Figure 1. Schematic presentation of variable clinical courses of diabetic nephropathy. The case and control definitions used in the primary GWAS in Sandholm et al. [9] are indicated by green bold (controls) and red double-lined boxes (cases). GFR, glomerular filtration rate; ESRD, end stage renal disease. Microalbuminuria, urinary albumin excretion rate of 30–300 mg per day; macroalbuminuria, urinary albumin excretion rate of .300 mg per day. *, GFR and albuminuria may progress independently of each other, i.e., patients may have micro- or macroalbuminuria even though their GFR is normal or even slightly elevated. However, macroalbuminuria is usually associated with reduced GFR, and is a strong risk factor for progressive loss of eGFR and ESRD. doi:10.1371/journal.pgen.1002989.g001 ping stages of declining GFR and progres- sive proteinuria [23], finally leading to ESRD, with mortality as a competing risk. However, we have learned that protein- uria is more variable in DN than initially thought. In early stages, regression to normoalbuminuria is frequently observed [24]. Further, severe albuminuria (also termed macroalbuminuria) is not an invariate antecedent for profound kidney damage. Indeed, studies indicate that chronic kidney disease in diabetes may evolve in the absence of considerable References 1. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, et al. (2010) Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 376: 419–430. 2. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, et al. (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358: 2545–2559. 3. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358: 2560–2572. 4. Haller H, Ito S, Izzo JL, Jr., Januszewicz A, Katayama S, et al. (2011) Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 364: 907–917. 5. Reaven PD, Moritz TE, Schwenke DC, Ander- son RJ, Criqui M, et al. (2009) Intensive glucose- lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial partici- proteinuria and progress to ESRD [25], justifying GENIE’s analytic design con- trasting diabetic patients with ESRD to all other diabetic subjects. The present study consists primarily of cross-sectional studies and cannot capture the definitive DN outcome on an individ- ual level. Using the most severe forms of DN to define cases reduces some potential misclassification but definitely does not overcome the critical inaccuracy of case definition not based on histology (many other kidney diseases can cause macroal- pants with lower calcified coronary atherosclero- sis. Diabetes 58: 2642–2648. 6. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2003) Sustained effect of intensive treat- ment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 290: 2159– 2167. 7. Seaquist ER, Goetz FC, Rich S, Barbosa J (1989) Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320: 1161–1165. 8. Bo¨ger C, Heid I (2011) Chronic kidney disease: novel insights from genome wide association studies. Kidney Blood Press Res 34: 27–36. 9. Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, et al. (2012) New susceptibility loci associated with kidney disease in type 1 buminuria and ESRD). Further, the diabetic patient is exposed to many nonspecific kidney-damaging events in the course of disease (e.g., contrast agent imaging, nephrotoxic drugs, prerenal phases in infection and cardiovascular events), which in their sum also contribute to progression to ESRD. Overall, the sum of potential misclassification involved in using an exclusively clinical DN definition in cross-sectional studies reduces statistical power to detect underlying genetic vari- ants. With this meta-analysis of DN in T1D patients, Sandholm et al. have taken an important step towards defining the ge- netic architecture of DN. Strengths of the study include its large sample size, consid- eration of alternative DN phenotypes based on reproducible epidemiological and genetic data reported by other groups studying kidney diseases, and experimental support for the associated loci. Now the challenge will be building on these results. Two consortia, FIND and SUMMIT, should be reporting GWAS results for type 2 DN, and it will be interesting to see if common or unique genetic loci are identified of DN in T1D and T2D patients. Similarities in the clinical pheno- types and treatment responses of patients with T1D and T2D DN suggest a shared pathogenesis. Finally, additional meta- analyses of T1D and T2D DN cohorts with larger sample sizes, application of sequencing technologies, and use of more precise DN phenotypes from longitudinal studies should further define the genetic architecture of this most common cause of chronic kidney disease. These data will provide the foundation needed to advance understanding of diabetic nephropathy and impact patient outcomes. diabetes. PLoS Genet 8: e1002921. doi:10.1371/ journal.pgen.1002921. 10. Veikkolainen V, Naillat F, Railo A, Chi L, Manninen A, et al. (2012) ErbB4 modulates tubular cell polarity and lumen diameter during kidney development. J Am Soc Nephrol 23: 112– 122. 11. Ellis JW, Chen MH, Foster MC, Liu CT, Larson MG, et al. (2012) Validated SNPs for eGFR and their associations with albuminuria. Hum Mol Genet 21: 3293–3298. 12. Placha G, Canani LH, Warram JH, Krolewski AS (2005) Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes. Adv Chronic Kidney Dis 12: 155–169. 13. Bo¨ger C, Chen MH, Tin A, Olden M, Ko¨ttgen A, de Boer, IH, et al (2011) CUBN is a Gene Locus for Albuminuria. J Am Soc Nephrol 22: 555–570. 14. Ko¨ttgen A, Pattaro C, Bo¨ger CA, Fuchsberger C, Olden M, et al. (2010) New loci associated with PLOS Genetics | www.plosgenetics.org 2 September 2012 | Volume 8 | Issue 9 | e1002989