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Using human genetics to improve safety assessment of therapeutics

Abstract

Human genetics research has discovered thousands of proteins associated with complex and rare diseases. Genome-wide association studies (GWAS) and studies of Mendelian disease have resulted in an increased understanding of the role of gene function and regulation in human conditions. Although the application of human genetics has been explored primarily as a method to identify potential drug targets and support their relevance to disease in humans, there is increasing interest in using genetic data to identify potential safety liabilities of modulating a given target. Human genetic variants can be used as a model to anticipate the effect of lifelong modulation of therapeutic targets and identify the potential risk for on-target adverse events. This approach is particularly useful for non-clinical safety evaluation of novel therapeutics that lack pharmacologically relevant animal models and can contribute to the intrinsic safety profile of a drug target. This Review illustrates applications of human genetics to safety studies during drug discovery and development, including assessing the potential for on- and off-target associated adverse events, carcinogenicity risk assessment, and guiding translational safety study designs and monitoring strategies. A summary of available human genetic resources and recommended best practices is provided. The challenges and future perspectives of translating human genetic information to identify risks for potential drug effects in preclinical and clinical development are discussed.

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Fig. 1: Overview of the applications of human genetics to drug safety.
Fig. 2: Population genetics methods overview.
Fig. 3: Proposed framework for incorporating human germline genetics in target safety reviews.

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The authors contributed equally to all aspects of the article.

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A.M.D., L.D.W., M.F. and J.Y. are former employees of Amgen. K.J.C. and P.N. are employees of AstraZeneca. A.D.R.E. is a former employee of Novartis Institutes for BioMedical Research and is currently employed by GentiBio, Inc. J.M. is an employee of Novartis Institutes for BioMedical Research. D.D. is an employee of Takeda Development Center America. D.A.K. is an employee of GlaxoSmithKline. M.R.N. is an employee of Deerfield Management Company, L.P. F.D.S. is a former employee and currently a part-time contractor of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenliworth, NJ, USA. A.M.D. and L.D.W. are employees and stockholders of Alnylam Pharmaceuticals. J.Y. is an employee of Pfizer.

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Glossary

Genome-wide association studies

Studies of phenotypes performed by testing correlation of genotyped markers with a phenotype in a large population of unrelated individuals. Results are usually relatively common coding or noncoding variants associated with relatively weak effects on the phenotype.

Mendelian disease

A typically rare disease caused by variants in a single gene. Studies of family members with these diseases usually uncover relatively rare variants with high penetrance.

Phenome-wide association study

A study of a genetic variant performed by testing the correlation of the variant with many phenotypes, typically all of the phenotypes available in a biobank or electronic medical system.

Expression quantitative trait loci

Variants, typically common and noncoding, whose genotype correlates with expression of a gene, usually nearby, in a given tissue or cell type.

Endogamous populations

Populations in which reproduction is restricted to relatively small social groups or extended families, resulting in a higher degree of consanguinity between partners and a higher incidence of homozygosity of alleles.

Gene constraint

Reduced nucleotide diversity in the coding sequence of a gene resulting from negative selection on deleterious variants.

Haploinsufficient genes

Genes in which heterozygous loss of function causes a phenotypic change; that is, the remaining (haploid) functional copy is insufficient to maintain the wild-type phenotype.

QT prolongation

A delay in ventricular repolarization during the cardiac cycle, visible by electrocardiography and a common drug-induced adverse event.

PROTACs

Heterobifunctional small molecules composed of two ligand binding moieties connected via a linker. One moiety binds to the target protein, while the second moiety engages with cell E3 ubiquitin ligase complexes to induce proteolysis of the target protein.

Seed hybridization

Interaction of a short sequence at the 5′ end of a micro RNA (miRNA) or a small interfering RNA (siRNA) with the 3′ untranslated region of a mRNA, resulting in targeted degradation. Although this is the natural behaviour of endogenous miRNA, it can be an unintentional off-target activity of exogenous siRNA therapeutics.

Cancer driver genes

The genes in a tumour in which somatic mutations have been positively selected, facilitating tumour growth.

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Carss, K.J., Deaton, A.M., Del Rio-Espinola, A. et al. Using human genetics to improve safety assessment of therapeutics. Nat Rev Drug Discov 22, 145–162 (2023). https://doi.org/10.1038/s41573-022-00561-w

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