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Biomedical subjects

Julie A Johnson

Publications and source records attributed to Julie A Johnson.

At least 19 recordsLinked to original sources
PubMed2026

Genotype-Guided Antidepressant Prescribing for Patients With Depression: A Randomized Clinical Trial.

IMPORTANCE: The effectiveness of pharmacogenetics to guide prescribing of selective serotonin reuptake inhibitors (SSRIs) for depression remains unclear, despite the well-established association between SSRI pharmacokinetics and genetic variation. OBJECTIVE: To determine whether pharmacogenetic-guided prescribing of SSRIs improves treatment response in patients with depression. DESIGN, SETTING, AND PARTICIPANTS: The ADOPT PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) Depression pragmatic randomized clinical trial was conducted from August 10, 2021, through April 27, 2024, at primary care, psychiatry, or family medicine clinics at enrolling sites throughout the US. Patients were aged 8 years or older and had experienced depression for 3 months or longer. INTERVENTION: Patients were randomized to genotype-guided SSRI prescribing (intervention group) or usual care (control group). Actionable drug metabolism phenotypes were defined as those for which pharmacogenetic clinical guidelines recommend alternative medication selection or dose adjustment. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Patient-Reported Outcomes Measurement Information System (PROMIS) depression T scores at 3 months among patients with the actionable phenotype. Secondary end points included adverse effect severity of SSRIs at 3 months and depression remission (measured with PROMIS depression scores and Patient Health Questionnaire-8 [PHQ-8] scores) at 6 months. RESULTS: This study of 1460 patients included 1239 adults (84.9%) (mean [SD] age, 40.6 [16.7] years) and 221 children (15.1%) (mean [SD] age, 14.6 [1.8] years). Most patients were female (1096 [75.1%]). A total of 692 patients (47.4%) had an actionable phenotype; 351 (50.7%) were assigned to the intervention, and 341 (49.3%) were assigned to usual care. At baseline, 463 of the 692 patients (66.9%) reported having depressive symptoms for more than 2 years, 603 (87.1%) were receiving pharmacologic treatment, and 354 (51.2%) were receiving nonpharmacologic treatment. At 3 months, no significant differences were observed between the intervention and usual care groups in change in PROMIS depression T scores (mean [SD] change, -4.3 [8.4] vs -4.0 [8.1]; P = .68), medication adverse effect burden (mean [SD] change, 8.2 [4.3] vs 7.8 [4.5]; P = .37), or Patient Health Questionnaire-8 score change (mean [SD] change, -3.3 [5.2] vs -2.7 [4.8]; P  = .13). However, at 6 months, the PROMIS depression T-score remission rate (score ≤16) was higher in the intervention group compared with the usual care group (153 of 317 patients [48.3%] vs 122 of 310 patients [39.4%]; P = .02). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, genotype-guided prescribing of SSRIs did not improve control of depression symptoms at 3 months compared with usual care but was associated with higher depression remission rates at 6 months. These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04445792 (Master Protocol Research Program platform trial) and NCT05966155 (ADOPT PGx Depression trial).

Humans↗
PubMed2005

Cardiovascular pharmacogenomics.

There is large interpatient variability in the response to drugs, including cardiovascular drugs. Thus, while some patients achieve the desired therapeutic response from their drug therapy, others do not. There is also a subset of patients who will experience adverse effects, which can range from bothersome to life threatening. Research in recent years has provided compelling evidence that in many cases, genetics contributes importantly to this variable drug response. Thus, pharmacogenomics is a field focused on unravelling the genetic determinants of variable drug response. Examples from the literature of genetic associations with drug efficacy and toxicity are described to provide insight into the field, including the roles of genetic variability in drug-metabolizing enzymes and drug targets. There is also a detailed discussion of the experimental approaches used in cardiovascular pharmacogenomics. Current research is largely focused on a limited candidate gene approach, which allows for description of significant genetic associations with variable response, but often does not explain the genetic basis of variable drug response enough to be useful clinically. As such, there is a move towards genome-wide approaches, and the various technologies available to obtain genomic data are discussed. Cardiovascular pharmacogenomics has the potential for leading to improvements in the use of cardiovascular drug therapy, through selection of the most appropriate drug therapy in an individual based on their genetic information. It will probably be a decade or more before genetic information is widely used in drug therapy decisions, but it seems clear that important findings in the area will continue to expand and the experimental approaches will continue to evolve.

Animals↗
PubMed2005

beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure.

OBJECTIVE: beta-Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate beta-blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure. We also tested whether polymorphisms in the beta(2)-adrenergic receptor, G-protein alpha s subunit (G(s)alpha), and cytochrome P450 (CYP) 2D6 genes or S-metoprolol plasma concentrations were associated with beta-blocker tolerability. METHODS: Sixty-one beta-blocker-naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period. RESULTS: The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the beta(2)-adrenergic receptor or G(s)alpha polymorphisms with decompensated heart failure. CONCLUSIONS: Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during beta-blocker titration and thus may require more frequent follow-up during titration.

Cytochrome P-450 CYP2D6↗
PubMed2005

Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy.

OBJECTIVE: Large variability exists in the improvement in left ventricular (LV) function from beta-blocker treatment. We hypothesized that polymorphisms at codon 389 (Arg389Gly) and 49 (Ser49Gly) in the beta1-adrenergic receptor (AR) gene were associated with LV reverse remodeling changes in response to beta-blocker therapy among heart failure patients. METHODS: We prospectively enrolled 61 beta-blocker naive patients with systolic heart failure. Patients underwent baseline echocardiography followed by metoprolol CR/XL. The dose was doubled on a biweekly basis up to 200 mg/day or attainment of maximum tolerated dose. Echocardiography was repeated after the patient received the target or highest tolerated dose for 3 months. RESULTS: Among patients with the Arg389Arg genotype, ejection fraction (EF) increased from 23+/-5 to 29+/-10 (P=0.008). Gly389 carriers did not demonstrate any significant change in EF (22+/-9 to 23+/-11; P=0.45). There was a significant between-group difference in EF by genotype (P=0.04). The Arg389Arg genotype was also associated with significantly greater reductions in LV end-diastolic and end-systolic diameters compared to Gly389 carriers. Patients with the Gly49 variant also had a significantly greater reduction in LV end-diastolic diameter compared to Ser49 homozygotes. Multiple regression analysis modeling revealed that the codon 389 polymorphism was a significant predictor of an improvement in EF and both codon 49 and 389 polymorphisms were significant predictors of final LV end-diastolic diameter. CONCLUSIONS: Heart failure patients with the Arg389Arg genotype and Gly49 carriers had greater improvements in LV remodeling from beta-blocker treatment.

Adrenergic beta-Antagonists↗
PubMed2005

Hypertension pharmacogenomics: current status and future directions.

Hypertension is the most common chronic disease in the Western world, and while there are many drug classes from which to choose therapy, only 34% of North Americans currently have their blood pressure controlled. The potential clinical utility of pharmacogenomics in helping to guide antihypertensive drug therapy selection is described. The hypertension pharmacogenetics literature is reviewed, which highlights that only a small fraction of the genes that likely contribute to antihypertensive response have been studied to date. The genes for alpha-adducin (diuretic response), the beta1-adrenergic receptor (beta-blocker response) and angiotensinogen (response to multiple drug classes) are among the genes with the most compelling data (based on replication) as pharmacogenetic candidates. Potential limitations of current studies are also discussed. These include reliance on clinic blood pressure, which is probably a suboptimal response phenotype, and the relatively small sample sizes of most studies to date. Also discussed is the relatively simplistic genetic approach that has been taken, which has focused largely on a single gene or single nucleotide polymorphism within a gene. Multiple ways to overcome these potential limitations are described. Hypertension pharmacogenomics holds tremendous potential for providing a mechanism by which management of hypertensive patients might be improved, and future studies should help move this field towards its clinical potential.

Humans↗
PubMed2004

Influence of gender and race on hemodynamic response to dobutamine during dobutamine stress echocardiography.

This study sought to determine the influence of gender and/or race on the hemodynamic response to dobutamine during dobutamine stress echocardiography. Blood pressure response patterns differed by gender and race, and completion of testing was often limited because of adverse events, namely, hypertension. Gender and racial differences in blood pressure response merit consideration as potential contributors to the suboptimal response in dobutamine stress testing.

Adult↗
PubMed2004

Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension.

OBJECTIVE: Beta-Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed beta-blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension. METHODS: Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction-restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype-derived phenotype. RESULTS: Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration-time curve (AUC), and lower oral clearance (P < or = .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes. CONCLUSIONS: As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and beta-blocker-induced adverse effects or efficacy.

Adrenergic beta-Antagonists↗
PubMed2004

Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms.

Interethnic variability in pharmacokinetics can cause unexpected outcomes such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin undergoing medical treatment. It is important to realize that both genetic and environmental factors can lead to these differences among ethnic groups. The International Conference on Harmonization (ICH) published a guidance to facilitate the registration of drugs among ICH regions (European Union, Japan, the United States) by recommending a framework for evaluating the impact of ethnic factors on a drug's effect, as well as its efficacy and safety at a particular dosage and dosage regimen. This review focuses on the pharmacokinetic differences between East Asians and Caucasians. Differences in metabolism between East Asians and Caucasians are common, especially in the activity of several phase I enzymes such as CYP2D6 and the CYP2C subfamily. Before drug therapy, identification of either the genotype and/or the phenotype for these enzymes may be of therapeutic value, particularly for drugs with a narrow therapeutic index. Furthermore, these differences are relevant for international drug approval when regulatory agencies must decide if they accept results from clinical trials performed in other parts of the world.

Asian People↗
PubMed2004

Sequencing complex diseases With HapMap.

Determining the patterns of DNA sequence variation in the human genome is a useful first step toward identifying the genetic basis of a common disease. A haplotype map (HapMap), aimed at describing these variation patterns across the entire genome, has been recently developed by the International HapMap Consortium. In this article, we present a novel statistical model for directly characterizing specific sequence variants that are responsible for disease risk based on the haplotype structure provided by HapMap. Our model is developed in the maximum-likelihood context, implemented with the EM algorithm. We perform simulation studies to investigate the statistical properties of this disease-sequencing model. A worked example from a human obesity study with 155 patients was used to validate this model. In this example, we found that patients carrying a haplotype constituted by allele Gly16 at codon 16 and allele Gln27 at codon 27 genotyped within the beta2AR candidate gene display significantly lower body mass index than patients carrying the other haplotypes. The implications and extensions of our model are discussed.

Body Mass Index↗
PubMed2004

Comparison of cytochrome P450 2C9 genotyping methods and implications for the clinical laboratory.

STUDY OBJECTIVE: To compare the accuracy, speed, and cost of two methodologies used for genotyping known variants in the cytochrome P450 (CYP) 2C9 metabolizing enzyme gene. DESIGN: Comparative study. SETTING: University research center. SAMPLES: Fifteen-milliliter mouthwash samples collected from 253 subjects participating in a warfarin pharmacogenomic study. INTERVENTION: Genotyping for the isoleucine-to-leucine change at codon 359 (Ile359Leu [*3] polymorphism) was performed by using the Pyrosequencing and polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods in all 253 samples. Genotyping for the arginine-to-cysteine change at codon 144 (Arg144Cys [*2] polymorphism) was performed by using Pyrosequencing in all samples and by PCR-RFLP in a random subset of 136 samples. MEASUREMENTS AND MAIN RESULTS: Comparisons of genotyping success rates, time efficiency, and cost analyses were conducted for Pyrosequencing and PCR-RFLP at each variant site. Pyrosequencing and PCR-RFLP produced similar success rates on the first genotyping attempt for the Arg144Cys variant (93.3% vs 90.4%, respectively) and the Ile359Leu variant (83.8% vs 79.1%, respectively). With Pyrosequencing, genotyping 96 samples for either polymorphism could be performed in 1 hour. In contrast, genotyping 96 samples by RFLP took 10 hours for the Arg144Cys variant and 20 hours for the Ile359Leu variant. Total cost/sample for Arg144Cys genotyping was dollars 1.90 with PCR-Pyrosequencing and dollars 3.14 with PCR-RFLP. Total cost/sample for Ile359Leu genotyping was dollars 1.88 with PCR-Pyrosequencing and dollars 10.18 with PCR-RFLP CONCLUSION: Compared with RFLP, genotype determination by Pyrosequencing is a more time-efficient, cost-effective, and robust method for CYP2C9 genotyping. Because of its wide applicability and ease of use, Pyrosequencing is a promising technology for future pharmacogenomic investigations.

Alleles↗
PubMed2003

Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol.

OBJECTIVES: Marked interpatient variability exists in blood pressure response to beta-blocker monotherapy. We tested the hypothesis that 2 common polymorphisms in the gene for beta(1)-adrenergic receptor are associated with antihypertensive response to metoprolol in patients with uncomplicated hypertension. METHODS: Forty hypertensive men and women aged 35 to 65 years were studied. Baseline studies included 24-hour ambulatory blood pressure monitoring. Patients took 50 mg metoprolol twice daily with weekly titration to response or 200 mg twice daily. After a minimum of 4 weeks at stable dose, treatment phase 24-hour ambulatory blood pressure monitoring was repeated. The codon 49 and 389 genotypes for beta(1)-adrenergic receptor were determined by polymerase chain reaction with restriction fragment length polymorphism. Multilinear regression was performed to determine the impact of genotype and other variables on blood pressure response to metoprolol. RESULTS: Patients homozygous for Arg at codon 389 had a nearly 3-fold greater reduction in daytime diastolic blood pressure (-13.3% +/- 8.4% versus -4.5% +/- 8.2%, P =.0018) compared with those who carried the variant allele. The haplotype pair (diplotype) for beta(1)-adrenergic receptor was also a significant predictor of response, with patients having the Ser49Arg389/Ser49Arg389 diplotype demonstrating a decline in blood pressure of 14.7 mm Hg versus 0.5 mm Hg in patients with the Gly49Arg389/Ser49Gly389 diplotype. In multiregression analysis, baseline daytime diastolic blood pressure, codon 389 genotype, and codon 49 genotype were significant predictors of blood pressure after treatment. CONCLUSIONS: Our data suggest that beta(1)-adrenergic receptor polymorphisms are important determinants of antihypertensive response to metoprolol. In the future, codon 49 and 389 genotypes or beta(1)-adrenergic receptor haplotypes might be used to predict the diastolic blood pressure response to metoprolol in patients with hypertension.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2003

A haplotype-based algorithm for multilocus linkage disequilibrium mapping of quantitative trait loci with epistasis.

For tightly linked loci, cosegregation may lead to nonrandom associations between alleles in a population. Because of its evolutionary relationship with linkage, this phenomenon is called linkage disequilibrium. Today, linkage disequilibrium-based mapping has become a major focus of recent genome research into mapping complex traits. In this article, we present a new statistical method for mapping quantitative trait loci (QTL) of additive, dominant, and epistatic effects in equilibrium natural populations. Our method is based on haplotype analysis of multilocus linkage disequilibrium and exhibits two significant advantages over current disequilibrium mapping methods. First, we have derived closed-form solutions for estimating the marker-QTL haplotype frequencies within the maximum-likelihood framework implemented by the EM algorithm. The allele frequencies of putative QTL and their linkage disequilibria with the markers are estimated by solving a system of regular equations. This procedure has significantly improved the computational efficiency and the precision of parameter estimation. Second, our method can detect marker-QTL disequilibria of different orders and QTL epistatic interactions of various kinds on the basis of a multilocus analysis. This can not only enhance the precision of parameter estimation, but also make it possible to perform whole-genome association studies. We carried out extensive simulation studies to examine the robustness and statistical performance of our method. The application of the new method was validated using a case study from humans, in which we successfully detected significant QTL affecting human body heights. Finally, we discuss the implications of our method for genome projects and its extension to a broader circumstance. The computer program for the method proposed in this article is available at the webpage http://www.ifasstat.ufl.edu/genome/~LD.

Algorithms↗
PubMed2003

Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges.

The pharmacogenetics literature of drug receptors and effector proteins is in its relative infancy compared to that of drug metabolism pharmacogenetics. Nonetheless, in a short time period, numerous studies have demonstrated that receptor/effector polymorphisms contribute to variable drug response. We review the current status, and list challenges that confront drug target pharmacogenetics before we can use genetic information in drug-therapy decision-making. We focus our review on G protein coupled receptors (GPCRs), which represent over 50% of all drug targets, and use specific examples from the beta-adrenergic receptor pharmacogenetic literature to illustrate important issues. Recent resequencing efforts of GPCR genes suggest that they have more coding region and nonsynonymous polymorphisms than non-GPCR genes, thus making GPCRs important foci for pharmacogenetic investigation. Our inability to use drug target genetic information to guide in the selection of drug therapy is due to several factors, including (i) the relatively subtle functional effects of the single gene polymorphisms, which do not account for enough of the drug response variability to accurately predict response and (ii) inconsistencies between studies. The latter may be due to some studies having inadequate sample sizes, studying different drug response phenotypes and patient populations, difficulties in identifying and measuring a valid drug response phenotype, and focusing on single polymorphisms in single genes, rather than haplotypes or multiple genes. To move the field to the point of clinical application, future studies will need to be larger, and will have to consider the complexity of the drug response, either by inclusion of polymorphisms from signal transduction proteins and other proteins relevant to the drug response, or through a genomics approach. Finally, the literature suggests that, for those drugs with multiple pharmacologic effects, or effects in multiple organs, the genetic contribution to each drug response phenotype will have to be considered separately. The knowledge necessary to move forward on all these fronts is not yet available, but will be increasingly accessible over the next few years.

Amino Acid Sequence↗
PubMed2003

The evolving role of nesiritide in advanced or decompensated heart failure.

Nesiritide is a recombinant form of human brain natriuretic peptide (BNP) that is structurally and biochemically identical to endogenously produced BNP. In humans, BNP is important in hemodynamic and neurohormonal equilibrium, helping to maintain adequate vascular volume and pressure in response to volume overload. The pharmacodynamic effects of nesiritide mimic the biologic effects of BNP. The molecular biology and actions of nesiritide and BNP are reviewed, with the therapeutic rationale for nesiritide in patients with acute or advanced decompensated heart failure highlighted. In addition, recommendations for its administration are provided, and unresolved therapeutic considerations are discussed.

Heart Failure↗
PubMed2002

Molecular diagnostics as a predictive tool: genetics of drug efficacy and toxicity.

There is a rapidly growing body of evidence linking genetic polymorphisms with functional changes in proteins that are responsible for the metabolism and disposition of many medications. Likewise, polymorphisms in genes encoding the targets of medications (e.g. receptors) can alter the pharmacodynamics of the drug response by changing receptor sensitivity. As a result, the inherited basis of drug effects is often polygenic in nature, and thus more challenging to define. However, technological advances, coupled with new insights into the molecular pharmacology of medications and the functional consequences of polymorphisms in the human genome, are providing the tools needed to elucidate genetic determinants of drug response, and translate functional genomics into personalized medicine.

Drug Design↗
PubMed2002

Beta-adrenergic receptor polymorphisms: cardiovascular disease associations and pharmacogenetics.

The beta-adrenergic receptors (betaAR) play important roles in cardiovascular function and disease, and both agonists and antagonists are widely used in various settings for treatment of cardiovascular disease. Both the beta1AR and beta2AR genes have several polymorphisms that are common in the population and result in encoding of different amino acids. More importantly, in vitro functional studies suggest that these polymorphisms have functional significance. In this review we summarize the literature on the relationship between the betaAR polymorphisms and cardiovascular disease as well as the literature on the impact of these polymorphisms on drug response. Additionally, the polymorphisms in both the beta1AR and beta2AR genes are in linkage disequilibrium; thus, the relevance of single polymorphism vs. haplotype analysis is discussed. Further study of the betaAR genetic polymorphisms is likely to enhance our understanding of cardiovascular disease and improve our use of beta-agonists and beta-antagonists in treatment of cardiovascular disease.

Amino Acid Sequence↗