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. 2024 May;81(5):1156-1166.
doi: 10.1161/HYPERTENSIONAHA.123.22614. Epub 2024 Mar 6.

Associations of Proteomics With Hypertension and Systolic Blood Pressure: KORA S4/F4/FF4 and KORA Age1/Age2 Cohort Studies

Jie-Sheng Lin  1   2 , Agnese Petrera  3 , Stefanie M Hauck  3 , Christian L Müller  4   5   6 , Annette Peters  1   7   8 , Barbara Thorand  1   2   8
Affiliations

Associations of Proteomics With Hypertension and Systolic Blood Pressure: KORA S4/F4/FF4 and KORA Age1/Age2 Cohort Studies

Jie-Sheng Lin et al. Hypertension. 2024 May.

Abstract

Background: Hypertension, a complex condition, is primarily defined based on blood pressure readings without involving its pathophysiological mechanisms. We aimed to identify biomarkers through a proteomic approach, thereby enhancing the future definition of hypertension with insights into its molecular mechanisms.

Methods: The discovery analysis included 1560 participants, aged 55 to 74 years at baseline, from the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 cohort study, with 3332 observations over a median of 13.4 years of follow-up. Generalized estimating equations were used to estimate the associations of 233 plasma proteins with hypertension and systolic blood pressure (SBP). For validation, proteins significantly associated with hypertension or SBP in the discovery analysis were validated in the KORA Age1/Age2 cohort study (1024 participants, 1810 observations). A 2-sample Mendelian randomization analysis was conducted to infer causalities of validated proteins with SBP.

Results: Discovery analysis identified 49 proteins associated with hypertension and 99 associated with SBP. Validation in the KORA Age1/Age2 study replicated 7 proteins associated with hypertension and 23 associated with SBP. Three proteins, NT-proBNP (N-terminal pro-B-type natriuretic peptide), KIM1 (kidney injury molecule 1), and OPG (osteoprotegerin), consistently showed positive associations with both outcomes. Five proteins demonstrated potential causal associations with SBP in Mendelian randomization analysis, including NT-proBNP and OPG.

Conclusions: We identified and validated 7 hypertension-associated and 23 SBP-associated proteins across 2 cohort studies. KIM1, NT-proBNP, and OPG demonstrated robust associations, and OPG was identified for the first time as associated with blood pressure. For NT-proBNP (protective) and OPG, causal associations with SBP were suggested.

Keywords: Mendelian randomization analysis; blood pressure; cohort studies; hypertension; proteomics.

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Conflict of interest statement

Disclosures None.

Figures

Figure 1.
Figure 1.
Flowchart of study participants. A, Participants from KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 study included in discovery analysis. B, Participants from KORA Age1/Age2 study included in validation analysis.
Figure 2.
Figure 2.
Associations of 49 proteins with hypertension in the discovery and validation studies. A, Significant associations of 49 proteins with hypertension in the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 study (Benjamini-Hochberg false discovery rate [FDR] <0.05). B, Validation of the associations of 49 proteins with hypertension in the KORA Age1/Age2 study. Proteins were considered validated at a threshold of P<0.05. This figure illustrates the results of model 2, as detailed in Table S9. Proteins in bold and red are successfully validated. OR indicates odds ratio. Full names of the proteins can be found in Table S1.
Figure 3.
Figure 3.
Associations of 99 proteins with systolic blood pressure (SBP) in the discovery and validation studies. A, Significant associations of 99 proteins with SBP in the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 study (Benjamini-Hochberg false discovery rate <0.05). B, Validation of the associations of 99 proteins with SBP in the KORA Age1/Age2 study. Proteins were considered validated at a threshold of P<0.05. This figure illustrates the results of model 2, as detailed in Table S10. Proteins in bold and red are successfully validated. NA indicates not available. Full names of the proteins can be found in Table S1.
Figure 4.
Figure 4.
Overlap of proteins associated with hypertension (HTN) and systolic blood pressure (SBP). A, Overlap of proteins associated with HTN and SBP in the discovery analysis in the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 study. Detailed results are presented in Table S8. B, Overlap of proteins associated with HTN and SBP in the validation analysis in the KORA Age1/Age2 study. Detailed results are presented in Tables S9 and S10. OR indicates odds ratio. Full names of the proteins can be found in Table S1.
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