Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Lupus ; 28(14): 1640-1647, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31684818

ABSTRACT

BACKGROUND: Women with lupus have an increased risk of preeclampsia and preterm birth, and aspirin 81 mg/day is recommended as a preventative measure for preeclampsia. This pilot study quantified the association between a 60-gene aspirin response signature (ARS) gene expression with preterm birth and preeclampsia risk among women with lupus taking aspirin. METHODS: The analysis included 48 RNA samples from 23 pregnancies in the Duke Autoimmunity Pregnancy Registry. RNA was isolated from peripheral blood, and quantitative polymerase chain reaction was performed for ARS genes. The primary outcome was poor pregnancy outcome (preeclampsia or preterm birth). Gene expression was modeled as a response to presence or absence of a poor pregnancy outcome using linear regression models, stratified by trimester. RESULTS: Of the 23 pregnancies, nine delivered preterm and four had preeclampsia. Expression of PBX1 and MMD was higher in the second trimester among patients who experienced a poor pregnancy outcome compared to those who did not. However, in a global test of all ARS genes, we identified no association between expression of ARS genes and poor pregnancy outcomes. CONCLUSION: Our pilot study identified two candidate genes that are reflective of the platelet function response to aspirin. Further work is needed to determine the role of these genes in identifying women with lupus at high risk for preeclampsia and preterm delivery despite aspirin therapy.


Subject(s)
Aspirin/administration & dosage , Lupus Erythematosus, Systemic/complications , Platelet Aggregation Inhibitors/administration & dosage , Pre-Eclampsia/genetics , Premature Birth/genetics , Adult , Female , Gene Expression , Humans , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Pilot Projects , Pre-B-Cell Leukemia Transcription Factor 1/genetics , Pre-Eclampsia/blood , Pre-Eclampsia/prevention & control , Pregnancy , Pregnancy Complications/prevention & control , Pregnancy Outcome , Premature Birth/blood , Premature Birth/prevention & control , Prospective Studies , Risk Assessment , Risk Factors
3.
Clin Pharmacol Ther ; 96(4): 423-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24918167

ABSTRACT

Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Muscular Diseases/chemically induced , Organic Anion Transporters/genetics , Simvastatin/therapeutic use , Drug Interactions , Genotype , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Liver-Specific Organic Anion Transporter 1 , Pharmacogenetics , Polymorphism, Genetic , Simvastatin/adverse effects , Simvastatin/pharmacokinetics
4.
Clin Pharmacol Ther ; 96(4): 470-6, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24897241

ABSTRACT

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Muscular Diseases/chemically induced , Autoimmune Diseases/chemically induced , Autoimmune Diseases/classification , Humans , Muscular Diseases/classification , Myalgia/chemically induced , Myalgia/classification , Myositis/chemically induced , Myositis/classification , Phenotype , Rhabdomyolysis/chemically induced , Rhabdomyolysis/classification , Risk Factors , Terminology as Topic , Time Factors
5.
Clin Pharmacol Ther ; 92(1): 112-7, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22617227

ABSTRACT

Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A non-synonymous coding single-nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Muscular Diseases , Organic Anion Transporters/genetics , Polymorphism, Single Nucleotide , Simvastatin , Drug Prescriptions , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Liver-Specific Organic Anion Transporter 1 , Muscular Diseases/chemically induced , Muscular Diseases/genetics , Pharmacogenetics , Precision Medicine , Risk Assessment , Risk Factors , Simvastatin/administration & dosage , Simvastatin/adverse effects , Simvastatin/pharmacokinetics
6.
Clin Pharmacol Ther ; 87(4): 445-51, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20200517

ABSTRACT

Warfarin demonstrates a wide interindividual variability in response that is mediated partly by variants in cytochrome P450 2C9 (CYP2C9) and vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1). It is not known whether variants in calumenin (CALU) (vitamin K reductase regulator) have an influence on warfarin dose requirements. We resequenced CALU regions in a discovery cohort of dose outliers: patients with high (>90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African-American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans.


Subject(s)
Anticoagulants/administration & dosage , Black or African American/genetics , Calcium-Binding Proteins/genetics , Mixed Function Oxygenases/metabolism , Warfarin/administration & dosage , Adult , Aged , Alleles , Cohort Studies , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Vitamin K Epoxide Reductases , White People/genetics
7.
Clin Pharmacol Ther ; 84(3): 326-31, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18305455

ABSTRACT

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.


Subject(s)
Anticoagulants/administration & dosage , Aryl Hydrocarbon Hydroxylases/genetics , Mixed Function Oxygenases/genetics , Pharmacogenetics , Warfarin/administration & dosage , Aged , Algorithms , Anticoagulants/adverse effects , Anticoagulants/metabolism , Cohort Studies , Cytochrome P-450 CYP2C9 , Dose-Response Relationship, Drug , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Polymorphism, Genetic , Predictive Value of Tests , Vitamin K Epoxide Reductases , Warfarin/adverse effects , Warfarin/metabolism
8.
Metabolism ; 48(6): 738-44, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10381148

ABSTRACT

The effect of prolonged exposure to a reduced fraction of inspired oxygen ([FiO2] 0.17 for 3 days) on maternal glucose kinetics, placental glucose transporters GLUT1 and GLUT3, and fetal growth was examined in rat pregnancy. Arterial and venous catheters were placed 3 days before the study. [3-(3)H]glucose tracer and deuterium labeling of water were used to measure the rates of glucose turnover and gluconeogenesis (GNG), respectively. Glucose uptake by maternal tissues was measured using [14C]2-deoxyglucose. Exposure to a reduced FiO2 resulted in a significant decrease (mean +/- SE) in fetal weight (room air, 4.02 +/- 0.04 g; 0.17 FiO2, 3.27 +/- 0.6 g, P < .02). There was a significant increase in the maternal-fetal glucose gradient (maternal-fetal glucose ratio: room air, 1.48 +/- 0.11; 0.17 FiO2, 2.26 +/- 0.24, P < .05), but there was no change in the maternal or fetal blood lactate concentration. No significant change in maternal blood pH was observed; however, a significant decrease in the blood partial pressure of O2 (PO2) occurred (room air, 97 +/- 0.5 torr; 0.17 FiO2, 81 +/- 1.8) on day 3. There was no change in the rate of turnover of glucose or GNG in the maternal compartment, nor was there any effect on glucose uptake by the maternal tissues. Placental GLUT1 and GLUT3 mRNA were not different in the control or experimental animals. We conclude that a mild reduction in the FiO2 for 3 days in rat pregnancy results in a significant fetal growth restriction that is not related to any observed alteration in maternal glucose metabolism. The lower glucose concentration in the fetal blood may be the consequence of an increase in fetal glucose metabolism, thereby resulting in an increased maternal-fetal gradient of glucose.


Subject(s)
Blood Glucose/metabolism , Embryonic and Fetal Development , Fetus/metabolism , Nerve Tissue Proteins , Oxygen/blood , Pregnancy, Animal/blood , Animals , Female , Glucose Transporter Type 1 , Glucose Transporter Type 3 , Hypoxia/blood , Kinetics , Lactic Acid/blood , Monosaccharide Transport Proteins/metabolism , Pregnancy , Rats , Rats, Sprague-Dawley
9.
Proc Natl Acad Sci U S A ; 95(26): 15400-5, 1998 Dec 22.
Article in English | MEDLINE | ID: mdl-9860980

ABSTRACT

Kss1, a yeast mitogen-activated protein kinase (MAPK), in its unphosphorylated (unactivated) state binds directly to and represses Ste12, a transcription factor necessary for expression of genes whose promoters contain filamentous response elements (FREs) and genes whose promoters contain pheromone response elements (PREs). Herein we show that two nuclear proteins, Dig1 and Dig2, are required cofactors in Kss1-imposed repression. Dig1 and Dig2 cooperate with Kss1 to repress Ste12 action at FREs and regulate invasive growth in a naturally invasive strain. Kss1-imposed Dig-dependent repression of Ste12 also occurs at PREs. However, maintenance of repression at PREs is more dependent on Dig1 and/or Dig2 and less dependent on Kss1 than repression at FREs. In addition, derepression at PREs is more dependent on MAPK-mediated phosphorylation than is derepression at FREs. Differential utilization of two types of MAPK-mediated regulation (binding-imposed repression and phosphorylation-dependent activation), in combination with distinct Ste12-containing complexes, contributes to the mechanisms by which separate extracellular stimuli that use the same MAPK cascade can elicit two different transcriptional responses.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Fungal Proteins/metabolism , Gene Expression Regulation, Fungal , Mitogen-Activated Protein Kinases , Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae/genetics , Transcription Factors/metabolism , Transcription, Genetic , Fungal Proteins/genetics , Genes, Reporter , Genotype , Models, Biological , Pheromones/physiology , Phosphorylation , Promoter Regions, Genetic , Recombinant Proteins/metabolism , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism , Transcription Factors/genetics
10.
Genes Dev ; 12(18): 2887-98, 1998 Sep 15.
Article in English | MEDLINE | ID: mdl-9744865

ABSTRACT

The mitogen-activated protein kinase (MAPK) Kss1 has a dual role in regulating filamentous (invasive) growth of the yeast Saccharomyces cerevisiae. The stimulatory function of Kss1 requires both its catalytic activity and its activation by the MAPK/ERK kinase (MEK) Ste7; in contrast, the inhibitory function of Kss1 requires neither. This study examines the mechanism by which Kss1 inhibits invasive growth, and how Ste7 action overcomes this inhibition. We found that unphosphorylated Kss1 binds directly to the transcription factor Ste12, that this binding is necessary for Kss1-mediated repression of Ste12, and that Ste7-mediated phosphorylation of Kss1 weakens Kss1-Ste12 interaction and relieves Kss1-mediated repression. Relative to Kss1, the MAPK Fus3 binds less strongly to Ste12 and is correspondingly a weaker inhibitor of invasive growth. Analysis of Kss1 mutants indicated that the activation loop of Kss1 controls binding to Ste12. Potent repression of a transcription factor by its physical interaction with the unactivated isoform of a protein kinase, and relief of this repression by activation of the kinase, is a novel mechanism for signal-dependent regulation of gene expression.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Fungal Proteins/metabolism , Mitogen-Activated Protein Kinases , Protein Kinases/metabolism , Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae/metabolism , Transcription Factors/metabolism , Amino Acid Sequence , Base Sequence , Binding Sites/genetics , Calcium-Calmodulin-Dependent Protein Kinases/genetics , DNA, Recombinant/genetics , Enzyme Activation , Fungal Proteins/genetics , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Fungal , Mitogen-Activated Protein Kinase Kinases , Models, Biological , Molecular Sequence Data , Mutation , Phosphorylation , Protein Binding , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Sequence Homology, Amino Acid , Signal Transduction , Transcription, Genetic
SELECTION OF CITATIONS
SEARCH DETAIL
...