Human Genetics and Drug Development
Abstract
Current tools in the field of human genetics can reliably estimate both the intended and the adverse effects of modifying a therapeutic target to guide the clinical development of medicines.1 The distinction between an adverse effect of a drug that is target-mediated, and thus a characteristic of all drugs in the same class, and an adverse effect that is off-target, affecting typically an individual drug (rather than a drug class), is critical to decision making in drug development. Although relevant studies of human genetics cannot characterize off-target effects (), extrapolations may be feasible in certain limited circumstances. For example, . . .
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Using genetic variants associated with higher BMI as instruments in an individual-level Mendelian randomization study, higher BMI increased hospital costs with little evidence for non-linearity in this effect.
“Using genetic variants associated with higher BMI as instruments in an individual-level MR study to estimate the effect of BMI on hospitalization costs,147 the authors found that higher BMI increased hospital costs with little evidence for non-linearity in this effect.”
From Mendelian randomization (2022) · cites this paper as [147]
Multiple trials of drugs targeting LDL-C lowering show cardiovascular benefit.
“Multiple trials of drugs targeting LDL- C lowering show cardiovascular benefit 39,116”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [116]
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Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1707914 · Cited by 9,482 · see citing works
Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians
Davies, N. M., Holmes, M. V., & Davey Smith, G. (2018) · BMJ · doi:10.1136/bmj.k601 · Cited by 4,404 · see citing works
Self-citationEffects of torcetrapib in patients at high risk for coronary events
Barter, P. J., Caulfield, M., Eriksson, M., Grundy, S. M., Kastelein, J. J. P., Komajda, M., Lopez-Sendon, J., Mosca, L., Tardif, J.-C., Waters, D. D., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa0706628 · Cited by 3,139 · see citing works
(2012) · The Lancet · doi:10.1016/s0140-6736(12)60110-x · Cited by 1,146 · see citing works
Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol
Ray, K. K., Bays, H. E., Catapano, A. L., Lalwani, N. D., Bloedon, L. T., Sterling, L. R., Robinson, P. L., & Ballantyne, C. M. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1803917 · Cited by 807 · see citing works
Mendelian randomization in cardiometabolic disease: challenges in evaluating causality
Holmes, M. V., Ala-Korpela, M., & Smith, G. D. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.78 · Cited by 679 · see citing works
Self-citationPinkosky, S. L., Newton, R. S., Day, E. A., Ford, R. J., Lhotak, S., Austin, R. C., Birch, C. M., Smith, B. K., Filippov, S., Groot, P. H. E., et al. (2016) · Nature Communications · doi:10.1038/ncomms13457 · Cited by 498 · see citing works
Mendelian Randomization Study of ACLY and Cardiovascular Disease
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Secretory Phospholipase A2-IIA and Cardiovascular Disease
Holmes, M. V., Simon, T., Exeter, H. J., Folkersen, L., Asselbergs, F. W., Guardiola, M., Cooper, J. A., Palmen, J., Hubacek, J. A., Carruthers, K. F., et al. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.06.044 · Cited by 119 · see citing works
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Sanderson, E., Glymour, M. M., Holmes, M. V., Kang, H., Morrison, J., Munafò, M. R., Palmer, T., Schooling, C. M., Wallace, C., Zhao, Q., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-021-00092-5 · Cited by 2,229 · see citing works
Self-citationRichardson, T. G., Sanderson, E., Palmer, T. M., Ala-Korpela, M., Ference, B. A., Davey Smith, G., & Holmes, M. V. (2020) · PLOS Medicine · doi:10.1371/journal.pmed.1003062 · Cited by 843 · see citing works
Self-citationUsing Mendelian Randomization to Improve the Design of Randomized Trials
Ference, B. A., Holmes, M. V., & Smith, G. D. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a040980 · Cited by 338 · see citing works
Self-citationHolmes, M. V., Richardson, T. G., Ference, B. A., Davies, N. M., & Davey Smith, G. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00493-1 · Cited by 184 · see citing works
Self-citationBovijn, J., Krebs, K., Chen, C.-Y., Boxall, R., Censin, J. C., Ferreira, T., Pulit, S. L., Glastonbury, C. A., Laber, S., Millwood, I. Y., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay6570 · Cited by 119 · see citing works
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- Authors
- Holmes, M. V.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Holmes, Michael V.
- ORCID
- Holmes, Michael V.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-03-14
- Volume
- 380
- Issue
- 11
- Pages
- 1076-1079
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2922489701
- Cited by
- 28
- References
- 10
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 9 · 2019: 3
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- British Heart Foundation (FS/18/23/33512)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- human genetics, drug development, pharmacogenomics, adverse drug reactions, off-target effects, drug target modification
- MeSH terms
- Human Genetics, Drug Development, Dicarboxylic Acids, Fatty Acids, Humans, Cholesterol, LDL
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