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Classical risk factors for primary coronary artery disease from an aging perspective through Mendelian Randomization

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Abstract

The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis < 50 years; OR 1.02 diagnosis > 70 years), blood pressure (OR 1.12 < 50 years; OR 1.04 > 70 years), LDL cholesterol (OR 1.16 < 50 years; OR 1.02 > 70 years), and triglyceride levels (OR 1.11 < 50 years; 1.04 > 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age.

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Data availability

Data of the UK Biobank is available upon acceptance of a research proposal submitted to UK Biobank Resources (https://www.ukbiobank.ac.uk/).

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Acknowledgements

This research was conducted using the UK Biobank study under Application Number 56340.

Funding

This work was supported by an innovation grant from the Dutch Heart Foundation (grant number 2019T103 to R.N.).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands

    Swetta A. Jansen, Stella Trompet, Simon P. Mooijaart, Diana van Heemst & Raymond Noordam

  2. Data Science Lab, Amsterdam, the Netherlands

    Swetta A. Jansen & Bas Huiskens

  3. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

    JWouter Jukema

  4. Netherlands Heart Institute, Utrecht, the Netherlands

    JWouter Jukema

  5. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

    Ko Willems van Dijk

  6. Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands

    Ko Willems van Dijk

  7. Leiden Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Ko Willems van Dijk

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  1. Swetta A. Jansen
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  2. Bas Huiskens
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Contributions

Study design: SAJ, BH, DvH, RN. Data acquisition: RN. Data interpretation: SAJ, BH, JWJ, ST, SPM, KWvD, DvH, RN. Drafting the manuscript: SAJ, RN. Critical comments on the manuscript: all authors. Final approval of the manuscript: RN. Guarantator of the study: RN.

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Correspondence to Raymond Noordam.

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Jansen, S.A., Huiskens, B., Trompet, S. et al. Classical risk factors for primary coronary artery disease from an aging perspective through Mendelian Randomization. GeroScience 44, 1703–1713 (2022). https://doi.org/10.1007/s11357-021-00498-9

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