Identification of a Common Risk Haplotype for Diabetic Nephropathy at the Protein Kinase C-β1 (PRKCB1) Gene Locus

Abstract

Abstract. Abnormal activation of protein kinase C-␤ 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-␤1 gene (PRKCB1), which encodes both ␤I and ␤II 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 (Ϫ1504C/T and Ϫ546C/G) differed significantly between case patients and control patients (P Ͻ 0.05). These associations were particularly strong with diabetes mellitus duration of Ͻ24 yr (P ϭ 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the Ϫ1504C/T SNP, compared with noncarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the Ϫ546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of Ն24 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.

Polymorphisms of the Protein Kinase C-β Gene (PRKCB1) Accelerate Kidney Disease in Type 2 Diabetes Without Overt Proteinuria

“…In our previous study (8), a T-G haplotype consisting of two single nucleotide polymorphisms (Ϫ1504C/T and Ϫ546C/G) in the promoter region was associated with twofold increased risk of diabetic nephropathy. Although our report provided the first evidence that the PRKCB1 polymorphisms may contribute to genetic susceptibility to diabetic nephropathy (8), several questions remain unclear: whether this relevance extrapolates to type 2 diabetic subjects, whether the risk haplotype is associated with early diabetic nephropathy, and whether this risk haplotype of PRKCB1 influences kidney function. Therefore, in the present study, we investigated the effect of the risk haplotype of PRKCB1 on diabetic nephropathy by assessing two renal outcomes: transition from any given stage to the more advanced stage of diabetic nephropathy defined by albumin excretion rate (AER) as a time-to-event outcome and kidney function defined by the annual decline rate of estimated glomerular filtration rate (eGFR) as a slope-based outcome.…”

“…Fragments containing the five polymorphic sites in the promoter region of PRKCB1 (Ϫ1504C/T, Ϫ546C/G, Ϫ348A/G, Ϫ278C/T, and Ϫ238C/G) were amplified by the PCR method according to a previously described method (8). Genotyping for all polymorphisms was performed by hybridization with allele-specific oligonucleotide probes (14).…”

“…Thus, the gene (PRKCB1) encoding this protein is considered to be a candidate gene for susceptibility to diabetic nephropathy. Recently, we first reported the association between the PRKCB1 polymorphisms and diabetic nephropathy in type 1 diabetic patients by using two independent methods, a case-control study and a familybased study (8). In our previous study (8), a T-G haplotype consisting of two single nucleotide polymorphisms (Ϫ1504C/T and Ϫ546C/G) in the promoter region was associated with twofold increased risk of diabetic nephropathy.…”

“…Recently, we first reported the association between the PRKCB1 polymorphisms and diabetic nephropathy in type 1 diabetic patients by using two independent methods, a case-control study and a familybased study (8). In our previous study (8), a T-G haplotype consisting of two single nucleotide polymorphisms (Ϫ1504C/T and Ϫ546C/G) in the promoter region was associated with twofold increased risk of diabetic nephropathy. Although our report provided the first evidence that the PRKCB1 polymorphisms may contribute to genetic susceptibility to diabetic nephropathy (8), several questions remain unclear: whether this relevance extrapolates to type 2 diabetic subjects, whether the risk haplotype is associated with early diabetic nephropathy, and whether this risk haplotype of PRKCB1 influences kidney function.…”

Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism

“…Mice in which the PRKCB gene was disrupted showed an immunodeficiency. 70 In this context, it is noteworthy that Araki et al 71 recently reported a PRKCB1 association with diabetic nephropathy in type 1 diabetics, a clear autoimmune disease. These findings might link the PRKCB1 gene to both some of the learning inabilities and the immune alterations sometimes seen in autism.…”