Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials

Grossman, N.; Ortega, Victor E.; King, Tonya S.; Bleecker, Eugene R.; Ampleford, Elizabeth; Bacharier, Leonard B.; Cabana, Michael D.; Cardet, Juan Carlos; Carr, Tara F.; Castro, Mario; Denlinger, Loren C.; Denson, Joshua L.; Fandino, Nicolas; Fitzpatrick, Anne M.; Hawkins, Gregory A.; Holguín, Fernando; Krishnan, Jerry A.; Lazarus, Stephen C.; Nyenhuis, Sharmilee M.; Phipatanakul, Wanda; Ramratnam, Sima; Wenzel, Sally E.; Peters, Stephen P.; Meyers, Deborah A.; Wechsler, Michael E.; Israel, Elliot

doi:10.1016/j.jaci.2019.08.033

Cited by 26 publications

(18 citation statements)

References 49 publications

(119 reference statements)

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“…Comorbidities are highly prevalent among EPA patients. We did not find a correlation between EPA and rhinitis or GERD, which were previously reported to be associated with increased exacerbation risk in Blacks [18]. A possible reason is that the prevalence of GERD in East Asia (2.5–7.8%) is much lower than that in North America (18.1–27.8%), South America (23.0%), and Europe (8.8–25.9%) [56].…”

Section: Discussionmentioning

confidence: 58%

“…A more recently published study based on multiethnic individuals from 12 Asthma Clinical Research Network and Asthma Net trials showed that the risk factors of EPA differed according to race. Grossman et al [18] identified chronic rhinosinusitis, allergic rhinitis, and GERD were only associated with increased exacerbation risk in Blacks rather than Caucasians. Since few studies focus on EPA in Asians and there are no available data from a Chinese population, it is unclear whether these risk factors contribute to frequent exacerbations in the Chinese population.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment

Feng

Zhang

et al. 2020

Respiration

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Background: Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking. Objective: To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population. Methods: We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (n = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations. Results: Of 546 participants, 61.9% had no exacerbations (n = 338), 29.6% had few exacerbations (n = 162), and 8.4% were exacerbation prone (n = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all p < 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV1 (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers. Conclusion: EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment

Feng

Zhang

et al. 2020

Respiration

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“…We performed a two-stage GWAS and identified a novel locus for susceptibility to asthma with exacerbations that reached genomewide significance in the combined meta-analysis. The high asthma prevalence among African-admixed individuals, particularly in developed countries, [6][7][8][9][10] suggests a shared genetic basis that may be a risk factor for asthma under environmental influences that are absent in non-Westernized societies. 8 In this work, we leveraged this specific genetic background to identify a novel locus for severe asthma exacerbations.…”

Section: Discussionmentioning

confidence: 99%

“…6 Moreover, African ancestry has been associated with a higher risk of developing asthma among African Americans 7 and Puerto Ricans, 8 as well as with an increased risk of exacerbations among African Americans. 9,10 These data point to a genetic component potentially contributing to the disparities in asthma exacerbations.…”

Section: Introductionmentioning

confidence: 94%

Genome‐wide association study reveals a novel locus for asthma with severe exacerbations in diverse populations

Herrera‐Luis

Espuela‐Ortiz

Lorenzo-Díaz

et al. 2020

Pediatric Allergy Immunology

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Background: Severe asthma exacerbations are a major cause of asthma morbidity and increased healthcare costs. Several studies have shown racial and ethnic differences in asthma exacerbation rates. We aimed to identify genetic variants associated with severe exacerbations in two high-risk populations for asthma. Methods: A genome-wide association study of asthma in children and youth with severe exacerbations was performed in 1283 exacerbators and 2027 controls without asthma of Latino ancestry. Independent suggestive variants (P ≤ 5 × 10 −6) were selected for replication in 448 African Americans exacerbators and 595 controls. Case-only analyses were performed comparing the exacerbators with additional 898 Latinos and 524 African Americans asthma patients without exacerbations, while adjusting by treatment category as a proxy of asthma severity. We analyzed the functionality of associated variants with in silico methods and by correlating genotypes with methylation levels in whole blood in a subset of 473 Latinos. Results: We identified two genome-wide significant associations for susceptibility to asthma with severe exacerbations, including a novel locus located at chromosome 2p21 (rs4952375, odds ratio = 1.39, P = 3.8 × 10 −8), which was also associated with asthma exacerbations in a case-only analysis (odds ratio = 1.25, P = 1.95 × 10 −3). This polymorphism is an expression quantitative trait locus of the long intergenic nonprotein coding RNA 1913 (LINC01913) in lung tissues (P = 1.3 × 10 −7) and influences | 107 HERRERA-LUIS Et AL.

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“…First, we explored a highly specific subset of patients with severe asthma. The response to poly I:C may vary across asthma endotypes, particularly in exacerbation-prone subgroups [39][40][41] . Second, we examined PBMCs, while other studies have evaluated the airway compartment 11,12 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell Profiling of the Response to Poly I:C in Peripheral Blood Mononuclear Cells in Severe Asthma

Chen

Diaz-Soto

Sanmamed

et al. 2020

Preprint

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Background: Asthma has been associated with impaired interferon responses. Multiple cell types have been implicated in these impaired responses and may be responsible for increased exacerbations and immunopathology of asthma. Objective: Characterize the single-cell response to Poly I:C of peripheral blood mononuclear cells (PBMCs) of patients with severe asthma (SA). Methods: Two complementary single-cell methods, DropSeq for single-cell RNA sequencing (scRNA-Seq) and mass cytometry (CyTOF), were used to profile PBMCs of SA and healthy controls (HC). Poly I:C and unstimulated cells were analyzed in this study. Results: PBMCs (n=9,414) from five SA (n=6,099) and three HC (n=3,315) were profiled using scRNA-Seq. Six main cell subsets, including CD4+ T cells, CD8+ T cells, natural killer (NK) cells, B cells, dendritic cells (DCs), and monocytes, were identified. CD4+ T cells were the main cell type and demonstrated a pro-inflammatory profile characterized by increased JAK1 expression in unstimulated cells. Following Poly I:C stimulation, PBMCs from SA had a robust induction of interferon pathways compared with HC. Additional analyses to identify core regulators of the enhanced interferon response in SA identified IRF1, STAT1, IRF7, STAT2, and IRF9. CyTOF profiling of Poly I:C and unstimulated PBMCs (n=120,000) from the same individuals (SA=4; HC=2) demonstrated higher numbers of CD8+ effector cells and Th1 CD4+ T cells in unstimulated conditions, followed by a decrease of these two cell subsets after poly I:C stimulation. Conclusion: Single-cell profiling of PBMCs with scRNA-seq and CyTOF in patients with SA identified activation of pro-inflammatory pathways at baseline and strong response to Poly I:C, as well as quantitative changes in CD8+ effector cells and Th1 cells. Thus, transcriptomic and cell quantitative changes are associated with immune cell heterogeneity in severe asthma.

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Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials

Cited by 26 publications

References 49 publications

Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment

Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment

Genome‐wide association study reveals a novel locus for asthma with severe exacerbations in diverse populations

Single-cell Profiling of the Response to Poly I:C in Peripheral Blood Mononuclear Cells in Severe Asthma

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