Almost one year ago, Nate posted here about the results of a large GWA study of chronic kidney disease by Kottgen et al. This project was the result of a collaboration between 4 groups, and produced many exciting results, including the identification of the UMOD gene as being associated with CKD, reviewed here. Since then, these investigators have formed a collaboration with 16 other studies to form the CKDGen consortium, containing data on over 90,000 members of the general population of European ancestry. This past weekend they published the results of their latest GWAS, identifying no less than 13 further novel loci associated with chronic kidney disease, defined as eGFR < 60 ml/min. Of note, an independent consortium published the results of their CKD GWAS on the same day, identifying several of the same genes (ALMS1/NAT8 and SCL7A9). Some very interesting candidate genes emerge from this body of work, so I’ll briefly touch on a few of them here:
- SLC7A9: encodes an amino acid transporter expressed in renal proximal tubule cells, mutations in which cause cystinuria and are associated with cysteine nephrolithiasis.
- SLC34A1: encodes the Na-Pi co-transporter in the proximal tubule, mutations in which cause hypophosphatemic nephrolithiasis.
- ALMS1: Mutations in this gene are associated with renal ciliopathies, as well as the Alstrom syndrome, an autosomal recessive condition characterized by retinal degeneration, hearing loss, obesity, diabetes and renal failure.
- NAT8: This interesting candidate gene is involved in drug metabolism via de-acetylation, suggesting that polymorphisms in it may confer susceptibility to drug-induced nephrotoxicity. Also, there are reported associations between NAT8 polymorphisms and systolic blood pressure and renal function.
- DAB2: an adaptor protein in the proximal tubule which physically links megalin and non-muscle myosin heavy polypeptide 9 (MYH9), a critical susceptibility allele for non-diabetic kidney disease in African Americans, see blog posts here and here.
- VEGFA: Vascular endothelial growth factor A plays a key role in renal angiogenesis and vascular permeability.
The paucity of therapeutic options in Nephrology can lead to a certain diagnostic nihilism, and a large body of patients carry loosely applied clinical diagnoses such as “nephrosclerosis”, and “interstitial renal disease”. Studies such as this shed light on the real underlying causes of such presentations, and hint at an exciting new molecular toxonomy on the horizon.