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Open Access 01-06-2017 | Review

Human genetics as a model for target validation: finding new therapies for diabetes

Authors: Soren K. Thomsen, Anna L. Gloyn

Published in: Diabetologia | Issue 6/2017

Abstract

Type 2 diabetes is a global epidemic with major effects on healthcare expenditure and quality of life. Currently available treatments are inadequate for the prevention of comorbidities, yet progress towards new therapies remains slow. A major barrier is the insufficiency of traditional preclinical models for predicting drug efficacy and safety. Human genetics offers a complementary model to assess causal mechanisms for target validation. Genetic perturbations are ‘experiments of nature’ that provide a uniquely relevant window into the long-term effects of modulating specific targets. Here, we show that genetic discoveries over the past decades have accurately predicted (now known) therapeutic mechanisms for type 2 diabetes. These findings highlight the potential for use of human genetic variation for prospective target validation, and establish a framework for future applications. Studies into rare, monogenic forms of diabetes have also provided proof-of-principle for precision medicine, and the applicability of this paradigm to complex disease is discussed. Finally, we highlight some of the limitations that are relevant to the use of genome-wide association studies (GWAS) in the search for new therapies for diabetes. A key outstanding challenge is the translation of GWAS signals into disease biology and we outline possible solutions for tackling this experimental bottleneck.

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Title: Human genetics as a model for target validation: finding new therapies for diabetes
Authors: Soren K. Thomsen
Anna L. Gloyn
Publication date: 01-06-2017
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 6/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-017-4270-y

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