Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans
Background Large‐artery stiffness (LAS) significantly contributes to cardiovascular morbidity and death and is characterized by increased pulse pressure (PP). The biology underlying large‐artery stiffness in humans remains incompletely understood. Methods and Results We investigated associations bet...
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| Format: | Article |
| Language: | English |
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Wiley
2025-08-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.037596 |
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| author | Marie‐Joe Dib Devendra Meena James Yarmolinsky Joe D. Azzo Oday Salman Hamed Tavolinejad Sushrima Gan Cameron Beeche Bianca Pourmussa Dipender Gill Stephen Burgess Julio A. Chirinos |
| author_facet | Marie‐Joe Dib Devendra Meena James Yarmolinsky Joe D. Azzo Oday Salman Hamed Tavolinejad Sushrima Gan Cameron Beeche Bianca Pourmussa Dipender Gill Stephen Burgess Julio A. Chirinos |
| author_sort | Marie‐Joe Dib |
| collection | DOAJ |
| description | Background Large‐artery stiffness (LAS) significantly contributes to cardiovascular morbidity and death and is characterized by increased pulse pressure (PP). The biology underlying large‐artery stiffness in humans remains incompletely understood. Methods and Results We investigated associations between PP and circulating levels of 2941 proteins among 53 016 UK Biobank participants. Analyses were adjusted for age, sex, mean arterial pressure, body mass index and stroke volume. Interaction analyses assessed the effect modification by sex on these relationships. We evaluated causal associations between plasma protein levels and PP, using inverse variance–weighted Mendelian randomization as the main analysis and Bayesian colocalization as a sensitivity analysis. A 5% false discovery rate threshold was used to account for multiple comparisons. Measured levels of 871 proteins were significantly associated with PP when adjusting for age, sex, mean arterial pressure, and body mass index, and 61 remained significantly associated after further adjusting for stroke volume. Top associations included NPPB (natriuretic peptide B), thrombospondin‐2, paraoxonase‐2, and sclerostin. Genetic analyses indicated that genetically predicted levels for 16 proteins were significantly associated with PP after false discovery rate correction, including fibroblast growth factor 5 (βIVW per SD change in protein levels=0.47 [95% CI, 0.34–0.61]), NPPB (βIVW=−1.40 [95% CI, −1.85 to −0.95]), insulin‐like growth factor binding 3 (βIVW=−1.143 [95% CI, −1.57 to −0.71]), and furin (βIVW, 1.31 [95% CI, 0.88–1.73]). Conclusions Using complementary epidemiological approaches to triangulate findings, our study identifies novel proteins with a putative causal effect on PP. Notably, our findings identify NPPB with high statistical confidence. This may have potentially impactful implications given the current availability of Food and Drug Administration–approved medications to boost NPPB effects. |
| format | Article |
| id | doaj-art-644d14032e254cb3a6263fbd1483c381 |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-644d14032e254cb3a6263fbd1483c3812025-08-20T07:24:59ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-08-01141610.1161/JAHA.124.037596Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in HumansMarie‐Joe Dib0Devendra Meena1James Yarmolinsky2Joe D. Azzo3Oday Salman4Hamed Tavolinejad5Sushrima Gan6Cameron Beeche7Bianca Pourmussa8Dipender Gill9Stephen Burgess10Julio A. Chirinos11Division of Cardiovascular Medicine Hospital of the University of Pennsylvania Philadelphia PADepartment of Epidemiology and Biostatistics, School of Public Health Imperial College London UKDepartment of Epidemiology and Biostatistics, School of Public Health Imperial College London UKUniversity of Pennsylvania Perelman School of Medicine Philadelphia PAUniversity of Pennsylvania Perelman School of Medicine Philadelphia PADivision of Cardiovascular Medicine Hospital of the University of Pennsylvania Philadelphia PADepartment of Pediatrics (Cardiology) and Cardiovascular Institute Stanford University Palo Alto CADivision of Cardiovascular Medicine Hospital of the University of Pennsylvania Philadelphia PADivision of Cardiovascular Medicine Hospital of the University of Pennsylvania Philadelphia PADepartment of Epidemiology and Biostatistics, School of Public Health Imperial College London UKMRC Biostatistics Unit University of Cambridge Cambridge UKDivision of Cardiovascular Medicine Hospital of the University of Pennsylvania Philadelphia PABackground Large‐artery stiffness (LAS) significantly contributes to cardiovascular morbidity and death and is characterized by increased pulse pressure (PP). The biology underlying large‐artery stiffness in humans remains incompletely understood. Methods and Results We investigated associations between PP and circulating levels of 2941 proteins among 53 016 UK Biobank participants. Analyses were adjusted for age, sex, mean arterial pressure, body mass index and stroke volume. Interaction analyses assessed the effect modification by sex on these relationships. We evaluated causal associations between plasma protein levels and PP, using inverse variance–weighted Mendelian randomization as the main analysis and Bayesian colocalization as a sensitivity analysis. A 5% false discovery rate threshold was used to account for multiple comparisons. Measured levels of 871 proteins were significantly associated with PP when adjusting for age, sex, mean arterial pressure, and body mass index, and 61 remained significantly associated after further adjusting for stroke volume. Top associations included NPPB (natriuretic peptide B), thrombospondin‐2, paraoxonase‐2, and sclerostin. Genetic analyses indicated that genetically predicted levels for 16 proteins were significantly associated with PP after false discovery rate correction, including fibroblast growth factor 5 (βIVW per SD change in protein levels=0.47 [95% CI, 0.34–0.61]), NPPB (βIVW=−1.40 [95% CI, −1.85 to −0.95]), insulin‐like growth factor binding 3 (βIVW=−1.143 [95% CI, −1.57 to −0.71]), and furin (βIVW, 1.31 [95% CI, 0.88–1.73]). Conclusions Using complementary epidemiological approaches to triangulate findings, our study identifies novel proteins with a putative causal effect on PP. Notably, our findings identify NPPB with high statistical confidence. This may have potentially impactful implications given the current availability of Food and Drug Administration–approved medications to boost NPPB effects.https://www.ahajournals.org/doi/10.1161/JAHA.124.037596arterial stiffnessMendelian randomizationproteomicspulse pressure |
| spellingShingle | Marie‐Joe Dib Devendra Meena James Yarmolinsky Joe D. Azzo Oday Salman Hamed Tavolinejad Sushrima Gan Cameron Beeche Bianca Pourmussa Dipender Gill Stephen Burgess Julio A. Chirinos Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease arterial stiffness Mendelian randomization proteomics pulse pressure |
| title | Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans |
| title_full | Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans |
| title_fullStr | Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans |
| title_full_unstemmed | Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans |
| title_short | Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans |
| title_sort | proteome wide mendelian randomization identifies natriuretic peptide b and novel proteins as potential regulators of pulse pressure in humans |
| topic | arterial stiffness Mendelian randomization proteomics pulse pressure |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.037596 |
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