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Whole genome sequencing and proteomic analysis of mucus plugging in COPDGene

Submitted by
Kim, Kangjin
Authors
Kangjin Kim1, Hrudaya P. Nath4, Scott Grumley5, Jose L Orejas3, Wojciech R. Dolliver3, Sofia Mettler1, Andrew A. Yen5, Kathleen Jacobs5, Padma P. Manapragada4, Mostafa Abozeed4, Muhammad Usman Aziz4, Mohd Zahid4, Sushilkumar Sonavane6, Trans-Omics in Precision Medicine (TOPMed), Edwin K. Silverman1,2, Russell Bowler7, Alejandro Diaz3, Michael H. Cho1,2

1Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 2Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115 3Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA. 4Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA. 5Department of Radiology, University of California San Diego, San Diego, CA, USA. 6Department of Radiology, Mayo Clinic, Jacksonville, FL, USA, 7National Jewish Health, Denver, CO, USA
Name and Date of Professional Meeting
ASHG 2023 Conference (Nov 3, 2023)
Associated paper proposal(s)
Genetic association of bronchiectasis and mucus plugging in TOPMed
Working Group(s)
Lung
Abstract Text
Introduction:
Mucus plugs in smokers with and without COPD are associated with worse lung function and may represent an important treatable trait in airways disease. While genetic risk factors have been identified for symptomatic syndromes associated with mucus plugging (e.g. bronchiectasis), genetic risk factors for CT-identified mucus plugs, which are often asymptomatic, have not been identified.

Methods:
We performed a whole genome sequencing association study of mucus plugs in 3,433 non-Hispanic white (NHW) and 1,021 African American (AA) individuals in the Genetic Epidemiology of COPD (COPDGene) using data generated from the Trans-Omics in Precision Medicine (TOPMed) study. We calculated lung mucus plugging scores using chest CT scans. We analyzed a dichotomized overall score after adjusting for age, gender, smoking pack-years, current smoking status, sequencing center, and genetic ancestry. We also performed a secondary analysis using the value in each lobe. We investigated genome-wide single variants, loss-of-function rare variants within genes and candidate associations in genes with reported associations for related phenotypes (cough, phlegm, bronchiectasis). We considered a P-value of 5x10-8 for genome-wide significance. We also used SomaScan 1.3k data in a subset of 518 individuals to investigate the association between the trait and proteins.

Results:
We found no significant associations in the single variant, rare variant, and protein analyses using the binary score for whole mucus plugging. Our top findings in single variant associations were near FAM80B and SLC2A13 (P = < 2 x10-7). In rare variant analysis, the top association for high-confidence loss-of-function rare variants was in HAL (P = 3.84x10-6), while our top protein association was CXCL13 (P = 2.29x10-4). Notably, we did not identify any associations with previously described associations with cough, phlegm, or in other candidate genes associated with bronchiectasis. In a secondary analysis of lobar mucus plugging binary scores, we identified 4 genome-wide significant regions; our top finding was near ZNF407 (8.02x10-9) with other less significant associations near ZNF816, CCSER1, and L3HYPDH.

Conclusions: In a whole genome sequencing and proteomic study of mucus plugging, we did not identify genome- or proteome-wide significant associations; nor did we find associations in a set of candidate genes and variants. In a secondary analysis, we did identify associations with lobe-specific values, though their clinical significance remains unclear. Future work will include analysis of quantitative phenotypes and in additional samples.