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- W3080477490 endingPage "453" @default.
- W3080477490 startingPage "435" @default.
- W3080477490 abstract "Drug development in cardiovascular disease is stagnating, with lack of efficacy and adverse effects being barriers to innovation. Human genetics can provide compelling evidence of causation through approaches such as Mendelian randomization, with genetic support for causation increasing the probability of a clinical trial succeeding. Mendelian randomization applied to quantitative traits can identify risk factors for disease that are both causal and amenable to therapeutic modification. However, important differences exist between genetic investigations of a biomarker (such as HDL cholesterol) and a drug target aimed at modifying the same biomarker of interest (such as cholesteryl ester transfer protein), with implications for the methodology, interpretation and application of Mendelian randomization to drug development. Differences include the comparative nature of the genetic architecture - that is, biomarkers are typically polygenic, whereas protein drug targets are influenced by either cis-acting or trans-acting genetic variants - and the potential for drug targets to show disease associations that might differ from those of the biomarker that they are intended to modify (target-mediated pleiotropy). In this Review, we compare and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits. We explain how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials." @default.
- W3080477490 created "2020-09-01" @default.
- W3080477490 creator A5013184354 @default.
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- W3080477490 creator A5047938778 @default.
- W3080477490 creator A5061002857 @default.
- W3080477490 creator A5079897358 @default.
- W3080477490 date "2021-03-11" @default.
- W3080477490 modified "2023-10-03" @default.
- W3080477490 title "Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development" @default.
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