A family-based strategy to identify genes for diabetic nephropathy

Diabetic nephropathy (DN) clusters in families and specific ethnic groups, suggesting a genetic basis of disease transmission. Identification of DN su sceptibility loci should reveal new therapeutic targets but requires accura te phenotyping. A powerful family-based strategy, which is novel to the pur suit of nephropathy genes in type 2 diabetes, is being used to collect a sa mple for candidate gene and genome scan analyses. Sib pairs that include DN index cases plus (1) sibs concordant for type 2 diabetes and DN (affected sib pairs [ASPs]) and (2) sibs concordant for type 2 diabetes but discordan t for DN (discordant sib pairs [DSPs]) are targeted specifically for recrui tment. Type 2 diabetes and DN phenotype criteria for index cases include di abetes onset after 38 years of age, duration 10 years or longer, no initial Insulin treatment, diabetic retinopathy, end-stage renal disease (ESRD), a nd history of nephrotic proteinuria. ESRD patients were screened by questio nnaire and medical record review (n = 2114). Of 666 patients with ESRD seco ndary to DN, 227 had a family history of ESRD, 150 had a living diabetic si b, and 124 families were enrolled. Sixty-five families, with 86 diabetic re lative pairs (69 sibs, 17 children), have been completely phenotyped. If ne phropathy in diabetic sibs is defined as albuminuria greater than 0.3 g/24 h, 31 ASPs end 26 DSPs (diabetic sib with albuminuria <0.3 g/24 h) were ide ntified. Applying more stringent criteria, only 12 ASPs (sib with diabetes >10 years, diabetic retinopathy, and nephrotic proteinuria) and 9 DSPs (sib with diabetes >10 years and normal urine albumin excretion) were identifie d. Extrapolating from the number of subjects recruited using stringent phen otyping criteria, nearly 10,000 ESRD patients are required for screening to achieve adequate statistical power for linkage analysis (80% power to dete ct locus-specific relative risk of 2.2 at a lod score of 3.0). Careful phen otyping requires a large recruitment effort but is necessary to reduce popu lation heterogeneity, a strategy that increases the likelihood of identifyi ng DN loci. (C) 2001 by the National Kidney Foundation, Inc.