Outcome Definition Influences the Relationship Between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients.

Genes (Basel). 2019 May 10;10(5):

Authors: Zazuli Z, Otten LS, Drögemöller BI, Medeiros M, Monzon JG, Wright GEB, Kollmannsberger CK, Bedard PL, Chen Z, Gelmon KA, McGoldrick N, Kitchlu A, Vijverberg SJH, Masereeuw R, Ross CJD, Liu G, Carleton BC, Maitland-van der Zee AH

Abstract
Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009-2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI:0.08-0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI:1.96-9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI:1.69-15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.

PMID: 31083486 [PubMed]

Genetic variability and population diversity of the human SLCO (OATP) transporter family.

Pharmacol Res. 2019 01;139:550-559

Authors: Zhang B, Lauschke VM

Abstract
Organic anion transporting polypeptides (OATP) encoded by the SLCO gene family constitute clinically important transporters involved in the disposition of endogenous compounds and many commonly prescribed drugs, including statins, methotrexate and antihypertensive medications. Common genetic polymorphisms in SLCO genes are known to affect OATP function and modulate efficacy and safety of OATP substrates. However, current frequency data of these variants and haplotypes is generally based on few rather heterogenous populations of relatively small sample size. Furthermore, the genetic variability beyond these selected pharmacogenetic biomarkers has not been systematically analyzed. Here, we provide a global consolidated map of SLCO variability by leveraging fully compatible Next Generation Sequencing data from 138,632 unrelated individuals across seven major human populations. Overall, we find 9811 exonic single nucleotide variants and 155 copy number variations of which 99.3% were rare with frequencies <1%. Using orthogonal computational functionality predictors optimized for pharmacogenetic assessments, we find that four out of five individuals carry at least one deleterious variant in an SLCO transporter gene and rare variants contribute 23% to the genetically encoded functional variability. Moreover, 74.9% of all variants were found to be population-specific with important consequences for population-specific genotyping strategies and precision public health approaches. Combined, our analyses provide the most comprehensive data set of SLCO variability published to date and incentivize the integration of comprehensive NGS-based genotyping into personalized predictions of OATP substrate disposition.

PMID: 30359687 [PubMed - indexed for MEDLINE]

Critical Issues and Optimized Practices in Quantification of Protein Abundance Level to Determine Interindividual Variability in DMET Proteins by LC-MS/MS Proteomics.

Clin Pharmacol Ther. 2018 04;103(4):619-630

Authors: Bhatt DK, Prasad B

Abstract
Protein quantification data on drug metabolizing enzymes and transporters (collectively referred as DMET proteins) in human tissues are useful in predicting interindividual variability in drug disposition. While targeted proteomics is an emerging technique for quantification of DMET proteins, the methodology involves significant technical challenges especially when multiple samples are analyzed in a single study over a long period of time. Therefore, it is important to thoroughly address the critical variables that could affect DMET protein quantification.

PMID: 28833066 [PubMed - indexed for MEDLINE]

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.

Clin Pharmacol Ther. 2018 04;103(4):712-721

Authors: Rotroff DM, Pijut SS, Marvel SW, Jack JR, Havener TM, Pujol A, Schluter A, Graf GA, Ginsberg HN, Shah HS, Gao H, Morieri ML, Doria A, Mychaleckyi JC, McLeod HL, Buse JB, Wagner MJ, Motsinger-Reif AA, ACCORD/ACCORDion Investigators

Abstract
Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10-6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D.

PMID: 28736931 [PubMed - indexed for MEDLINE]

Catechol O-Methyltransferase Pharmacogenomics: Challenges and Opportunities.

Clin Pharmacol Ther. 2019 May 13;:

Authors: Ho MF, Weinshilboum RM

PMID: 31081936 [PubMed - as supplied by publisher]

Chemotherapy, cardiovascular disease and precision medicine: Toward truly individualized treatment for precision cardio-oncology?

Int J Cardiol. 2019 04 01;280:198-199

Authors: Carnevale R, Lanzetta G, Biondi-Zoccai G, Frati G

PMID: 30691726 [PubMed - indexed for MEDLINE]

Proton-coupled folate transporter as a biomarker of outcome to treatment for pleural mesothelioma.

Pharmacogenomics. 2018 07 01;19(10):811-814

Authors: Petri GL, Cascioferro S, Parrino B, Peters GJ, Diana P, Giovannetti E

PMID: 29916298 [PubMed - indexed for MEDLINE]

Prolactin levels: sex differences in the effects of risperidone, 9-hydroxyrisperidone levels, CYP2D6 and ABCB1 variants.

Pharmacogenomics. 2018 07 01;19(10):815-823

Authors: Schoretsanitis G, de Leon J, Diaz FJ

Abstract
AIM: The role of sex on the association of plasma prolactin levels with risperidone (R) and 9-hydroxyrisperidone (9-OHR) concentrations is investigated.
METHODS: Plasma R and prolactin concentrations, CYP2D6 and exon 21 and 26 ABCB1 gene variants were studied in 110 patients.
RESULTS: In females, a 1 ng/ml increase in R levels was associated with a significant 1.02% increase in prolactin levels. In males, a 1 ng/ml increase in 9-OHR levels was associated with a significant 1.18% increase in prolactin levels. ABCB1 haplotype 12 had significant but opposite effects in males and females. In the combined sample, 9-OHR, but not R levels had significant effects on prolactin levels.
CONCLUSION: Genes had sex-specific effects on risperidone-associated prolactin elevations.

PMID: 29914302 [PubMed - indexed for MEDLINE]

Bidirectional scaling of vocal variability by an avian cortico-basal ganglia circuit.

Physiol Rep. 2018 04;6(8):e13638

Authors: Heston JB, Simon J, Day NF, Coleman MJ, White SA

Abstract
Behavioral variability is thought to be critical for trial and error learning, but where such motor exploration is generated in the central nervous system is unclear. The zebra finch songbird species offers a highly appropriate model in which to address this question. The male song is amenable to detailed measurements of variability, while the brain contains an identified cortico-basal ganglia loop that underlies this behavior. We used pharmacogenetic interventions to separately interrogate cortical and basal ganglia nodes of zebra finch song control circuitry. We show that bidirectional manipulations of each node produce near mirror image changes in vocal control: Cortical activity promotes song variability, whereas basal ganglia activity promotes song stability. Furthermore, female conspecifics can detect these pharmacogenetically elicited changes in song quality. Our results indicate that cortex and striatopallidum can jointly and reciprocally affect behaviorally relevant levels of vocal variability, and point to endogenous mechanisms for its control.

PMID: 29687960 [PubMed - indexed for MEDLINE]

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.

Nat Genet. 2018 02;50(2):206-218

Authors: Chen M, Zhang J, Sampieri K, Clohessy JG, Mendez L, Gonzalez-Billalabeitia E, Liu XS, Lee YR, Fung J, Katon JM, Menon AV, Webster KA, Ng C, Palumbieri MD, Diolombi MS, Breitkopf SB, Teruya-Feldstein J, Signoretti S, Bronson RT, Asara JM, Castillo-Martin M, Cordon-Cardo C, Pandolfi PP

Abstract
Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.

PMID: 29335545 [PubMed - indexed for MEDLINE]

Richtlinie der Gendiagnostik-Kommission (GEKO) für die Beurteilung genetischer Eigenschaften hinsichtlich ihrer Bedeutung für die Wirkung eines Arzneimittels bei einer Behandlung gemäß § 23 Abs. 2 Nr. 1b GenDG : In der Fassung vom 25. 11. 2016, veröffentlicht und in Kraft getreten am 06. 12. 2016.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2017 Apr;60(4):472-475

Authors:

PMID: 28342063 [PubMed - indexed for MEDLINE]

Correction to: TNF-α G-308A genetic variants, serum CRP-hs concentration and DNA damage in obese women.

Mol Biol Rep. 2019 May 11;:

Authors: Włodarczyk M, Ciebiera M, Nowicka G

Abstract
The original publication has been updated. The names in the original publication were not in the correct order. The family name was followed by the first name. This is now corrected.

PMID: 31079317 [PubMed - as supplied by publisher]

Prospective evaluation of finger two-point discrimination and carpal tunnel syndrome among women with breast cancer receiving adjuvant aromatase inhibitor therapy.

Breast Cancer Res Treat. 2019 May 11;:

Authors: Sheng JY, Blackford AL, Bardia A, Venkat R, Rosson G, Giles J, Hayes DF, Jeter SC, Zhang Z, Hayden J, Nguyen A, Storniolo AM, Tarpinian K, Henry NL, Stearns V

Abstract
PURPOSE: Aromatase inhibitors (AIs) are associated with musculoskeletal symptoms and risk of developing carpal tunnel syndrome (CTS), which can impair quality of life and prompt treatment discontinuation. The incidence of CTS and clinical utility of diagnostic tests such as 2-point discrimination (2-PD) have not been prospectively examined among women receiving AIs.
METHODS: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were enrolled in a randomized clinical trial investigating adjuvant AIs (Exemestane and Letrozole Pharmacogenetics, ELPh) underwent prospective evaluation of 2-PD with the Disc-criminator™ (sliding aesthesiometer) and completed a CTS questionnaire at baseline, 3, 6, and 12 months, following initiation of AI. Changes in mean 2-PD were analyzed with multivariable mixed effects modelling. A p value < 0.05 was considered statistically significant.
RESULTS: Of 100 women who underwent baseline 2-PD testing, CTS was identified by questionnaire in 11% at baseline prior to AI initiation. Prevalence of CTS at any time in the first year was 26%. A significant increase in worst 2-PD score was observed from baseline to 3 months (3.7 mm to 3.9 mm, respectively, p = 0.03) when adjusted for age, prior chemotherapy, randomized treatment assignment, and diabetes. There were no significant differences in treatment discontinuation due to CTS between the arms.
CONCLUSION: For women receiving adjuvant AI, 2-PD scores were significantly worse at 3 months compared to baseline. Studies are required to assess whether change in 2-PD is an adequate objective assessment for CTS with AI therapy. Early diagnosis of CTS may expedite management, improve AI adherence, and enhance breast cancer outcomes.

PMID: 31079282 [PubMed - as supplied by publisher]

Distribution of the cytochrome P450 2C8*2 allele in Brazzaville, Republic of Congo.

Int J Infect Dis. 2019 May 09;:

Authors: Peko SM, Ntoumi F, Vouvoungui C, Nderu D, Kobawila SC, Thirumalaisamy VP, Koukouikila Koussounda F

Abstract
BACKGROUND: Cytochrome P450 (CYP) enzymes are essential in the metabolism of most drugs used today. Single nucleotide polymorphism(s) occurring in CYP genes can adversely affect drug pharmacokinetics, efficacy and safety. Individuals carrying CYP2C8*2 c.805A > T (CYP2C8*2; rs11572103) allele have impaired amodiaquine (AQ) metabolism, increased risk of amodiaquine - related adverse events and may promote selection of drug - resistant parasite strains. This study investigated the distribution of CYP2C8*2 allele in Brazzaville, Republic of Congo, where artenusate + amodiaquine is used as second - line treatment for uncomplicated P. falciparum malaria.
METHODS: A total of 285 febrile children visiting the Marien Ngouabi pediatric hospital were genotyped for CYP2C8*2 using PCR - Restriction Fragment Length Polymorphism (PCR-RFLP). The allele frequencies and genotype distribution were determined.
RESULTS: The CYP2C8*2 allele was successfully genotyped in 75% (213/285) of the study participants. CYP2C8*2A allele had a frequency of 63% whereas CYP2C8*2T allele had 37%. Genotypes CYP2C8*2AA (rapid metaboliser), CYP2C8*2AT (intermediate metaboliser) and CYP2C8*2TT (poor metaboliser) were observed in 44%, 38% and 18% of the investigated participants, respectively.
CONCLUSION: This study gives the first description of CYP2C8*2 allele distribution in the Republic of Congo and highlights the potential risk of AQ - related adverse events. Information from this study will be beneficial during pharmacovigilance investigations.

PMID: 31078747 [PubMed - as supplied by publisher]

Should we treat bacteremic prostatitis for 7 days?

Clin Infect Dis. 2019 May 11;:

Authors: De Greef J, Doyen L, Henrard S, Elens L, Vandercam B, Belkhir L

PMID: 31077264 [PubMed - as supplied by publisher]

Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists.

J Mol Diagn. 2019 May 07;:

Authors: Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Moyer AM, Scott SA, Whirl-Carrillo M, Weck KE

Abstract
The goals of the Association for Molecular Pathology Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee are to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9 testing. The Working Group considered functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. Our goal is to promote standardization of testing PGx genes/allele testing across clinical laboratories. These recommendations are not to be interpreted as restrictive but to provide a reference guide. The current document will focus on CYP2C9 testing that can be applied to all CYP2C9-related medications. A separate recommendation on warfarin PGx testing is being developed to include recommendations on CYP2C9 alleles and additional warfarin sensitivity-associated genes/alleles.

PMID: 31075510 [PubMed - as supplied by publisher]

Unraveling the genetic underpinnings of sleep deprivation-induced impairments in human cognition.

Prog Brain Res. 2019;246:127-158

Authors: Satterfield BC, Stucky B, Landolt HP, Van Dongen HPA

Abstract
The biobehavioral phenomena of sleep and cognition involve complex phenotype-genotype associations, i.e., complex relationships between observable traits and the genetic variants that contribute to the expression of those traits. There is a general belief that investigating such relationships requires large sample sizes. However, sleep- and cognition-related phenotype-genotype associations may be strengthened through carefully controlled laboratory studies that amplify a given cognitive phenotype by perturbing the biobehavioral system through sleep deprivation and/or pharmacogenetic interventions. Utilization of performance tasks that dissociate cognitive processes allows for cognitive endophenotyping, that is, making precise measurements that capture the essence of a cognitive phenotype. This enables assessment of the genetic underpinnings of cognitive impairment due to sleep deprivation without necessarily requiring large samples. Theory-driven gene selection, selective population sampling techniques to avoid underrepresentation of rare genetic variants, and modern statistical techniques informed by prior knowledge further enhance statistical power. Here we illustrate these approaches on the basis of recent findings, supplemented with some new results, as well as a discussion of modern regression methods for statistical analysis. Ongoing research employing these methods is driving advancements in the understanding of the genetic underpinnings of cognitive impairment associated with sleep loss.

PMID: 31072559 [PubMed - in process]

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pharmacogenomics

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12 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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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.

Relative proteome quantification of alpha, beta, gamma and delta globin chains in early eluting peaks of Bio-Rad variant II® CE-HPLC of hemoglobin from healthy and beta-thalassemia subjects in Malaysia.

Biochem Biophys Rep. 2019 Jul;18:100635

Authors: Abdullah UYH, Ibrahim HM, Jassim HM, Salleh MZ, Kek TL, Fakhruzzaman Bin Noorizhab MN, Zilfalil BA, Wilairat P, Fucharoen S

Abstract
This is the first report of QQQ-mass spectrometric identification and quantification of the Hb subunits, alpha, beta, delta and gamma globin peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the Bio-Rad cation-exchange chromatography of haemoglobin. The objectives were to assess the relationship of the quantity of the free alpha, beta, delta and gamma globin chains with the phenotypic diversity of beta-thalassaemias (β-thal). The results demonstrate that the pools of free globin chains in red blood cells were correlating with the severity of the disease in patients with different phenotypes of β-thal. The mechanism and the regulation of synthesis of free globin chains pool in a normal individual and in patients with different β-thal phenotypes could arise from several mechanisms which will require further investigation. The role of the free globin pool in patients with β-thal for development of novel therapeutic approaches based on these potential targets requires further investigation. Pertinent biomarkers improves the diagnosis of the β-thal, especially in low-income countries where they are most common and allows more effective therapeutic intervention leading to more successful therapeutic outcome.

PMID: 31061897 [PubMed]