There is evidence that susceptibility to diabetic nephropathy has a significant genetic component. This investigation tested the hypothesis that variations in the structural or regulatory regions of the MEP1B gene are related to susceptibility to diabetic nephropathy in the Pima Indian population. The structure of the human MEP1B gene on chromosome 18 was determined by polymerase chain reaction (PCR) amplification. Samples from 154 diabetic individuals were analyzed for polymorphisms. These individuals belonged to 65 sibships with at least one sibling pair discordant for diabetic nephropathy. Approximately half of the individuals had diabetic nephropathy. Of the 154 samples, there were 91 discordant sibling pairs. Sequencing revealed 19 single nucleotide polymorphisms (SNPs) in the MEP1B gene. SNPs 1-5 were in the 5' region upstream of the start site for transcription; SNPs 6, 7, 9, 11-15, 17, and 19 were within introns; SNPs 8, 10, 16, and 18 were in exons 4, 9, 12, and 14. SNP 18 was the only one that results in an amino acid change (proline to leucine in the cytoplasmic tail). No overall associations were found for individual SNPs. Within-family association tests found significant results for SNPs 1, 3, 4, 5, 6, 9, 11, 18, and 19 such that the more common allele was more frequently observed in those with nephropathy than in their unaffected siblings. The present study demonstrates significant within-family association for SNPs in MEP1B gene with diabetic nephropathy. These results could be explained by functional effects of one or more of these SNPs or by linkage disequilibrium with a nearby functional locus.