Secretory leukocyte protease inhibitor and risk of heart failure in the Multi-Ethnic Study of Atherosclerosis

Konrad Teodor Sawicki; Drew R. Nannini; Suzette J. Bielinski; Nicholas B. Larson; Donald M. Lloyd-Jones; Bruce Psaty; Kent D. Taylor; Sanjiv J. Shah; Laura J. Rasmussen-Torvik; John T. Wilkins; Elizabeth M. McNally; Ravi B. Patel

doi:10.1038/s41598-023-27679-0

Secretory leukocyte protease inhibitor and risk of heart failure in the Multi-Ethnic Study of Atherosclerosis

Konrad Teodor Sawicki, Drew R. Nannini, Suzette J. Bielinski, Nicholas B. Larson, Donald M. Lloyd-Jones, Bruce Psaty, Kent D. Taylor, Sanjiv J. Shah, Laura J. Rasmussen-Torvik, John T. Wilkins, Elizabeth M. McNally, Ravi B. Patel^*

^*Corresponding author for this work

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

4 Scopus citations

Abstract

Circulating protease inhibitors are important regulators of inflammation that are implicated in the pathophysiology of heart failure (HF). Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which protects pulmonary tissues against inflammatory damage; however, its role in HF is not well understood. We sought to evaluate associations of circulating SLPI and genetically-mediated serum SLPI with incident HF and its subtypes in a multi-ethnic cohort of adults using clinical and genetic epidemiological approaches. Among 2,297 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), each doubling of serum SLPI was independently associated with incident HF (HR 1.77; 95% CI 1.02–3.02; P = 0.04), particularly incident HF with preserved ejection fraction (HFpEF; HR 2.44; 95% CI 1.23–4.84; P = 0.01) but not HF with reduced ejection fraction (HFrEF; HR 0.95; 95% CI 0.36–2.46; P = 0.91). Previously reported circulating SLPI protein quantitative trait loci (pQTLs) were not associated with serum SLPI levels or incident HF among MESA participants. In conclusion, baseline serum SLPI levels, but not genetically-determined serum SLPI, were significantly associated with incident HF and HFpEF over long-term follow-up in a multi-ethnic cohort. Serum circulating SLPI may be a correlate of inflammation that sheds insight on the pathobiology of HFpEF.

Original language	English (US)
Article number	604
Journal	Scientific reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-27679-0
State	Published - Dec 2023

Funding

This research was supported by T32-HL069771, KL2-TR001424, UL1‐TR‐000040, UL1‐TR‐001079, and UL1‐TR‐001420 from the National Institutes of Health. Funding for adhesion protein levels was supported by R01HL98077 from the National Institutes of Health. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by 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, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. We would like to thank the other investigators, the staff, and the participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by 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, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. We would like to thank the other investigators, the staff, and the participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org .

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10.1038/s41598-023-27679-0

Cite this

Sawicki, K. T., Nannini, D. R., Bielinski, S. J., Larson, N. B., Lloyd-Jones, D. M., Psaty, B., Taylor, K. D., Shah, S. J., Rasmussen-Torvik, L. J., Wilkins, J. T., McNally, E. M., & Patel, R. B. (2023). Secretory leukocyte protease inhibitor and risk of heart failure in the Multi-Ethnic Study of Atherosclerosis. Scientific reports, 13(1), Article 604. https://doi.org/10.1038/s41598-023-27679-0

@article{7de57db793be4e0dbd1365a91d48e627,

title = "Secretory leukocyte protease inhibitor and risk of heart failure in the Multi-Ethnic Study of Atherosclerosis",

abstract = "Circulating protease inhibitors are important regulators of inflammation that are implicated in the pathophysiology of heart failure (HF). Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which protects pulmonary tissues against inflammatory damage; however, its role in HF is not well understood. We sought to evaluate associations of circulating SLPI and genetically-mediated serum SLPI with incident HF and its subtypes in a multi-ethnic cohort of adults using clinical and genetic epidemiological approaches. Among 2,297 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), each doubling of serum SLPI was independently associated with incident HF (HR 1.77; 95% CI 1.02–3.02; P = 0.04), particularly incident HF with preserved ejection fraction (HFpEF; HR 2.44; 95% CI 1.23–4.84; P = 0.01) but not HF with reduced ejection fraction (HFrEF; HR 0.95; 95% CI 0.36–2.46; P = 0.91). Previously reported circulating SLPI protein quantitative trait loci (pQTLs) were not associated with serum SLPI levels or incident HF among MESA participants. In conclusion, baseline serum SLPI levels, but not genetically-determined serum SLPI, were significantly associated with incident HF and HFpEF over long-term follow-up in a multi-ethnic cohort. Serum circulating SLPI may be a correlate of inflammation that sheds insight on the pathobiology of HFpEF.",

author = "Sawicki, {Konrad Teodor} and Nannini, {Drew R.} and Bielinski, {Suzette J.} and Larson, {Nicholas B.} and Lloyd-Jones, {Donald M.} and Bruce Psaty and Taylor, {Kent D.} and Shah, {Sanjiv J.} and Rasmussen-Torvik, {Laura J.} and Wilkins, {John T.} and McNally, {Elizabeth M.} and Patel, {Ravi B.}",

note = "Funding Information: This research was supported by T32-HL069771, KL2-TR001424, UL1‐TR‐000040, UL1‐TR‐001079, and UL1‐TR‐001420 from the National Institutes of Health. Funding for adhesion protein levels was supported by R01HL98077 from the National Institutes of Health. Funding Information: MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by 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, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. We would like to thank the other investigators, the staff, and the participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Funding Information: MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by 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, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. We would like to thank the other investigators, the staff, and the participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org . Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41598-023-27679-0",

language = "English (US)",

volume = "13",

journal = "Scientific reports",

issn = "2045-2322",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Secretory leukocyte protease inhibitor and risk of heart failure in the Multi-Ethnic Study of Atherosclerosis

AU - Sawicki, Konrad Teodor

AU - Nannini, Drew R.

AU - Bielinski, Suzette J.

AU - Larson, Nicholas B.

AU - Lloyd-Jones, Donald M.

AU - Psaty, Bruce

AU - Taylor, Kent D.

AU - Shah, Sanjiv J.

AU - Rasmussen-Torvik, Laura J.

AU - Wilkins, John T.

AU - McNally, Elizabeth M.

AU - Patel, Ravi B.

N1 - Funding Information: This research was supported by T32-HL069771, KL2-TR001424, UL1‐TR‐000040, UL1‐TR‐001079, and UL1‐TR‐001420 from the National Institutes of Health. Funding for adhesion protein levels was supported by R01HL98077 from the National Institutes of Health. Funding Information: MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by 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, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. We would like to thank the other investigators, the staff, and the participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Funding Information: MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by 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, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. We would like to thank the other investigators, the staff, and the participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org . Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Circulating protease inhibitors are important regulators of inflammation that are implicated in the pathophysiology of heart failure (HF). Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which protects pulmonary tissues against inflammatory damage; however, its role in HF is not well understood. We sought to evaluate associations of circulating SLPI and genetically-mediated serum SLPI with incident HF and its subtypes in a multi-ethnic cohort of adults using clinical and genetic epidemiological approaches. Among 2,297 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), each doubling of serum SLPI was independently associated with incident HF (HR 1.77; 95% CI 1.02–3.02; P = 0.04), particularly incident HF with preserved ejection fraction (HFpEF; HR 2.44; 95% CI 1.23–4.84; P = 0.01) but not HF with reduced ejection fraction (HFrEF; HR 0.95; 95% CI 0.36–2.46; P = 0.91). Previously reported circulating SLPI protein quantitative trait loci (pQTLs) were not associated with serum SLPI levels or incident HF among MESA participants. In conclusion, baseline serum SLPI levels, but not genetically-determined serum SLPI, were significantly associated with incident HF and HFpEF over long-term follow-up in a multi-ethnic cohort. Serum circulating SLPI may be a correlate of inflammation that sheds insight on the pathobiology of HFpEF.

AB - Circulating protease inhibitors are important regulators of inflammation that are implicated in the pathophysiology of heart failure (HF). Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which protects pulmonary tissues against inflammatory damage; however, its role in HF is not well understood. We sought to evaluate associations of circulating SLPI and genetically-mediated serum SLPI with incident HF and its subtypes in a multi-ethnic cohort of adults using clinical and genetic epidemiological approaches. Among 2,297 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), each doubling of serum SLPI was independently associated with incident HF (HR 1.77; 95% CI 1.02–3.02; P = 0.04), particularly incident HF with preserved ejection fraction (HFpEF; HR 2.44; 95% CI 1.23–4.84; P = 0.01) but not HF with reduced ejection fraction (HFrEF; HR 0.95; 95% CI 0.36–2.46; P = 0.91). Previously reported circulating SLPI protein quantitative trait loci (pQTLs) were not associated with serum SLPI levels or incident HF among MESA participants. In conclusion, baseline serum SLPI levels, but not genetically-determined serum SLPI, were significantly associated with incident HF and HFpEF over long-term follow-up in a multi-ethnic cohort. Serum circulating SLPI may be a correlate of inflammation that sheds insight on the pathobiology of HFpEF.

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U2 - 10.1038/s41598-023-27679-0

DO - 10.1038/s41598-023-27679-0

M3 - Article

C2 - 36635319

AN - SCOPUS:85146195166

SN - 2045-2322

VL - 13

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 604

ER -

Secretory leukocyte protease inhibitor and risk of heart failure in the Multi-Ethnic Study of Atherosclerosis

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