Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease

Kristina L. Buschur; Tess D. Pottinger; Jens Vogel-Claussen; Charles A. Powell; Francois Aguet; Norrina B. Allen; Kristin Ardlie; David A. Bluemke; Peter Durda; Emilia A. Hermann; Eric A. Hoffman; João A.C. Lima; Yongmei Liu; Daniel Malinsky; Ani Manichaikul; Amin Motahari; Wendy S. Post; Martin R. Prince; Stephen S. Rich; Jerome I. Rotter; Benjamin M. Smith; Russell P. Tracy; Karol Watson; Hinrich B. Winther; Tuuli Lappalainen; R. Graham Barr

doi:10.1513/AnnalsATS.202305-417OC

Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease

Kristina L. Buschur, Tess D. Pottinger, Jens Vogel-Claussen, Charles A. Powell, Francois Aguet, Norrina B. Allen, Kristin Ardlie, David A. Bluemke, Peter Durda, Emilia A. Hermann, Eric A. Hoffman, João A.C. Lima, Yongmei Liu, Daniel Malinsky, Ani Manichaikul, Amin Motahari, Wendy S. Post, Martin R. Prince, Stephen S. Rich, Jerome I. RotterBenjamin M. Smith, Russell P. Tracy, Karol Watson, Hinrich B. Winther, Tuuli Lappalainen, R. Graham Barr^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with >10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-кB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-кB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

Original language	English (US)
Pages (from-to)	884-894
Number of pages	11
Journal	Annals of the American Thoracic Society
Volume	21
Issue number	6
DOIs	https://doi.org/10.1513/AnnalsATS.202305-417OC
State	Published - Jun 2024

Funding

Supported by T32-HL144442 from the National Heart, Lung, and Blood Institute (NHLBI). The MESA COPD Study is supported by R01-HL093081 and R01-HL077612. MESA is conducted by the NHLBI in collaboration with MESA investigators and supported by NHLBI contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. Multi-Ethnic Study of Atherosclerosis (MESA) (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (National Institutes of Health 3R01HL-117626-02S1, contract HHSN268201800002I) (Broad RNA Seq, Proteomics HHSN268201600034I, UW RNA Seq HHSN268201600032I, USC DNA Methylation HHSN268201600034I, Broad Metabolomics HHSN268201600038I). Phenotype harmonization, data management, sample-identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393; U01HL-120393; contract HHSN268180001I). This work was also supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by NHLBI grant R01HL105756. The authors thank the other investigators, the staff, and the participants of the MESA Study for their valuable contributions. A full list of participating MESA investigators and institutions and information about how to access the human cohort data can be found at http://www.mesanhlbi.org. Supported by T32-HL144442 from the National Heart, Lung, and Blood Institute (NHLBI). The MESA COPD Study is supported by R01-HL093081 and R01-HL077612. MESA is conducted by the NHLBI in collaboration with MESA investigators and supported by NHLBI contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. Multi-Ethnic Study of Atherosclerosis (MESA) (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (National Institutes of Health 3R01HL-117626-02S1, contract HHSN268201800002I) (Broad RNA Seq, Proteomics HHSN268201600034I, UW RNA Seq HHSN268201600032I, USC DNA Methylation HHSN268201600034I, Broad Metabolomics HHSN268201600038I). Phenotype harmonization, data management, sample-identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393; U01HL-120393; contract HHSN268180001I). This work was also supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by NHLBI grant R01HL105756.

Keywords

COPD
gene expression
pulmonary microvascular perfusion

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

Access to Document

10.1513/AnnalsATS.202305-417OC

Cite this

Buschur, K. L., Pottinger, T. D., Vogel-Claussen, J., Powell, C. A., Aguet, F., Allen, N. B., Ardlie, K., Bluemke, D. A., Durda, P., Hermann, E. A., Hoffman, E. A., Lima, J. A. C., Liu, Y., Malinsky, D., Manichaikul, A., Motahari, A., Post, W. S., Prince, M. R., Rich, S. S., ... Barr, R. G. (2024). Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease. Annals of the American Thoracic Society, 21(6), 884-894. https://doi.org/10.1513/AnnalsATS.202305-417OC

@article{321481f5b9d94c73bad4af69f4c56905,

title = "Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease",

abstract = "Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with >10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-кB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-кB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.",

keywords = "COPD, gene expression, pulmonary microvascular perfusion",

author = "Buschur, {Kristina L.} and Pottinger, {Tess D.} and Jens Vogel-Claussen and Powell, {Charles A.} and Francois Aguet and Allen, {Norrina B.} and Kristin Ardlie and Bluemke, {David A.} and Peter Durda and Hermann, {Emilia A.} and Hoffman, {Eric A.} and Lima, {Jo{\~a}o A.C.} and Yongmei Liu and Daniel Malinsky and Ani Manichaikul and Amin Motahari and Post, {Wendy S.} and Prince, {Martin R.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Smith, {Benjamin M.} and Tracy, {Russell P.} and Karol Watson and Winther, {Hinrich B.} and Tuuli Lappalainen and Barr, {R. Graham}",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 by the American Thoracic Society.",

year = "2024",

month = jun,

doi = "10.1513/AnnalsATS.202305-417OC",

language = "English (US)",

volume = "21",

pages = "884--894",

journal = "Annals of the American Thoracic Society",

issn = "2329-6933",

publisher = "American Thoracic Society",

number = "6",

}

Buschur, KL, Pottinger, TD, Vogel-Claussen, J, Powell, CA, Aguet, F, Allen, NB, Ardlie, K, Bluemke, DA, Durda, P, Hermann, EA, Hoffman, EA, Lima, JAC, Liu, Y, Malinsky, D, Manichaikul, A, Motahari, A, Post, WS, Prince, MR, Rich, SS, Rotter, JI, Smith, BM, Tracy, RP, Watson, K, Winther, HB, Lappalainen, T & Barr, RG 2024, 'Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease', Annals of the American Thoracic Society, vol. 21, no. 6, pp. 884-894. https://doi.org/10.1513/AnnalsATS.202305-417OC

Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease. / Buschur, Kristina L.; Pottinger, Tess D.; Vogel-Claussen, Jens et al.
In: Annals of the American Thoracic Society, Vol. 21, No. 6, 06.2024, p. 884-894.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease

AU - Buschur, Kristina L.

AU - Pottinger, Tess D.

AU - Vogel-Claussen, Jens

AU - Powell, Charles A.

AU - Aguet, Francois

AU - Allen, Norrina B.

AU - Ardlie, Kristin

AU - Bluemke, David A.

AU - Durda, Peter

AU - Hermann, Emilia A.

AU - Hoffman, Eric A.

AU - Lima, João A.C.

AU - Liu, Yongmei

AU - Malinsky, Daniel

AU - Manichaikul, Ani

AU - Motahari, Amin

AU - Post, Wendy S.

AU - Prince, Martin R.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Smith, Benjamin M.

AU - Tracy, Russell P.

AU - Watson, Karol

AU - Winther, Hinrich B.

AU - Lappalainen, Tuuli

AU - Barr, R. Graham

PY - 2024/6

Y1 - 2024/6

N2 - Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with >10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-кB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-кB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

AB - Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with >10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-кB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-кB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

KW - COPD

KW - gene expression

KW - pulmonary microvascular perfusion

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DO - 10.1513/AnnalsATS.202305-417OC

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AN - SCOPUS:85195226955

SN - 2329-6933

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JO - Annals of the American Thoracic Society

JF - Annals of the American Thoracic Society

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ER -

Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease

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