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  • Review Article
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The genetics of diabetic complications

Nature Reviews Nephrology volume 11, pages 277–287 (2015)Cite this article

Subjects

Key Points

  • The majority of the morbidity and mortality associated with diabetes mellitus is due to complications, such as diabetic kidney disease

  • A limited understanding of the underlying mechanisms responsible for the development of diabetic complications compromises efforts to develop novel strategies for treatment and prevention

  • Studies of human genetics offer powerful tools for delivering robust mechanistic insights into complex traits, such as diabetic complications, which have a substantial genetic component

  • Scientific progress to date has been limited by small sample sizes and/or phenotypic imprecision; however, several major discovery efforts are underway that have been designed to address these issues

  • The identification of genetic variants with robust effects on the risk of developing diabetic complications will accelerate efforts to develop more effective strategies for treatment and prevention

Abstract

The rising global prevalence of diabetes mellitus is accompanied by an increasing burden of morbidity and mortality that is attributable to the complications of chronic hyperglycaemia. These complications include blindness, renal failure and cardiovascular disease. Current therapeutic options for chronic hyperglycaemia reduce, but do not eradicate, the risk of these complications. Success in defining new preventative and therapeutic strategies hinges on an improved understanding of the molecular processes involved in the development of these complications. This Review explores the role of human genetics in delivering such insights, and describes progress in characterizing the sequence variants that influence individual predisposition to diabetic kidney disease, retinopathy, neuropathy and accelerated cardiovascular disease. Numerous risk variants for microvascular complications of diabetes have been reported, but very few have shown robust replication. Furthermore, only limited evidence exists of a difference in the repertoire of risk variants influencing macrovascular disease between those with and those without diabetes. Here, we outline the challenges associated with the genetic analysis of diabetic complications and highlight ongoing efforts to deliver biological insights that can drive translational benefits.

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Figure 1: Schematic of the workflow of genome-wide association studies.
Figure 2: GWAS sample sizes and locus discovery rates for complex traits.
Figure 3: Regional association plot of the correlation of SNPs in the 9p21.3 region with T2DM and CAD.
Figure 4: Schematic of future directions for characterizing genetic associations with complications of diabetes.

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Authors and Affiliations

  1. Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Entrance 72, University Hospital in Malmö, Lund University, Malmö, 205 02, Sweden

    Emma Ahlqvist & Leif C. Groop

  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Natalie R. van Zuydam

  3. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, OX3 7LJ, Oxford, UK

    Mark I. McCarthy

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  1. Emma Ahlqvist
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  2. Natalie R. van Zuydam
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  3. Leif C. Groop
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  4. Mark I. McCarthy
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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article, and undertook review and/or editing of the manuscript before submission.

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Correspondence to Mark I. McCarthy.

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Competing interests

E.A. and N.R.V.Z. have received salary support, and L.C.G. and M.I.M, have received research support, from the Innovative Medicines Initiative and the Juvenile Diabetes Research Foundation for research on the genetic basis of diabetic complications.

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Ahlqvist, E., van Zuydam, N., Groop, L. et al. The genetics of diabetic complications. Nat Rev Nephrol 11, 277–287 (2015). https://doi.org/10.1038/nrneph.2015.37

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