TY - JOUR
T1 - Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults
AU - Bortnick, Anna E.
AU - Austin, Thomas R.
AU - Hamerton, Emily
AU - Gudmundsdottir, Valborg
AU - Emilsson, Valur
AU - Jennings, Lori L.
AU - Gudnason, Vilmundur
AU - Owens, David S.
AU - Massera, Daniele
AU - Dufresne, Line
AU - Yang, Ta Yu
AU - Engert, James C.
AU - Thanassoulis, George
AU - Tracy, Russell P.
AU - Gerszten, Robert E.
AU - Psaty, Bruce M.
AU - Kizer, Jorge R.
N1 - Publisher Copyright:
© 2025 The Author(s).
PY - 2025/3/4
Y1 - 2025/3/4
N2 - BACKGROUND: Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions. METHODS AND RESULTS: We undertook large-scale plasma proteomics in a cohort study of adults ≥65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer-based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES-RS (Age, Gene/Environment Susceptibility-Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2-sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomographyquantified AVC or AS as outcomes. Six proteins showed Bonferroni-corrected significant relationships with AVC in CHS. Three of these, CXCL-12 (C-X-C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES-RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near-significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=−0.25, P=0.009). CONCLUSIONS: This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.
AB - BACKGROUND: Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions. METHODS AND RESULTS: We undertook large-scale plasma proteomics in a cohort study of adults ≥65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer-based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES-RS (Age, Gene/Environment Susceptibility-Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2-sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomographyquantified AVC or AS as outcomes. Six proteins showed Bonferroni-corrected significant relationships with AVC in CHS. Three of these, CXCL-12 (C-X-C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES-RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near-significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=−0.25, P=0.009). CONCLUSIONS: This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.
KW - Age Factors
KW - Aged
KW - Aged, 80 and over
KW - Aortic Valve Stenosis/blood
KW - Aortic Valve/diagnostic imaging
KW - Biomarkers/blood
KW - Blood Proteins/genetics
KW - Calcinosis/blood
KW - Chemokine CXCL12/blood
KW - Echocardiography
KW - Female
KW - Humans
KW - Male
KW - Mendelian Randomization Analysis
KW - Proteomics/methods
KW - Severity of Illness Index
UR - http://www.scopus.com/inward/record.url?scp=86000552100&partnerID=8YFLogxK
U2 - 10.1161/jaha.124.036336
DO - 10.1161/jaha.124.036336
M3 - Article
C2 - 40008515
AN - SCOPUS:86000552100
SN - 2047-9980
VL - 14
SP - e036336
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 5
M1 - e036336
ER -