Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives.

Pharmacogenet Genomics. 2020 Feb 26;:

Authors: Haas DW, Cramer YS, Godfrey C, Rosenkranz SL, Aweeka F, Berzins B, Coombs R, Coughlin K, Moran LE, Gingrich D, Zorrilla CD, Baker P, Cohn SE, Scarsi KK, AIDS Clinical Trials Group A5316 Study Team

Abstract
OBJECTIVE: In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions.
METHODS: In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 μg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed.
RESULTS: The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers.
CONCLUSION: CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

PMID: 32106141 [PubMed - as supplied by publisher]

Down-regulating NQO1 promotes cellular proliferation in K562 cells via elevating DNA synthesis.

Life Sci. 2020 Feb 24;:117467

Authors: Xiao FY, Jiang ZP, Yuan F, Zhou FJ, Kuang W, Zhou G, Chen XP, Liu R, Zhou HH, Zhao XL, Cao S

Abstract
BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear.
MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth.
RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects.
SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.

PMID: 32105706 [PubMed - as supplied by publisher]

Association of PARP1 polymorphisms with response to chemotherapy in patients with high-risk neuroblastoma.

J Cell Mol Med. 2020 Feb 27;:

Authors: Avitabile M, Lasorsa VA, Cantalupo S, Cardinale A, Cimmino F, Montella A, Capasso D, Haupt R, Amoroso L, Garaventa A, Quattrone A, Corrias MV, Iolascon A, Capasso M

Abstract
The genetic aetiology and the molecular mechanisms that characterize high-risk neuroblastoma are still little understood. The majority of high-risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients' datasets and in 20 neuroblastomas analysed by qRT-PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non-coding region with response chemotherapy in 121 Italian patients with high-risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high-risk NB.

PMID: 32103589 [PubMed - as supplied by publisher]

Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance.

Sci Transl Med. 2020 Feb 26;12(532):

Authors: Azzimato V, Jager J, Chen P, Morgantini C, Levi L, Barreby E, Sulen A, Oses C, Willerbrords J, Xu C, Li X, Shen JX, Akbar N, Haag L, Ellis E, Wålhen K, Näslund E, Thorell A, Choudhury RP, Lauschke VM, Rydén M, Craige SM, Aouadi M

Abstract
Obesity and insulin resistance are risk factors for nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. Because no approved medication nor an accurate and noninvasive diagnosis is currently available for NAFLD, there is a clear need to better understand the link between obesity and NAFLD. Lipid accumulation during obesity is known to be associated with oxidative stress and inflammatory activation of liver macrophages (LMs). However, we show that although LMs do not become proinflammatory during obesity, they display signs of oxidative stress. In livers of both humans and mice, antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) was down-regulated with obesity and insulin resistance, yielding an impaired response to lipid accumulation. At the molecular level, a microRNA-targeting NRF2 protein, miR-144, was elevated in the livers of obese insulin-resistant humans and mice, and specific silencing of miR-144 in murine and human LMs was sufficient to restore NRF2 protein expression and the antioxidant response. These results highlight the pathological role of LMs and their therapeutic potential to restore the impaired endogenous antioxidant response in obesity-associated NAFLD.

PMID: 32102936 [PubMed - in process]

The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy. An Italian case-control study.

Br J Cancer. 2019 04;120(8):834-839

Authors: Iachetta F, Bonelli C, Romagnani A, Zamponi R, Tofani L, Farnetti E, Nicoli D, Damato A, Banzi M, Casali B, Pinto C

Abstract
BACKGROUND: Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined.
METHODS: In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. We planned a case-control study with all cases of DPYD*2A wild type who developed toxicity ≥G3 and with a cohort of patients who did not present severe toxicities. Then, we tested the additional SNPs: c.2846A>T, c.1679T>G, c.2194G>A.
RESULTS: From 2011 to 2016, we screened 1827 patients for DPD deficiency; of those, 31 subjects (1.7%) showed DPYD*2A SNP. We selected 146 subjects who developed severe toxicities (Cases) and 220 patients who experienced no or mild toxicities (Controls); 53 patients carried one of the additional SNPs: 35 subjects (66%) fell into the Cases and 18 (34%) into the Controls (p < 0.0001). c.2194G>A was the most frequent SNP (12.5%) and showed a correlation with neutropenia. We confirmed that c.2846A>T and c.1679T>G were related to various toxicities.
CONCLUSIONS: The additional DPYD polymorphisms could enhance the prevention of fluoropyrimidine toxicity. c.2194G>A is the most frequent polymorphism and it was found to be associated with neutropenia.

PMID: 30858516 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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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

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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.

Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

Proc Natl Acad Sci U S A. 2020 Feb 24;:

Authors: Suiter CC, Moriyama T, Matreyek KA, Yang W, Scaletti ER, Nishii R, Yang W, Hoshitsuki K, Singh M, Trehan A, Parish C, Smith C, Li L, Bhojwani D, Yuen LYP, Li CK, Li CH, Yang YL, Walker GJ, Goodhand JR, Kennedy NA, Klussmann FA, Bhatia S, Relling MV, Kato M, Hori H, Bhatia P, Ahmad T, Yeoh AEJ, Stenmark P, Fowler DM, Yang JJ

Abstract
As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

PMID: 32094176 [PubMed - as supplied by publisher]

The role of candidate genetic polymorphisms in the interaction between voriconazole and cyclosporine in patients undergoing allogeneic hematopoietic cell transplantation: An explorative study.

Curr Res Transl Med. 2020 Feb 21;:

Authors: Zgheib NK, Alameddine R, Massoud R, Nasr R, Zahreddine A, El Cheikh J, Mahfouz R, Bazarbachi A

Abstract
PURPOSE: To evaluate polymorphisms in genes of drug metabolizing enzymes and transporters involved in cyclosporine and/or voriconazole disposition among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT).
METHODS: DNA from forty patients was genotyped using the DMETPlus array. The average ratio of cyclosporine concentration/dose (C/D in (ng/mL)/(mg/kg)) per participant's weight was computed using available trough levels and daily doses.
RESULTS: The C/D cyclosporine ratio was significantly higher when it was administered with voriconazole as compared to when it was administered alone: median: 116.75 vs. 25.40 (ng/mL)/(mg/kg) with and without voriconazole respectively, (P < 0.001). There was also a significant association between the C/D cyclosporine ratio combined with voriconazole and the ABCB1 2677 G > T > A (rs2032582) genetic polymorphism (P = 0.05). In parallel, ABCB1 variant allele carriers had higher creatinine in combination therapy with a median creatinine (mg/dL) of 0.74 vs. 0.56 for variant allele carriers vs. reference; P = 0.003. Interestingly, CYP2C9, CYP2C19, and CYP3A5 extensive metabolizers tended to be associated with lower cyclosporine C/D ratio when combined with voriconazole, but the results were not statistically significant.
CONCLUSION: To the best of our knowledge, this is the first pharmacogenetic study on the interaction between voriconazole and cyclosporine in patients undergoing allo-HCT. Results suggest that the ABCB1 2677 G > T > A genetic polymorphism plays a role in this interaction with cyclosporine related nephrotoxicity. Pre-emptive genotyping for this genetic variant may be warranted for cyclosporine dose optimization. Larger studies are needed to potentially show significant associations with more candidate genes such as CYP3A4/5, CYP2C9, and CYP2C19, among others.

PMID: 32094096 [PubMed - as supplied by publisher]

Melatonin Orchestrates Lipid Homeostasis through the Hepatointestinal Circadian Clock and Microbiota during Constant Light Exposure.

Cells. 2020 Feb 20;9(2):

Authors: Hong F, Pan S, Xu P, Xue T, Wang J, Guo Y, Jia L, Qiao X, Li L, Zhai Y

Abstract
Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining hepatointestinal circadian homeostasis is vital for improving lipid homeostasis. Melatonin is a chronobiotic substance that plays a main role in stabilizing bodily rhythm and has shown beneficial effects in protecting against obesity. Based on the dual effect of circadian rhythm regulation and antiobesity, we tested the effect of melatonin in mice under constant light exposure. Exposure to 24-h constant light (LL) increased weight and insulin resistance compared with those of the control group (12-h light-12-h dark cycle, LD), and simultaneous supplementation in the melatonin group (LLM) ameliorated this phenotype. Constant light exposure disturbed the expression pattern of a series of transcripts, including lipid metabolism, circadian regulation and nuclear receptors in the liver. Melatonin also showed beneficial effects in improving lipid metabolism and circadian rhythm homeostasis. Furthermore, the LL group had increased absorption and digestion of lipids in the intestine as evidenced by the elevated influx of lipids in the duodenum and decrease in the efflux of lipids in the jejunum. More interestingly, melatonin ameliorated the gut microbiota dysbiosis and improved lipid efflux from the intestine. Thus, these findings offer a novel clue regarding the obesity-promoting effect attributed to LAN and suggest a possibility for obesity therapy by melatonin in which melatonin could ameliorate rhythm disorder and intestinal dysbiosis.

PMID: 32093272 [PubMed - in process]

Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene.

Mol Cell Biol. 2019 11 15;39(22):

Authors: Demma MJ, Mapelli C, Sun A, Bodea S, Ruprecht B, Javaid S, Wiswell D, Muise E, Chen S, Zelina J, Orvieto F, Santoprete A, Altezza S, Tucci F, Escandon E, Hall B, Ray K, Walji A, O'Neil J

Abstract
The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by chromatin immunoprecipitation (CHIP). Here, we demonstrate by both a proximity ligation assay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo, Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo.

PMID: 31501275 [PubMed - indexed for MEDLINE]

Centralized scientific communities are less likely to generate replicable results.

Elife. 2019 07 02;8:

Authors: Danchev V, Rzhetsky A, Evans JA

Abstract
Concerns have been expressed about the robustness of experimental findings in several areas of science, but these matters have not been evaluated at scale. Here we identify a large sample of published drug-gene interaction claims curated in the Comparative Toxicogenomics Database (for example, benzo(a)pyrene decreases expression of SLC22A3) and evaluate these claims by connecting them with high-throughput experiments from the LINCS L1000 program. Our sample included 60,159 supporting findings and 4253 opposing findings about 51,292 drug-gene interaction claims in 3363 scientific articles. We show that claims reported in a single paper replicate 19.0% (95% confidence interval [CI], 16.9-21.2%) more frequently than expected, while claims reported in multiple papers replicate 45.5% (95% CI, 21.8-74.2%) more frequently than expected. We also analyze the subsample of interactions with two or more published findings (2493 claims; 6272 supporting findings; 339 opposing findings; 1282 research articles), and show that centralized scientific communities, which use similar methods and involve shared authors who contribute to many articles, propagate less replicable claims than decentralized communities, which use more diverse methods and contain more independent teams. Our findings suggest how policies that foster decentralized collaboration will increase the robustness of scientific findings in biomedical research.

PMID: 31264964 [PubMed - indexed for MEDLINE]

NUDT15 Polymorphism in Native American Populations of Brazil.

Clin Pharmacol Ther. 2019 06;105(6):1321-1322

Authors: Suarez-Kurtz G, Brisson GD, Hutz MH, Petzl-Erler ML, Salzano FM

PMID: 30897207 [PubMed - indexed for MEDLINE]

Suicide epigenetics, a review of recent progress.

J Affect Disord. 2020 Mar 15;265:423-438

Authors: Cheung S, Woo J, Maes MS, Zai CC

Abstract
BACKGROUND: Suicide results in over 800,000 deaths every year, making it a major public health concern worldwide. It is highly complex, with genetic and environmental influences. Epigenetic mechanisms, including DNA methylation, miRNA, and histone modifications, could explain the complex interplay of environmental risk factors with genetic risk factors in the emergence of suicidal behavior.
METHODS: Here, we review the literature on suicide epigenetics over the past 10 years.
RESULTS: There has been significant progress in the field of suicide epigenetics, with emerging findings in the brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis genes.
LIMITATIONS: Studying patient subgroups is needed in order to extract more comparable and reproducible epigenetic findings in suicide.
CONCLUSIONS: It is crucial to consider suicidal patients or suicide victims' distal and proximal past history e.g., early-life adversity and psychiatric disorder in epigenetic studies of suicidality.

PMID: 32090769 [PubMed - in process]

Profiles of patients on warfarin anticoagulation therapy in a leading tertiary referral hospital in Kenya; findings and implications for Kenya.

Expert Rev Cardiovasc Ther. 2020 Feb 24;:

Authors: Nyamu DG, Guantai AN, Osanjo GO, Godman B, Aklillu E

Abstract
Background: Patients' profiles affect the outcome with warfarin; however, this data, and its implications, is scarce in resource-poor countries such as Kenya without access to pharmacogenetics or regular INR testing.Objectives: To characterize the profiles of patients on long-term warfarin therapy and subsequently use the findings to guide future anticoagulation management.Methods: Cross-sectional study undertaken among 180 adult patients receiving warfarin therapy in anticoagulation clinics at a leading referral hospital in Kenya. Sociodemographic characteristics were obtained through face-to-face interviews. Details of warfarin therapy, concomitant medication and comorbidities were retrieved from medical records. Associations between patients' profiles and the clinical indications of anticoagulation were computed p≤0.05.Results: Warfarin maintenance dose was 6.17 (±2.75) mg per day. Over 70% of patients received warfarin maintenance doses of ≥6mg per day. Venous thromboembolism (56.6%) amongst obese patients (p=0.0019) and cardioembolic events (48.3%) among males (p=0.0316) aged ≤50 years (p=0.0436) whose body mass indices were ≤ 25 (p<0.0001) were the most common indications. Two-fifths and 45.0% of the patients had at least one other disease and concomitant medications.Conclusions: Long term warfarin therapy among Kenyans is mainly for overweight or lean middle-aged individuals suffering from venous or cardioembolic diseases and requires high daily doses. Studies should correlate patients' profiles with warfarin response to guide future management.

PMID: 32090626 [PubMed - as supplied by publisher]

CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta-analysis.

Br J Clin Pharmacol. 2020 Feb 23;:

Authors: Meloche M, Khazaka M, Kassem I, Barhdadi A, Dubé MP, de Denus S

Abstract
CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain.
METHODS: We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta-analyses were performed on the impact of CYP2D6-inferred phenotypes on heart rate reduction (HR), diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all-type adverse events (AE) and bradycardia.
RESULTS: Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta-analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (p=0.017), and of SBP and DBP by 3 mmHg (p=0.0048) for PM compared to non-PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4-fold for PM, although significant heterogeneity was observed in regards to bradycardia, which limits the scope of this finding.
CONCLUSIONS: Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR, and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6-inferred phenotypes.

PMID: 32090368 [PubMed - as supplied by publisher]

Influence of MRP3 Genetics and Hepatic Expression Ontogeny for Morphine Disposition in Neonatal and Pediatric Patients.

J Clin Pharmacol. 2020 Feb 24;:

Authors: Hahn D, Fukuda T, Euteneuer JC, Mizuno T, Vinks AA, Sadhasivam S, Emoto C

Abstract
We have previously reported the influences of OCT1 ontogeny and genetic variation on morphine clearance in neonatal and pediatric patients. In the latter study, plasma morphine-glucuronide levels correlated with patient genotype for the rs4793665 single-nucleotide polymorphism (SNP) at the locus of MRP3, an efflux transporter of morphine glucuronides between hepatocytes and circulating blood. The link between MRP3 activity and overall morphine clearance has not been thoroughly investigated however, and the developmental profile of hepatic MRP3 protein expression remains thinly defined between neonates and adults. In the current study, previously determined morphine clearance values for neonatal (24-58 weeks postmenstrual age, N = 57) and pediatric (5-16 years, n = 85) patients were reanalyzed for correlation to the SNP genotype of patient rs4793665. Among OCT1 wild-type patients, pediatric morphine clearance showed a significant decreasing trend by MRP3 genotypes in the order of CC > CT > TT (P = .014), whereas for neonates, an identical but nonsignificant trend was observed. Pharmacogenetic differences in MRP3 and OCT1 ontogeny were evaluated by Western blot of hepatic membrane fractions from 50 subjects aged 1 day postnatal to 33 years old. Hepatic MRP3 protein level did not vary by rs4793665 genotype, and followed an atypical developmental pattern of increase up to 1-2 years of age, thereafter decreasing during preadolescence before increasing again to adult levels at maturity (17-33 years). By comparison, OCT1 expression was significantly decreased in OCT1 *1/*3 genotyped patients older than 1 year and followed a trajectory consistent with prior studies. Our results suggest that consideration of MRP3 pharmacogenetics and ontogeny may aid in identifying pediatric patients having different/atypical morphine requirements.

PMID: 32090339 [PubMed - as supplied by publisher]

Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver.

Cells. 2020 Feb 17;9(2):

Authors: Buniatian GH, Weiskirchen R, Weiss TS, Schwinghammer U, Fritz M, Seferyan T, Proksch B, Glaser M, Lourhmati A, Buadze M, Borkham-Kamphorst E, Gaunitz F, Gleiter CH, Lang T, Schaeffeler E, Tremmel R, Cynis H, Frey WH, Gebhardt R, Friedman SL, Mikulits W, Schwab M, Danielyan L

Abstract
The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver. In culture, activated hepatic stellate cells (HSC) internalized Aβ more efficiently than astrocytes and HSC degraded Aβ leading to suppressed expression of α-smooth muscle actin (α-SMA), collagen 1 and transforming growth factor β (TGFβ). Aβ also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGFβ in cultured human liver sinusoidal endothelial cells (hLSEC). Liver Aβ levels also correlate with the expression of eNOS in transgenic Alzheimer's disease mice and in human and rodent cirrhosis/fibrosis. These findings suggest a previously unexplored role of Aβ in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation.

PMID: 32089540 [PubMed - in process]

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis.

JAMA Neurol. 2019 04 01;76(4):480-491

Authors: Marini S, Crawford K, Morotti A, Lee MJ, Pezzini A, Moomaw CJ, Flaherty ML, Montaner J, Roquer J, Jimenez-Conde J, Giralt-Steinhauer E, Elosua R, Cuadrado-Godia E, Soriano-Tarraga C, Slowik A, Jagiella JM, Pera J, Urbanik A, Pichler A, Hansen BM, McCauley JL, Tirschwell DL, Selim M, Brown DL, Silliman SL, Worrall BB, Meschia JF, Kidwell CS, Testai FD, Kittner SJ, Schmidt H, Enzinger C, Deary IJ, Rannikmae K, Samarasekera N, Salman RA, Sudlow CL, Klijn CJM, van Nieuwenhuizen KM, Fernandez-Cadenas I, Delgado P, Norrving B, Lindgren A, Goldstein JN, Viswanathan A, Greenberg SM, Falcone GJ, Biffi A, Langefeld CD, Woo D, Rosand J, Anderson CD, International Stroke Genetics Consortium

Abstract
Importance: Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations.
Objective: To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH.
Design, Setting, and Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study.
Main Outcomes and Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies.
Results: In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity.
Conclusions and Relevance: APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.

PMID: 30726504 [PubMed - indexed for MEDLINE]

Does the CD33 rs3865444 Polymorphism Confer Susceptibility to Alzheimer's Disease?

J Mol Neurosci. 2020 Feb 22;:

Authors: Siokas V, Aslanidou P, Aloizou AM, Peristeri E, Stamati P, Liampas I, Arseniou S, Drakoulis N, Aschner M, Tsatsakis A, Mitsias PD, Bogdanos DP, Hadjigeorgiou GM, Dardiotis E

Abstract
Alzheimer's disease (AD) is a complex genetic disorder. To date, published data have reported conflicting results on the role of CD33 rs3865444 polymorphism in AD. The present study aimed at evaluating the effect of rs3865444 on AD in a large cohort of Greek native patients with AD. We also conducted a meta-analysis by pooling information from different studies on the same topic. Patients with AD (n = 327) and healthy controls (n = 327) were analyzed and genotyped for rs3865444. Single locus analyses were run to explore possible associations between CD33 rs3865444 polymorphism and AD. Our analysis yielded no significant interaction between AD and the CD33 rs3865444 polymorphism. The lack of interaction between the two variables persisted even after a pooled meta-analysis of 8 studies (with 13 datasets), with 4015 AD cases and 7981 controls. The overall results do not support the hypothesis that CD33 rs3865444 polymorphism increases the risk of AD. The results also suggest that the identification of functional variants in CD33 that are indisputably correlated with AD may be an important factor to investigate in future genetic screening studies.

PMID: 32088842 [PubMed - as supplied by publisher]