Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-β1 (PRKCB1) gene locus

Abnormal activation of protein kinase C-beta isoforms in the diabetic state has been implicated in the development of diabetic nephropathy. It is thus plausible that DNA sequence differences in the protein kinase C-beta1 gene (PRKCB1), which encodes both 01 and 011 isoforms, may influence susceptibility to nephropathy. Nine single-nucleotide polymorphisms (SNP) in PRKCB1 were tested for association with diabetic nephropathy in type I diabetes mellitus, by using both case-control and family-study designs. Allele and genotype distributions of two SNP in the promoter (-1504C/T and -546C/G) differed significantly between case patients and control patients (P < 0.05). These associations were particularly strong with diabetes mellitus duration of <24 yr (P = 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the -1504C/T SNP, compared with noricarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the -546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of greater than or equal to24 yr, these two SNP were not associated with diabetic nephropathy. These positive findings were confirmed by using the family-based transmission disequilibrium test. The T-G haplotype, with both risk alleles, was transmitted more frequently than expected from heterozygous parents to offspring who developed diabetic nephropathy during the first 24 yr of diabetes mellitus. It is concluded that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type I diabetes mellitus.