. 2021 Jun;77(6):2004-2013.

doi: 10.1161/HYPERTENSIONAHA.120.16534. Epub 2021 Apr 5.

Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses

Rainer Malik¹, Marios K Georgakis¹, Marijana Vujkovic^{2

3}, Scott M Damrauer^{2

3}, Paul Elliott^{4

5

6

7

8

9}, Ville Karhunen⁴, Alice Giontella^{10

11}, Cristiano Fava^{10

11}, Jacklyn N Hellwege¹², Megan M Shuey¹², Todd L Edwards¹³, Tormod Rogne^{14

15

16}, Bjørn O Åsvold^{17

18}, Ben M Brumpton^{19

18}, Stephen Burgess^{20

21}, Martin Dichgans^{1

22

23}, Dipender Gill^{4

5

24

25

26}

Affiliations

¹ Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany (R.M., M.K.G., M.D.).
² Perelman School of Medicine, University of Pennsylvania, Philadelphia (M.V., S.M.D.).
³ Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA (M.V., S.M.D.).
⁴ Department of Epidemiology and Biostatistics, School of Public Health (P.E., V.K., D.G.), Imperial College London, United Kingdom.
⁵ British Heart Foundation Centre of Research Excellence (P.E., D.G.), Imperial College London, United Kingdom.
⁶ School of Public Health, Medical Research Council-Public Health England Centre for Environment (P.E.).
⁷ UK Dementia Research Institute at Imperial College London, United Kingdom (P.E.).
⁸ Imperial Biomedical Research Centre, Imperial College London and Imperial College NHS Healthcare Trust, United Kingdom (P.E.).
⁹ Health Data Research UK London (P.E.).
¹⁰ Department of Medicine, University of Verona, Italy (A.G., C.F.).
¹¹ Department of Clinical Sciences, Clinical Research Centre, Lund University, Malmö, Sweden (A.G., C.F.).
¹² Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center (J.N.H., M.M.S.) Vanderbilt University Medical Center, Nashville, TN.
¹³ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute (T.L.E.), Vanderbilt University Medical Center, Nashville, TN.
¹⁴ Department of Circulation and Medical Imaging, Gemini Center for Sepsis Research, Norwegian University of Science and Technology, Trondheim, Norway (T.R.).
¹⁵ Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT (T.R.).
¹⁶ Clinic of Anaesthesia and Intensive Care (T.R.), St. Olav's Hospital, Trondheim University Hospital, Norway.
¹⁷ Department of Endocrinology, Clinic of Medicine (B.O.Å.), St. Olav's Hospital, Trondheim University Hospital, Norway.
¹⁸ Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (B.O.Å., B.M.B.).
¹⁹ Clinic of Thoracic and Occupational Medicine (B.M.B.), St. Olav's Hospital, Trondheim University Hospital, Norway.
²⁰ Cardiovascular Epidemiology Unit, University of Cambridge, United Kingdom (S.B.).
²¹ Medical Research Council Biostatistics Unit, University of Cambridge, United Kingdom (S.B.).
²² Munich Cluster for Systems Neurology, Germany (M.D.).
²³ German Centre for Neurodegenerative Diseases, Munich, Germany (M.D.).
²⁴ Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, United Kingdom (D.G.).
²⁵ Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, United Kingdom (D.G.).
²⁶ Novo Nordisk Research Centre Oxford, Old Road Campus, United Kingdom (D.G.).

PMID: 33813844
PMCID: PMC8115430
DOI: 10.1161/HYPERTENSIONAHA.120.16534

Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses

Rainer Malik et al. Hypertension. 2021 Jun.

. 2021 Jun;77(6):2004-2013.

doi: 10.1161/HYPERTENSIONAHA.120.16534. Epub 2021 Apr 5.

Authors

Affiliations

¹ Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany (R.M., M.K.G., M.D.).
² Perelman School of Medicine, University of Pennsylvania, Philadelphia (M.V., S.M.D.).
³ Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA (M.V., S.M.D.).
⁴ Department of Epidemiology and Biostatistics, School of Public Health (P.E., V.K., D.G.), Imperial College London, United Kingdom.
⁵ British Heart Foundation Centre of Research Excellence (P.E., D.G.), Imperial College London, United Kingdom.
⁶ School of Public Health, Medical Research Council-Public Health England Centre for Environment (P.E.).
⁷ UK Dementia Research Institute at Imperial College London, United Kingdom (P.E.).
⁸ Imperial Biomedical Research Centre, Imperial College London and Imperial College NHS Healthcare Trust, United Kingdom (P.E.).
⁹ Health Data Research UK London (P.E.).
¹⁰ Department of Medicine, University of Verona, Italy (A.G., C.F.).
¹¹ Department of Clinical Sciences, Clinical Research Centre, Lund University, Malmö, Sweden (A.G., C.F.).
¹² Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center (J.N.H., M.M.S.) Vanderbilt University Medical Center, Nashville, TN.
¹³ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute (T.L.E.), Vanderbilt University Medical Center, Nashville, TN.
¹⁴ Department of Circulation and Medical Imaging, Gemini Center for Sepsis Research, Norwegian University of Science and Technology, Trondheim, Norway (T.R.).
¹⁵ Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT (T.R.).
¹⁶ Clinic of Anaesthesia and Intensive Care (T.R.), St. Olav's Hospital, Trondheim University Hospital, Norway.
¹⁷ Department of Endocrinology, Clinic of Medicine (B.O.Å.), St. Olav's Hospital, Trondheim University Hospital, Norway.
¹⁸ Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (B.O.Å., B.M.B.).
¹⁹ Clinic of Thoracic and Occupational Medicine (B.M.B.), St. Olav's Hospital, Trondheim University Hospital, Norway.
²⁰ Cardiovascular Epidemiology Unit, University of Cambridge, United Kingdom (S.B.).
²¹ Medical Research Council Biostatistics Unit, University of Cambridge, United Kingdom (S.B.).
²² Munich Cluster for Systems Neurology, Germany (M.D.).
²³ German Centre for Neurodegenerative Diseases, Munich, Germany (M.D.).
²⁴ Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, United Kingdom (D.G.).
²⁵ Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, United Kingdom (D.G.).
²⁶ Novo Nordisk Research Centre Oxford, Old Road Campus, United Kingdom (D.G.).

PMID: 33813844
PMCID: PMC8115430
DOI: 10.1161/HYPERTENSIONAHA.120.16534

Abstract

[Figure: see text].

Keywords: blood pressure; coronary artery disease; hypertension; primary prevention; stroke.

PubMed Disclaimer

Figures

**Figure 1.**
**Nonlinear Mendelian randomization considering genetically proxied systolic blood pressure (SBP) and incident cardiovascular outcomes.** Nonlinear Mendelian randomization considering genetically proxied systolic blood pressure (SBP) and incident cardiovascular outcomes: (A) all incident cardiovascular disease (CVD) events, (B) incident coronary artery disease (CAD), and (C) incident stroke. Displayed on the x axis are SBP values in mm Hg. The y axis shows the hazard ratio for the respective incident cardiovascular event. Reference is set to a population mean SBP value of 136.5 mm Hg. Gray lines depict the 95% CI. Fractional polynomial test is a goodness-of-fit test assessing whether any improvement of fit using a nonlinear function to model the data compared with a linear function is greater than expected due to chance alone.

**Figure 2.**
**Nonlinear Mendelian randomization considering genetically proxied diastolic blood pressure (DBP) and incident cardiovascular outcomes.** Nonlinear Mendelian randomization considering genetically proxied diastolic blood pressure (DBP) and incident cardiovascular outcomes: (A) all incident cardiovascular disease (CVD) events, (B) incident coronary artery disease (CAD), and (C) incident stroke. Displayed on the x axis are DBP values in mm Hg. The y axis shows the hazard ratio for the respective incident cardiovascular event. Reference is set to a population mean DBP value of 81.8 mm Hg. Gray lines depict the 95% CI.

**Figure 3.**
**Nonlinear Mendelian randomization considering genetically proxied systolic blood pressure (SBP) and incident cardiovascular outcomes split by sex.** Nonlinear Mendelian randomization considering genetically proxied systolic blood pressure (SBP) and incident cardiovascular outcomes split by sex: (A) all incident cardiovascular disease (CVD) events in men, (B) incident coronary artery disease (CAD) in males, and (C) incident stroke in men. **D–F**, Equivalent analyses in women. Displayed on the x axis are SBP values in mm Hg. The y axis shows the hazard ratio for the respective incident cardiovascular event. Reference is set to a mean SBP value of 136.5 mm Hg. Gray lines depict the 95% CI.

**Figure 4.**
**Nonlinear Mendelian randomization considering genetically proxied diastolic blood pressure (DBP) and incident cardiovascular outcomes split by sex.** Nonlinear Mendelian randomization considering genetically proxied diastolic blood pressure (DBP) and incident cardiovascular outcomes split by sex: (A) all incident cardiovascular disease (CVD) events in men, (B) incident coronary artery disease (CAD) in men, and (C) incident stroke in men. **D–F**, Equivalent analyses in women. Displayed on the x axis are DBP values in mm Hg. The y axis shows the hazard ratio for the respective incident cardiovascular event. Reference is set to a mean DBP value of 81.8 mm Hg. Gray lines depict the 95% CI.

See this image and copyright information in PMC

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Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses

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Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses

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