Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes

Proteinuria and impaired kidney function are 2 major traits of diabetic nephropathy that aggregate (are heritable) in families of diabetic individuals. Although both traits are heritable, they are not genetically correlated. These findings not only support the hypothesis that the development of diabetic nephropathy consists of 2 distinct disease processes (ie, increasing proteinuria and declining kidney function) but also strongly justify searches for the putative genes that separately determine variation in these processes. These searches have used both genome-wide scans and candidate-gene approaches. By use of genome-scan approaches, several research groups have identified genetic regions on chromosomes 7q, 18q, and 22q that harbor genes that determine either variation in urinary albumin excretion or susceptibility to proteinuria in families who have type 2 diabetes. The evidence for linkage in these 3 genetic regions was suggestive or strong, but, except for 7q, the regions did not overlap across studies. Two genome scans performed in families who have type 2 diabetes identified genetic regions on chromosome 3q, 6q, 7p, and 18q that harbor susceptibility genes that determine variation in glomerular filtration rate or susceptibility to the development of end-stage renal disease (ESRD). The region on 7p overlapped in both studies. Optimism is growing that a positional cloning approach applied to these putative genetic regions will lead to the isolation of the susceptibility genes for proteinuria and ESRD. Meanwhile, significant efforts that make use of the candidate-gene approach have been directed to the search for susceptibility genes for diabetic nephropathy. Unfortunately, positive findings have not been consistent.