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Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study

The Pharmacogenomics Journal volume 20, pages 462–470 (2020)Cite this article

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Abstract

It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax = 40,914) and DIAGRAM (nmax = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: −0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.

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Fig. 1: Overview of two-sample Mendelian randomization (MR) study on the bidirectional association between statin-induced LDL cholesterol response and type 2 diabetes (T2D).
Fig. 2: Scatterplots of per-allele effects.
Fig. 3: Funnel plots of individual causal effect estimates.

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Acknowledgements

The authors gratefully acknowledge the DIAGRAM consortium for making their GWAS summary data publicly available. In addition, we wish to express our gratitude to all studies participating in the GIST consortium. Full study-specific acknowledgments for the GIST consortium are given in ref. [16].

Funding

JWJ is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). This work is also supported in part by the National Heart, Lung, and Blood Institute grants HL105756 (infrastructure grant for the Cohorts for Heart and Ageing Research in Genetic Epidemiology (CHARGE) consortium, to BMP), GM109145 (to CMS), and GM120523 (to QF).

Author information

Author notes

  1. These authors contributed equally: C. Michael Stein, J. Wouter Jukema

Authors and Affiliations

  1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

    Roelof A. J. Smit, Stella Trompet & J. Wouter Jukema

  2. Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Roelof A. J. Smit, Stella Trompet & Iris Postmus

  3. Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA

    Aaron Leong

  4. Harvard Medical School, Boston, MA, 02115, USA

    Aaron Leong & Daniel I. Chasman

  5. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Mark O. Goodarzi

  6. Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Mark O. Goodarzi

  7. William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK

    Helen Warren & Michael R. Barnes

  8. National Institute for Health Research, Barts Cardiovascular Biomedical Research Center, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK

    Helen Warren & Michael R. Barnes

  9. Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA, 94609, USA

    Elizabeth Theusch & Ronald M. Krauss

  10. Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada

    Benoit J. Arsenault

  11. Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada

    Benoit J. Arsenault

  12. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

    Xiaohui Li & Jerome I. Rotter

  13. Department of Medicine, Vanderbilt University, Nashville, TN, USA

    QiPing Feng & C. Michael Stein

  14. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    QiPing Feng & C. Michael Stein

  15. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, 02215, USA

    Daniel I. Chasman

  16. Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA

    L. Adrienne Cupples

  17. NHLBI Framingham Heart Study, Framingham, MA, 01702, USA

    L. Adrienne Cupples

  18. Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Graham A. Hitman

  19. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, 98101, USA

    Bruce M. Psaty

  20. Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA

    Bruce M. Psaty

  21. The Institute for Translational Genomics and Population Sciences, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

    Jerome I. Rotter

  22. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    Saskia le Cessie

  23. Section of Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

    Saskia le Cessie

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

    J. Wouter Jukema

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Correspondence to Roelof A. J. Smit.

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Conflict of interest

BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. DIC received research support for independent genetic analysis in JUPITER from AstraZeneca. RMK serves on the Merck Global Atherosclerosis Advisory Board. The remaining authors declare no conflict of interest.

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Smit, R.A.J., Trompet, S., Leong, A. et al. Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study. Pharmacogenomics J 20, 462–470 (2020). https://doi.org/10.1038/s41397-019-0125-x

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