more active than SOR (Kis 1.8 ± 0.3 μM and 34 ± 11 μM, respectively). Molecular docking studies of SOR and SNO were undertaken using multiple crystal structures of CYP2D6. Both molecules mediated interactions with key amino acid residues in putative substrate recognition sites of CYP2D6. However, a larger number of H-bonding interactions was noted between the N-oxide moiety of SNO and active site residues that account for its greater inhibition potency. These findings suggest that SNO has the potential to contribute to pharmacokinetic interactions involving SOR, perhaps in those individuals in whom SNO accumulates.

PMID: 31637538 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

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14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

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19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/07/01

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21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/07/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Evaluation of gene-drug common module identification methods using pharmacogenomics data.

Brief Bioinform. 2020 Jun 26;:

Authors: Huang J, Chen J, Zhang B, Zhu L, Cai H

Abstract
Accurately identifying the interactions between genomic factors and the response of cancer drugs plays important roles in drug discovery, drug repositioning and cancer treatment. A number of studies revealed that interactions between genes and drugs were 'many-genes-to-many drugs' interactions, i.e. common modules, opposed to 'one-gene-to-one-drug' interactions. Such modules fully explain the interactions between complex biological regulatory mechanisms and cancer drugs. However, strategies for effectively and robustly identifying the underlying common modules among pharmacogenomics data remain to be improved. In this paper, we aim to provide a detailed evaluation of three categories of state-of-the-art common module identification techniques from a machine learning perspective, including non-negative matrix factorization (NMF), partial least squares (PLS) and network analyses. We first evaluate the performance of six methods, namely SNMNMF, NetNMF, SNPLS, O2PLS, NSBM and HOGMMNC, using two series of simulated data sets with different noise levels and outlier ratios. Then, we conduct experiments using a real world data set of 2091 genes and 101 drugs in 392 cancer cell lines and compare the real experimental results from the aspect of biological process term enrichment, gene-drug and drug-drug interactions. Finally, we present interesting findings from our evaluation study and discuss the advantages and drawbacks of each method. Supplementary information: Supplementary file is available at Briefings in Bioinformatics online.

PMID: 32591780 [PubMed - as supplied by publisher]

Public interest in whole genome sequencing and information needs: an online survey study.

Per Med. 2020 Jun 26;:

Authors: Etchegary H, Wilson B, Rahman P, Simmonds C, Pullman D

Abstract
Aim: To survey the general public about whole genome sequencing interest, including pharmacogenomic testing, and to identify information important for sequencing decisions. Patients & methods: An online survey of 901 members of the general public in an Eastern Canadian province. Results: Interest in whole genome sequencing, including pharmacogenomic testing, was high with few differences among demographic variables. Issues identified as very important to sequencing decisions included familial implications of testing, whether treatment was available for conditions tested and knowing who could access genomic information. Most respondents would value support when interpreting sequencing results. Conclusion: Findings reveal the kind of information and support users of sequencing services would value and could inform the implementation of sequencing into care in ways that accord with public preferences and needs.

PMID: 32589098 [PubMed - as supplied by publisher]

Assessment of healthcare professionals' knowledge, attitudes, and perceived challenges of clinical pharmacogenetic testing in Egypt.

Per Med. 2020 Jun 26;:

Authors: Nagy M, Lynch M, Kamal S, Mohamed S, Hadad A, Abouelnaga S, Aquilante CL

Abstract
Aim: We evaluated healthcare practitioners' perspectives regarding clinical pharmacogenetics in Cairo, Egypt. Materials & methods: We administered a paper-based survey to pharmacists and physicians practicing at Children's Cancer Hospital Egypt. The survey assessed practitioners' knowledge, attitudes, and perspectives about pharmacogenetic testing. Results: The study included 184 respondents (67.9% pharmacists; 32.1% physicians. Overall, the pharmacogenetic knowledge was low (mean = 41.7%) but attitudes toward pharmacogenetic testing and its potential clinical application were generally positive. Pharmacists responded more favorably than physicians to statements attributing the responsibility of applying pharmacogenetics in the clinical setting to their profession. However, several challenges were identified; the most common being: lack of pharmacogenetic knowledge and skill, lack of pharmacogenetic testing devices, and limited funding. Conclusion: Future efforts to promote pharmacogenetic implementation should focus on foundational education, practical training, and exploration of potential funding sources.

PMID: 32589096 [PubMed - as supplied by publisher]

Metformin attenuates antipsychotic-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats.

Psychopharmacology (Berl). 2020 Jun 25;:

Authors: Luo C, Wang X, Mao X, Huang H, Liu Y, Zhao J, Zhou H, Liu Z, Li X

Abstract
RATIONALE: Second-generation antipsychotics are the first-line medications prescribed for schizophrenic patients; however, some of them, such as olanzapine and risperidone, may induce metabolic dysfunctions during short-term treatment. Metformin is an effective adjuvant that attenuates antipsychotic-induced metabolic dysfunctions (AIMD) in clinical practice. Whether metformin can reverse AIMD and whether metformin affects the therapeutic effects of antipsychotics in animal models of schizophrenia are questions that still need to be investigated.
METHODS: In this study, an animal model of schizophrenia was established by consecutive injections of MK801 during the neurodevelopmental period. In adulthood, different dosages of olanzapine or risperidone treatment were administered to the schizophrenia model animals for 14 days. Both therapeutic effects and metabolic adverse effects were measured by behavioral tests, histopathological tests, and biochemical tests. The coadministration of different doses of metformin with olanzapine or risperidone was used to evaluate the effects of metformin on both AIMD and the therapeutic effect of those antipsychotics.
RESULTS: The MK801-treated rats showed schizophrenia-like behavior and variations in the shape and volume of the hippocampus. Both olanzapine and risperidone reversed the MK801-induced behavioral abnormalities as the dosage increased; however, they degenerated the hepatocytes in the liver and influenced the blood lipid levels and blood glucose levels. The coadministration of metformin did not affect the therapeutic effects of olanzapine or risperidone on behavioral abnormalities but attenuated the metabolic dysfunctions induced by those antipsychotics.
CONCLUSION: Metformin attenuated the olanzapine- and risperidone-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats without reducing the therapeutic effects of the antipsychotics.

PMID: 32588080 [PubMed - as supplied by publisher]

Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian-randomization study.

Int J Epidemiol. 2020 Jun 26;:

Authors: Green HD, Beaumont RN, Wood AR, Hamilton B, Jones SE, Goodhand JR, Kennedy NA, Ahmad T, Yaghootkar H, Weedon MN, Frayling TM, Tyrrell J

Abstract
BACKGROUND: Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD.
METHODS: We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist-hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption.
RESULTS: Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference.
CONCLUSIONS: These results provide strong evidence that a higher waist-hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.

PMID: 32588049 [PubMed - as supplied by publisher]

Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

J Pediatr. 2020 Jul;222:213-220.e5

Authors: Van Driest SL, Sleeper LA, Gelb BD, Morris SA, Dietz HC, Forbus GA, Goldmuntz E, Hoskoppal A, James J, Lee TM, Levine JC, Li JS, Loeys BL, Markham LW, Meester JAN, Mital S, Mosley JD, Olson AK, Renard M, Shaffer CM, Sharkey A, Young L, Lacro RV, Roden DM

Abstract
OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial.
STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models.
RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status.
CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.

PMID: 32586526 [PubMed - in process]