Genetic Associations and Architecture of Asthma-COPD Overlap

John, Catherine; Guyatt, Anna L; Shrine, Nick; Packer, Richard; Liu, Jiangyuan; Hayden, Lystra P.; Chu, Su H.; Koskela, Jukka; Luan, Jian’an; Li, Xingnan; Terzikhan, Natalie; Xu, Hanfei; Bartz, Traci M.; Petersen, Hans; Leng, Shuguang; Belinsky, Steven A.; Cepelis, Aivaras; Cordero, Ana I Hernández; Obeidat, Ma’en; Þorleifsson, Guðmar; Meyers, Deborah A.; Bleecker, Eugene R.; Sakoda, Lori C.; Iribarren, Carlos; Tesfaigzi, Yohannes; Gharib, Sina A.; Dupuis, Josée; Brusselle, Guy; Lahousse, Lies; Ortega, Victor E.; Jónsdóttir, Ingileif; Sin, Don D.; Bossé, Yohan; Berge, Maarten van den; Nickle, David C.; Quint, Jennifer; Sayers, Ian; Hall, Ian P.; Langenberg, Claudia; Ripatti, Samuli; Laitinen, Tarja; Wu, Ann Chen; Lasky‐Su, Jessica; Bakke, Per; Gulsvik, Amund; Hersh, Craig P.; Hayward, Caroline; Brumpton, Ben; Stefánsson, Kári; Cho, Michael H.; Wain, Louise V.; Tobin, Martin D.

doi:10.1016/j.chest.2021.12.674

Cited by 20 publications

(10 citation statements)

References 53 publications

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“…While the details of the relationships between these molecules and phenotypes of hypertension and COVID-19 have yet to be dissected, a closer look at the cluster of genes on Chr5 revealed a second shared signal located downstream of CSF2. This signal falls within C5ORF56, a locus previously reported as an integral part of asthma-COPD overlap and a predisposing factor to Type 2 inflammation,55 which may reduce the risk for severe COVID-19 56. This finding also calls for much-needed investigations into the hypertension-COVID-19-asthma connection.The functional pathway constructed based on literature data may uncover some of the underlying mechanisms of the causal effect of hypertension on COVID-19.…”

supporting

confidence: 57%

Causal associations and shared genetics between hypertension and COVID‐19

Baranova

Cao

Zhang

2023

Journal of Medical Virology

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To evaluate the genetic relationship between hypertension and COVID-19 and explore the molecular pathways linking hypertension to COVID-19. We performed genetic correlation and Mendelian randomization (MR) analyses to assess potential associations between hypertension and hospitalized COVID-19. We compared genome-wide association signals to reveal shared genetic variation between hypertension and hospitalized COVID-19. Moreover, hypertension-driven molecular pathways were constructed based on large-scale literature data to understand the influence of hypertension on COVID-19 at the molecular level. Hypertension has a positive genetic correlation with COVID-19 (r g = 0.19). The MR analyses indicate that genetic liability to hypertension confers a causal effect on hospitalized COVID-19 (odds ratio [OR]: 1.05, confidence interval [CI]: 1.00-1.09, p = 0.030). Hypertension and hospitalized COVID-19 have three overlapping loci and share eight protein-coding risk genes, including ABO, CSF2, FUT2, IZUMO1, MAMSTR, NPNT, RASIP1, and WNT3. Molecular pathway analysis suggests that hypertension may promote the development of COVID-19 through the induction of inflammatory pathways. Our study suggests that genetically determined hypertension may increase the risk for severe COVID-19. The shared genetic variation and the connecting molecular pathways may underline causal links between hypertension and COVID-19.

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supporting

confidence: 57%

Causal associations and shared genetics between hypertension and COVID‐19

Baranova

Cao

Zhang

2023

Journal of Medical Virology

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“…In contrast, previous studies of cross-trait genetic correlations with asthma provide estimates of shared genetic effects among common variants but are less interpretable in terms of relative disease risk. 7 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 The relative risks between different disease pairs with similar genetic correlation estimates can vary dramatically. 61 PRS-based associations therefore offer a different view of multimorbidity with additional utility than cross-trait genetic correlation estimates alone.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies that have developed PRSs for asthma have focused on predictive performance 11 , 12 , 13 , 14 , 15 or associations with specific traits, 15 , 16 , 17 , 18 , 19 , 20 , 21 while broader studies of cross-trait genetic correlations between asthma and other conditions offer less interpretable findings than PRS associations in terms of relative disease risk. 7 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 In this study, we aimed to provide a quantitative overview of the genetic landscape for asthma in terms of other heritable traits and conditions and their associations with genetic asthma risk. We first modeled PRSs of asthma using GWAS summary statistics from the Trans-National Asthma Genetic Consortium (TAGC; 23,948 cases, 118,538 controls) 30 and the Global Biobank Meta-analysis Initiative (GBMI; 153,763 cases, 1,647,022 controls) 7 and then derived scores for individuals in the UK Biobank (UKB; n = 398,744).…”

Section: Introductionmentioning

confidence: 99%

Revealing polygenic pleiotropy using genetic risk scores for asthma

Dapas

Lee

Wentworth-Sheilds

et al. 2023

Human Genetics and Genomics Advances

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“…We therefore investigated the molecular features of ACO in the elderly using sputum transcriptomics. A recent large-scale genome-wide association study showed that ACO has a spectrum of shared genetic influences, some predominantly influencing asthma and others predominantly influencing fixed airflow obstruction [ 24 ]. In addition, changes in gene expression in the airway can co-occur in asthma and COPD, which explains the “asthma-like” features in patients with COPD [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of sputum cells reveals two distinct molecular phenotypes of “asthma and chronic obstructive pulmonary disease overlap” in the elderly

Lee

Park

2022

Eur J Med Res

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Background Little is known about the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO). This study examined the molecular phenotypes of ACO in the elderly. Methods A genome-wide investigation of gene expression in sputum cells from the elderly with asthma, ACO, or COPD was performed using gene set variation analysis (GSVA) with predefined asthma- or COPD-specific gene signatures. We then performed a subsequent cluster analysis using enrichment scores (ESs) to identify molecular clusters in the elderly with ACO. Finally, a second GSVA was conducted with curated gene signatures to gain insight into the pathogenesis of ACO associated with the identified molecular clusters. Results Seventy elderly individuals were enrolled (17 with asthma, 41 with ACO, and 12 with COPD). Two distinct molecular clusters of ACO were identified. Clinically, ACO cluster 1 (N = 23) was characterized by male and smoker dominance, more obstructive lung function, and higher proportions of both neutrophil and eosinophil in induced sputum compared to ACO cluster 2 (N = 18). ACO cluster 1 had molecular features similar to both asthma and COPD, with mitochondria and peroxisome dysfunction as important mechanisms in the pathogenesis of these diseases. The molecular features of ACO cluster 2 differed from those of asthma and COPD, with enhanced innate immune reactions to microorganisms identified as being important in the pathogenesis of this form of ACO. Conclusion Recognition of the unique biological pathways associated with the two distinct molecular phenotypes of ACO will deepen our understanding of ACO in the elderly.

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Genetic Associations and Architecture of Asthma-COPD Overlap

Cited by 20 publications

References 53 publications

Causal associations and shared genetics between hypertension and COVID‐19

Causal associations and shared genetics between hypertension and COVID‐19

Revealing polygenic pleiotropy using genetic risk scores for asthma

Transcriptome analysis of sputum cells reveals two distinct molecular phenotypes of “asthma and chronic obstructive pulmonary disease overlap” in the elderly

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