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The genetics of common kidney disease: a pathway toward clinical relevance

Abstract

Genome-wide association studies (GWASs) have advanced our understanding of the genetic basis for common renal diseases, including chronic kidney disease (CKD) and related traits such as hypertension. The 'common variant, common disease' hypothesis—the theoretical basis for gene mapping by GWASs—has, however, underestimated the complexity of the genetic architecture underlying these diseases. The disease-specific variants identified by GWASs, despite being supported by statistically robust associations, often fail to illuminate the biology underlying the association and explain only a small portion of the estimated heritability of these diseases, even in aggregate. Although these variants have highlighted novel pathways that can be targeted therapeutically, their small effect sizes have minimal effects on diagnosis, prognosis, and management of individual patients. At present, therefore, the data do not support the routine use of genetic testing in the management of patients with CKD. Advances in technology, such as massively parallel gene sequencing, and characterization of alternative modes of inheritance should further elucidate the genetic architecture of CKD and provide tools to improve patient care.

Key Points

  • The genetic architecture of common kidney diseases is more complex than is proposed by the 'common disease, common variant' hypothesis

  • Numerous genetic markers are associated with common kidney diseases and related traits, but such markers explain only a small percentage of these diseases' estimated heritability

  • MYH9 and APOL1 variants account for a large fraction of the excess prevalence of nondiabetic kidney diseases in African American patients

  • Addition of genetic markers to clinical models has not yet improved disease diagnosis or prediction

  • Data from pharmacogenomic studies might identify gene variants that can be targeted in personalized drug therapy

  • Novel techniques, including sequencing, will help to define the genetic architecture responsible for common diseases, including chronic kidney disease

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Figure 1: Influence of SLC12A3, SLC12A1 and KCNJ1 functional coding sequence variants on blood pressure.
Figure 2: The relationship between APOL1 and MYH9 genetic variants associated with common forms of kidney disease.
Figure 3: Hypothetical net reclassification improvement calculation.

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Drawz, P., Sedor, J. The genetics of common kidney disease: a pathway toward clinical relevance. Nat Rev Nephrol 7, 458–468 (2011). https://doi.org/10.1038/nrneph.2011.85

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