The Challenging Search for Diabetic Nephropathy Genes

It is widely appreciated that macroand microvascular complications, rather than hyperglycemia per se, are major contributors to morbidity and mortality in diabetes. In this issue of Diabetes, Williams et al. (1) report the results of a meta-analysis of genetic data from three moderately sized studies of patients with type 1 diabetes (T1D) and nephropathy. This report illustrates several challenges inherent in the genetic analysis of diabetes complications and is another step toward understanding the genetic basis of risk for diabetic nephropathy (DN). Insights into the genetics of DN will potentially lead to improved prediction of DN and novel approaches to prevent this serious complication of diabetes. There is compelling evidence in support of a major genetic component for diabetes complications, especially DN. Efforts to identify genes contributing to T1D and type 2 diabetes (T2D) have been highly successful, but with few exceptions, there is little evidence that diabetes-associated variants associate with complications. Thus, diabetes complications appear to have an independent genetic basis. The profound public health impact of DN has motivated the performance of multiple genetic studies. However, these studies are complicated by issues of disease origin (T1D or T2D), ethnicity (European and European American, African American, Hispanic, Asian), competing cardiovascular risk, and variable diagnostic criteria (glomerular filtration rate and albuminuria in mildly affected individuals, variable severity of chronic kidney disease or end-stage renal disease [ESRD] requiring renal replacement therapy). Consequently, existing genetic association studies of DN have included a mosaic of diabetes type, ethnic groups, and phenotypes. These methodological dissimilarities are complicated further by different technical approaches ranging from targeted studies of individual genes to various platforms for genome-wide analysis. Williams et al. (1) combined genetic data from three T1D cohorts: the U.K.-R.O.I., FinnDiane, and U.S. GoKinD studies, all of which contain participants of European ancestry. Important strengths of these combined studies include large (for DN studies) sample sizes of 3,162 T1D nephropathy (T1DN) case subjects and 3,845 control subjects, as well as focused efforts to harmonize phenotypes across studies. Genes with evidence of DN association from several recent studies and loci associated in an informatics-based meta-analysis of published DN genetics studies were targeted (2). With this approach, the authors note that they had sufficient power to detect evidence of association with P values in the range of 0.001. This research design (targeting specific genes) circumvents the power issues that make it difficult to identify significant associations using genome-wide approaches. In addition to evaluating specific single nucleotide polymorphisms (SNPs) from the primary literature, in some cases, such as the ELMO1 gene, the investigators also performed “locuswide” analysis to assess whether other SNPs near the index SNP were associated. Each approach was pursued with rigorous testing for statistical significance. Unfortunately, compelling evidence of association was not observed for any loci. One possible exception was a promoter variation in the erythropoietin gene (EPO). A single SNP was strongly associated with T1DN (combined with proliferative retinopathy) in a prior report that included the GoKinD samples (3). While evidence of association was not observed in U.K.-R.O.I. or FinnDiane, the P value for association remained strong in a combined analysis with GoKinD. Consistent with their rigorous standards, the authors felt this reflected limited evidence of association. A similar outcome was observed with other SNPs such as in FRMD3: strong association in U.S. GoKinD, but no association in other samples. Working primarily from the results of the meta-analysis of Mooyaart et al. (2) may have introduced limitations. Mooyaart et al. evaluated a diverse set of studies with varying participant numbers, ethnicities, and disease definitions. This approach may minimize evidence of association in a specific ethnic group or genes associated with a discrete phenotype. In addition, several recent manuscripts identified additional loci in better powered genome-wide association studies (GWASs) of diabetic ESRD in African Americans (4) and quantitative measures of kidney function in European-derived samples (5). It will be interesting to see whether variants from these reports are associated in this T1DN sample. Another challenge of the study presented by Williams et al. is that it addresses only one element in the mosaic of DN: T1DN in European-derived populations defined by ESRD. Realistically, this is the only practical approach, but this study consequently reflects most directly on variants that have been identified using this study design. As noted, researchers have investigated DN in various populations and with differing definitions of DN (e.g., albuminuria, chronic kidney disease, or ESRD). For example, the association between ELMO1 was initially observed in a GWAS of Japanese T2D-associated nephropathy (T2DN) (6) and, as the authors note, followed up in a study of African American T2DN (7) and then European American T1DN (8), the latter study in GoKinD itself. These contrasts are representative of the many issues that remain unresolved in DN genetics. In a background of largely negative comparisons, there are hints that some variants are associated with From the Department of Biochemistry, Centers for Diabetes Research and Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Wake Forest University, Winston-Salem, North Carolina; and the Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Wake Forest University, Winston-Salem, North Carolina. Corresponding author: Donald W. Bowden, [email protected]. DOI: 10.2337/db12-0596 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 2187.