Journal of Personalized Medicine

Research

9 pages, 441 KiB

Open AccessArticle

Pharmaco-Metabolomics of Inhaled Corticosteroid Response in Individuals with Asthma

by Priyadarshini Kachroo, Joanne E. Sordillo, Sharon M. Lutz, Scott T. Weiss, Rachel S. Kelly, Michael J. McGeachie, Ann Chen Wu and Jessica A. Lasky-Su

J. Pers. Med. 2021, 11(11), 1148; https://doi.org/10.3390/jpm11111148 - 4 Nov 2021

Cited by 7 | Viewed by 2139

Abstract

Metabolomic indicators of asthma treatment responses have yet to be identified. In this study, we aimed to uncover plasma metabolomic profiles associated with asthma exacerbations while on inhaled corticosteroid (ICS) treatment. We determined whether these profiles change with age from adolescence to adulthood. [...] Read more.

Metabolomic indicators of asthma treatment responses have yet to be identified. In this study, we aimed to uncover plasma metabolomic profiles associated with asthma exacerbations while on inhaled corticosteroid (ICS) treatment. We determined whether these profiles change with age from adolescence to adulthood. We utilized data from 170 individuals with asthma on ICS from the Mass General Brigham Biobank to identify plasma metabolites associated with asthma exacerbations while on ICS and examined potential effect modification of metabolite-exacerbation associations by age. We used liquid chromatography–high-resolution mass spectrometry-based metabolomic profiling. Sex-stratified analyses were also performed for the significant associations. The age range of the participating individuals was 13–43 years with a mean age of 33.5 years. Of the 783 endogenous metabolites tested, eight demonstrated significant associations with exacerbation after correction for multiple comparisons and adjusting for potential confounders (Bonferroni p value < 6.2 × 10⁻⁴). Potential effect modification by sex was detected for fatty acid metabolites, with males showing a greater reduction in their metabolite levels with ICS exacerbation. Thirty-eight metabolites showed suggestive interactions with age on exacerbation (nominal p-value < 0.05). Our findings demonstrate that plasma metabolomic profiles differ for individuals who experience asthma exacerbations while on ICS. The differentiating metabolites may serve as biomarkers of ICS response and may highlight metabolic pathways underlying ICS response variability. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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19 pages, 1487 KiB

Open AccessArticle

PTGDR2 Expression in Peripheral Blood as a Potential Biomarker in Adult Patients with Asthma

by Asunción García-Sánchez, Miguel Estravís, Maria J. Martin, Jacqueline Pérez-Pazos, Cristina Martín-García, María Gil-Melcón, Jacinto Ramos-González, Ibon Eguiluz-Gracia, Juan Carlos Triviño, María Isidoro-García, Ignacio Dávila and Catalina Sanz

J. Pers. Med. 2021, 11(9), 827; https://doi.org/10.3390/jpm11090827 - 24 Aug 2021

Cited by 7 | Viewed by 2285

Abstract

Background: Precision medicine is a promising strategy to identify biomarkers, stratify asthmatic patients according to different endotypes, and match them with the appropriate therapy. This proof-of-concept study aimed to investigate whether gene expression in peripheral blood could provide a valuable noninvasive approach for [...] Read more.

Background: Precision medicine is a promising strategy to identify biomarkers, stratify asthmatic patients according to different endotypes, and match them with the appropriate therapy. This proof-of-concept study aimed to investigate whether gene expression in peripheral blood could provide a valuable noninvasive approach for the molecular phenotyping of asthma. Methods: We performed whole-transcriptome RNA sequencing on peripheral blood of 30 non-atopic non-asthmatic controls and 30 asthmatic patients. A quantitative PCR (qPCR) validation study of PTGDR2 that encodes for CRTH2 receptor, expressed in cells involved in T2 inflammation, was developed in a cohort of 361 independent subjects: 94 non-asthmatic non-atopic controls, 187 asthmatic patients [including 82 with chronic rhinosinusitis with nasal polyposis (CRSwNP) and 24 with aspirin-exacerbated respiratory disease (AERD)], 52 with allergic rhinitis, and 28 with CRSwNP without asthma. Results: PTGDR2 was one of the most differentially overexpressed genes in asthmatic patients’ peripheral blood (p-value 2.64 × 10⁶). These results were confirmed by qPCR in the validation study, where PTGDR2 transcripts were significantly upregulated in asthmatic patients (p < 0.001). This upregulation was mainly detected in some subgroups such as allergic asthma, asthma with CRSwNP, AERD, eosinophilic asthma, and severe persistent asthma. PTGDR2 expression was detected in different blood cell types, and its correlation with eosinophil counts showed differences in some groups of asthmatic patients. Conclusions: We found that PTGDR2 expression levels could identify asthma patients, introduce a minimally invasive biomarker for adult asthma molecular phenotyping, and add additional information to blood eosinophils. Although further studies are required, analyzing PTGDR2 expression levels in peripheral blood of asthmatics might assist in selecting patients for treatment with specific antagonists. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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8 pages, 491 KiB

Open AccessArticle

Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept

by Joanne E. Sordillo, Sharon M. Lutz, Michael J. McGeachie, Jessica Lasky-Su, Scott T. Weiss, Juan C. Celedón and Ann Chen Wu

J. Pers. Med. 2021, 11(4), 319; https://doi.org/10.3390/jpm11040319 - 20 Apr 2021

Cited by 5 | Viewed by 2686

Abstract

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and [...] Read more.

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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9 pages, 1356 KiB

Open AccessArticle

Systems Approaches to Treatment Response to Imatinib in Severe Asthma: A Pilot Study

by Seung Han Baek, Dinah Foer, Katherine N. Cahill, Elliot Israel, Enrico Maiorino, Annika Röhl, Joshua A. Boyce and Scott T. Weiss

J. Pers. Med. 2021, 11(4), 240; https://doi.org/10.3390/jpm11040240 - 25 Mar 2021

Cited by 3 | Viewed by 2020

Abstract

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV₁) in a clinical [...] Read more.

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV₁) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders—patients with greater than 20% increase in FEV₁—uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5–10% FEV₁ increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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13 pages, 1037 KiB

Open AccessArticle

Drug Repurposing to Treat Glucocorticoid Resistance in Asthma

by Alberta L. Wang, Ronald Panganiban, Weiliang Qiu, Alvin T. Kho, Geoffrey Chupp, Deborah A. Meyers, Eugene R. Bleecker, Scott T. Weiss, Quan Lu and Kelan G. Tantisira

J. Pers. Med. 2021, 11(3), 175; https://doi.org/10.3390/jpm11030175 - 3 Mar 2021

Cited by 10 | Viewed by 2295

Abstract

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was [...] Read more.

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV₁). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV₁, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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6 pages, 581 KiB

Open AccessArticle

The Role of SNP Interactions when Determining Independence of Novel Signals in Genetic Association Studies—An Application to ARG1 and Bronchodilator Response

by Ryan Walsh, Kirsten Voorhies, Merry-Lynn McDonald, Michael McGeachie, Joanne E. Sordillo, Christoph Lange, Ann Chen Wu and Sharon M. Lutz

J. Pers. Med. 2021, 11(2), 145; https://doi.org/10.3390/jpm11020145 - 19 Feb 2021

Viewed by 2245

Abstract

Genome-wide association studies (GWAS) play a critical role in identifying many loci for common diseases and traits. There has been a rapid increase in the number of GWAS over the past decade. As additional GWAS are being conducted, it is unclear whether a [...] Read more.

Genome-wide association studies (GWAS) play a critical role in identifying many loci for common diseases and traits. There has been a rapid increase in the number of GWAS over the past decade. As additional GWAS are being conducted, it is unclear whether a novel signal associated with the trait of interest is independent of single nucleotide polymorphisms (SNPs) in the same region that has been previously associated with the trait of interest. The general approach to determining whether the novel association is independent of previous signals is to examine the association of the novel SNP with the trait of interest conditional on the previously identified SNP and/or calculate linkage disequilibrium (LD) between the two SNPs. However, the role of epistasis and SNP by SNP interactions are rarely considered. Through simulation studies, we examined the role of SNP by SNP interactions when determining the independence of two genetic association signals. We have created an R package on Github called gxgRC to generate these simulation studies based on user input. In genetic association studies of asthma, we considered the role of SNP by SNP interactions when determining independence of signals for SNPs in the ARG1 gene and bronchodilator response. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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9 pages, 1150 KiB

Open AccessArticle

Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

by Kirsten Voorhies, Joanne E. Sordillo, Michael McGeachie, Elizabeth Ampleford, Alberta L. Wang, Jessica Lasky-Su, Kelan Tantisira, Amber Dahlin, Rachel S. Kelly, Victor E. Ortega, Sharon M. Lutz and Ann C. Wu

J. Pers. Med. 2021, 11(1), 59; https://doi.org/10.3390/jpm11010059 - 19 Jan 2021

Cited by 5 | Viewed by 2798

Abstract

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) [...] Read more.

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10⁻⁸. Using a suggestive significance level of 5 × 10⁻⁶, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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9 pages, 234 KiB

Open AccessArticle

CASTER: Cross-Sectional Asthma STEroid Response Measurement

by Alvin T. Kho, Joanne Sordillo, Ann Chen Wu, Michael H. Cho, Sunita Sharma, Anshul Tiwari, Jessica Lasky-Su, Scott T. Weiss, Kelan G. Tantisira and Michael J. McGeachie

J. Pers. Med. 2020, 10(3), 95; https://doi.org/10.3390/jpm10030095 - 20 Aug 2020

Cited by 3 | Viewed by 2766

Abstract

Asthma patient response to inhaled corticosteroids (ICS) is variable and difficult to quantify. We aimed to define a measure of steroid response suitable for pharmacogenetic research in longitudinal and cross-sectional cohorts. Using longitudinal data from the Childhood Asthma Management Program (CAMP) asthma cohort, [...] Read more.

Asthma patient response to inhaled corticosteroids (ICS) is variable and difficult to quantify. We aimed to define a measure of steroid response suitable for pharmacogenetic research in longitudinal and cross-sectional cohorts. Using longitudinal data from the Childhood Asthma Management Program (CAMP) asthma cohort, we defined the Cross-sectional Asthma STEroid Response (CASTER) measure in cross-sectional data. We then applied this to cross-sectional slices of four independent asthma cohorts: The Improving Asthma Control Trial (IMPACT), the Salmeterol or Corticosteroids Study (SOCS), the Pediatric Asthma Controller Trial (PACT), and the Genetics of Asthma in Costa Rica Study (GACRS). CASTER achieved high accuracy on the childhood asthma cohorts: GACRS, PACT, and also on cross-sectional data from CAMP (AUCs 82%, 71%, 63%, respectively). This demonstrates that select cross-sectional clinical information is sufficient to identify good and poor responders to ICS treatment in childhood asthma. Thus, CASTER represents a major improvement in the usability and applicability of steroid response measures in asthma research. Full article

(This article belongs to the Special Issue APAA: Asthma Pharmacogenetics across Ages)

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