Biomedical subjects

Wendy C Moore

Publications and source records attributed to Wendy C Moore.

8 recordsLinked to original sources

PubMed2026

Aberrant mucin expression and keratinization distinguishing severe from mild asthma revealed by interpretable machine learning.

Type 2 (T2) immune cells dominate the airways of patients with mild-moderate asthma (MMA) with a more complex type 1 (T1)-T2 mixed immune response evident in treatment-refractory severe asthma (SA). We hypothesized that comparing the transcriptomes of the airway epithelium of patients with SA and MMA would reveal molecular signatures associated with more severe disease in the context of a complex immune response. Using our interpretable machine learning tool, SLIDE, meaningful latent factors (context-specific gene co-expression networks) were revealed that distinguished SA from MMA. Unexpectedly, an aberrant high expression of normally host-protective, membrane-tethered, and IFN-inducible mucins, MUC1 and MUC4, was identified in SA. Gene networks in the significant latent factors discriminating SA from MMA corresponded to enrichment of a keratinization program in SA airways. Keratinization was marked by increased expression of the stress keratin KRT16, signifying squamous metaplasia suggesting adaptive reprogramming of the airway epithelium in response to chronic stress. These mucins and KRT16 were inversely associated with lung function in 2 separate asthma cohorts. Imaging of endobronchial biopsies revealed significantly higher KRT16 protein expression in SA compared with MMA that strongly correlated with MUC1 protein expression. Our study identifies dysregulated host-protective and maladaptive repair responses in SA distinguishing from MMA.

Humans↗

PubMed2026

A cross-sectional study of oxidative stress pathway genotypes and their interactions with environmental pollutant levels identifies associations with gene expression and lung function.

BACKGROUND: Asthma is a heterogeneous disease influenced by genetic and environmental factors. Fine particulate matter (PM2.5) exacerbates asthma, likely through oxidative stress pathways, but whether genetic variation modifies this effect remains unclear. METHODS: We analysed data on 948 adults with asthma from the Severe Asthma Research Program (SARP), linking ZIP-code-level PM2.5 exposure with whole-genome sequencing data. We tested 4337 single nucleotide polymorphisms (SNPs) in 120 oxidative stress pathway genes for gene-environment (GxE) interactions with PM2.5 on lung function (forced expiratory volume in 1 s [FEV1] % predicted) using weighted linear regression. Gene expression data from bronchial epithelial cells (n = 170) were used to assess cis-expression quantitative trait loci (eQTLs). FINDINGS: Higher PM2.5 exposure was associated with lower FEV1% predicted (β per μg/m3 = -0.7, p = 0.01). We identified 20 SNPs across seven genes (OXSR1, PXDN, TPO, LRRK2, APP, MSRA, MSRB2) with significant GxE interactions after multiple-testing correction. Five SNPs were also eQTLs, linking PM2.5-modified gene expression to lung function. Minor alleles in OXSR1 and PXDN were associated with reduced gene expression and worsened FEV1% under high PM2.5 exposure. Conversely, TPO variants were associated with higher baseline expression and lower lung function, but under increasing PM2.5 exposure, minor allele carriers showed suppressed TPO expression and improved FEV1%. INTERPRETATION: This study identified 20 SNPs in oxidative stress pathway genes that modify the effect of PM2.5 on lung function in asthma. These findings highlight the importance of integrating environmental context in genetic studies and suggest potential therapeutic targets for pollution-sensitive asthma phenotypes. FUNDING: Supported by NIH grants.

Cross-Sectional Studies↗

PubMed2025

α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization.

BACKGROUND: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. OBJECTIVE: To characterize the influence of SERPINA1 variation on asthma severity. METHODS: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. RESULTS: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by-ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). CONCLUSIONS: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

Adult↗

PubMed2006

Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study.

RATIONALE: The comprehensive evaluation of gene variation, haplotype structure, and linkage disequilibrium is important in understanding the function of beta2-adrenergic receptor gene (ADRbeta2) on disease susceptibility, pulmonary function, and therapeutic responses in different ethnic groups with asthma. OBJECTIVES: To identify ADRbeta2 polymorphisms and haplotype structure in white and African American subjects and to test for genotype and haplotype association with asthma phenotypes. METHODS: A 5.3-kb region of ADRbeta2 was resequenced in 669 individuals from 429 whites and 240 African Americans. A total of 12 polymorphisms, representing an optimal haplotype tagging set, were genotyped in whites (338 patients and 326 control subjects) and African Americans (222 patients and 299 control subjects). RESULTS: A total of 49 polymorphisms were identified, 21 of which are novel; 31 polymorphisms (frequency > 0.03) were used to identify 24 haplotypes (frequency > 0.01) and assess linkage disequilibrium. Association with ratio (FEV1/FVC)2 for single-nucleotide polymorphism +79 (p < 0.05) was observed in African Americans. Significant haplotype association for (FEV1/FVC)2 was also observed in African Americans. CONCLUSIONS: There are additional genetic variants besides +46 (Gly16Arg) that are important in determining asthma phenotypes. These data suggest that the length of a poly-C repeat (+1269) in the 3' untranslated region of ADRbeta2 may influence lung function, and may be important in delineating variation in beta-agonist responses, especially in African Americans.

Black or African American↗

PubMed2006

Control of airway inflammation maintained at a lower steroid dose with 100/50 microg of fluticasone propionate/salmeterol.

BACKGROUND: Inhaled corticosteroids (ICSs) have been shown to reverse epithelial damage and decrease lamina reticularis thickness in patients with asthma. OBJECTIVE: This study investigated whether clinical asthma control and airway inflammation could be maintained after switching therapy from medium-dose fluticasone propionate (FP) to low-dose FP administered with the long-acting beta2-agonist (LABA) salmeterol. METHODS: Eighty-eight subjects (age, > or =18 years) who, during open-label screening, demonstrated improved asthma control after an increase from 100 microg of FP twice daily to 250 microg of FP twice daily were randomized to receive 100/50 microg of FP/salmeterol through a Diskus inhaler (GlaxoSmithKline, Research Triangle Park, NC) twice daily or continue 250 microg of FP twice daily through a Diskus inhaler for 24 weeks. Clinical outcomes were monitored, and bronchial biopsy specimens and bronchoalveolar lavage fluid were obtained before and after 24 weeks of treatment. RESULTS: There were no significant differences between treatments with respect to eosinophils in the bronchial mucosa and bronchoalveolar lavage fluid; mucosal mast cells, neutrophils, or CD3+, CD4+, CD8+, or CD25+ T lymphocytes; or concentration of mediators (GM-CSF, IL-8, and eosinophil cationic protein). The 2 treatments were not different with respect to lamina reticularis thickness. Consistent with the airway inflammatory measures, clinical and physiologic measures of asthma control were also similar. CONCLUSION: This study demonstrates that control of asthma and airway inflammation is maintained over the 24-week treatment period when patients requiring a medium-dose ICS are switched to a lower-dose ICS with a LABA. CLINICAL IMPLICATIONS: A lower-dose ICS with a LABA is effective in controlling inflammation and providing clinical asthma control, confirming current guideline recommendations.

Adrenergic beta-Agonists↗

PubMed2006

Severe asthma: an overview.

Severe asthma represents less than 10% of all asthma, but these patients are responsible for a disproportionate share of the health care costs and morbidity associated with the disease. A significant challenge in the diagnosis and management of severe asthma is the ability to identify accurately the patients most at risk for adverse outcomes, such as medication side effects, emergency department visits, hospitalization, near-fatal events, or disability from persistent symptoms or chronic lung function abnormalities. To improve the treatment of these patients, we must improve our understanding of the mechanisms responsible for severe disease. To achieve this goal, it is imperative to develop a common definition of severe asthma to allow adequate characterization of the disease clinically and provide the opportunity to compare results from many studies. Several severe asthma phenotypes have been described in the literature on the basis of the age of patients, age of disease onset, corticosteroid resistance, chronic airflow obstruction, and evidence for eosinophilic airway inflammation on biopsy. These phenotypes have led to an emerging interest in the use of noninvasive methods to monitor airway inflammation in severe asthma. Treatment algorithms based on markers of airway inflammation may decrease measures of health care utilization in severe asthma.

Adolescent↗

PubMed2004

A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects.

BACKGROUND: The role of variation in the IL4 gene in asthma and allergy susceptibility is controversial. This cytokine is important in IgE isotype switching and the regulation of allergic inflammation; however, published studies have not delineated the specific role of variation in this gene in allergic disorders. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) in IL4 and to evaluate the association of SNPs and haplotypes with asthma and allergic phenotypes (total serum IgE) in white, African American, and Hispanic asthmatic populations. METHODS: Sixteen individuals were resequenced, and 19 SNPs were identified; 2 novel and 17 SNPs were previously reported. Eleven of the SNPs were used to evaluate association in the 3 groups. RESULTS: Nine polymorphisms were associated with total serum IgE levels in white subjects (.0012 < or = P < or =.034), and 5 of these were also associated with asthma in this population (.010 < or = P < or =.031). Three common haplotypes were observed, and all were associated with either high or low serum IgE levels in white subjects (.00008 < or = P < or =.004). Inspection of the haplotypes revealed that 3017 G/T in intron 2 was the only SNP concordant with serum IgE levels (G allele with lower levels and T allele with higher levels). CONCLUSIONS: After a comprehensive genetic evaluation, our data suggest that the 3017 G/T variant or the haplotype it identifies influences IL4's ability to modulate total serum IgE levels. Inconsistencies with previously reported IL4 associations might be due to population differences in allele frequencies, the extent of linkage disequilibrium with this SNP or haplotype, or both.

Adolescent↗

PubMed2003

Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations.

BACKGROUND: Asthma is a complex genetic disease characterized by reversible intermittent airway obstruction and respiratory symptoms primarily caused by acute and chronic bronchial inflammation. Recently, a gene potentially involved in airway remodeling, a disintegrin and metalloprotease 33 (ADAM33), was implicated in asthma susceptibility. OBJECTIVE: We sought to determine whether polymorphisms in ADAM33 are associated with asthma or closely related phenotypes in 4 different asthma populations. METHODS: Eight single nucleotide polymorphisms (SNPs) were evaluated in the 3' portion of ADAM33 in 4 unique asthma populations (African American, US white, US Hispanic, and Dutch white). These SNPs were previously reported to be associated with asthma in white populations from the United States and United Kingdom. RESULTS: Significant associations were observed with at least one SNP and asthma in each population (P =.0009-.04). Related phenotypes that included total serum IgE levels and skin test responsiveness were also associated (P =.003-.05). However, no single SNP was associated across all populations. Additionally, haplotype analysis revealed that no single haplotype accounted for asthma susceptibility risk, although potential risk haplotypes existed within some of the populations. CONCLUSION: Replication of the original ADAM33 findings in these 4 additional asthma populations suggests that this gene (and perhaps others that interact with it) is important in the development and pathogenesis of asthma.

ADAM Proteins↗