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

Abstract

OBJECTIVE -We investigated the contribution of PKC-␤ gene (PRKCB1) polymorphisms to diabetic kidney disease in a prospective observational follow-up study.RESEARCH DESIGN AND METHODS -A total of 364 Japanese subjects with type 2 diabetes without overt proteinuria were enrolled during 1996 -1998 and followed until 2004. Five single nucleotide polymorphisms (Ϫ1504C/T, Ϫ546C/G, Ϫ348A/G, Ϫ278C/T, and Ϫ238C/G) in the promoter region of PRKCB1 were genotyped. The end points were transition from stage to stage of diabetic nephropathy as a time-to-event outcome and the annual decline rate of estimated glomerular filtration rate (eGFR) as a slope-based outcome.RESULTS -During the study (median 6 years), 34 of 364 subjects (9.3%) progressed. Kaplan-Meier estimation revealed that subjects with both T allele at Ϫ1054 C/T and G allele at Ϫ546 C/G polymorphisms frequently showed transition to advanced stages of diabetic nephropathy (P ϭ 0.015). The annual change rate in eGFR in the subjects with both alleles was also significantly higher than in others (Ϫ2.96 Ϯ 0.62 vs. Ϫ1.63 Ϯ 0.15 ml/min per 1.73 m 2 /year, P ϭ 0.02). The estimated frequency of this risk T-G haplotype was significantly higher in the progressors who showed transition to advanced nephropathy stages (12%) than in the nonprogressors (5%) (odds ratio 2.3 [95% CI 1.0 -5.2]), and it was also higher in those with accelerated decline of the ⌬ eGFR (Ն3 ml/min per 1.73 m 2 /year) than in those without (2.1 [1.1-3.9]).CONCLUSIONS -Our study indicates that PRKCB1 is a predictor for worsening of kidney disease in Japanese subjects with type 2 diabetes. Diabetes Care 29:864 -868, 2006D iabetic nephropathy associated with type 2 diabetes is a leading cause of end-stage renal disease. While clinical studies clearly show that prolonged hyperglycemia is an important risk factor for this microvascular complication (1,2), epidemiological and familial studies (3-6) suggest that genetic susceptibility also plays a pivotal role.An abnormal activation of protein kinase C (PKC)-␤ under diabetic condition is proposed as a putative mechanism in the pathogenesis of diabetic nephropathy (7). 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. 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 i...

The Clinical Characteristics of Normoalbuminuric Renal Insufficiency in Korean Type 2 Diabetic Patients: A Possible Early Stage Renal Complication

“…Interestingly, genetic susceptibility might play a role in the development of normoalbuminuric renal insufficiency. It has been reported that polymorphisms of the protein kinase C-β gene (PRKCB1) were associated with diabetic nephropathy that did not lead to albuminuria in Japanese patients (28). …”

Genetic Variants of the Protein Kinase C-β 1 Gene and Development of End-Stage Renal Disease in Patients With Type 2 Diabetes

“…Also, SNPs with r 2 Ն 0.80 are considered redundant because 80% of their information overlaps, so selecting just 1 of them would be more cost-effective. In addition, we selected 6 SNPs (rs3760106, rs2575390, rs3900007, rs3900008, rs432998, and rs3729904) with suggestive evidence of association from previous studies, 23,24 so a total of 18 SNPs were genotyped in all study participants in 2009 using genomic DNA.…”

“…Patients with type 1 diabetes carrying 2 single-nucleotide polymorphisms (SNPs) in the promoter region of PRKCB1 had increased risk of nephropathy, 23 while Japanese patients with type 2 diabetes carrying these variants had increased risk of deterioration in renal function. 24 Given the increasing recognition of interethnic differences in both distribution and frequency of SNPs for the same gene, 1,25 as well as the high risk for DKD in the Chinese population, 26 we used the HapMap database specific to the Han Chinese population (CHB) to examine the gene structure in Chinese individuals and examined whether polymorphisms in PRKCB1 are associated with risk of new-onset ESRD in a large prospective cohort of Chinese patients with type 2 diabetes.…”

Predictive impact of elevated serum level of IL-18 for early renal dysfunction in type 2 diabetes: an observational follow-up study

“…Subjects and examination A total of 249 Japanese type 2 diabetic patients without overt proteinuria were recruited from individuals who regularly visited the outpatient clinic of the Department of Medicine at Shiga University of Medical Science during 1996-1998, as reported previously [13]. Briefly, in the initial 2 years (baseline period) patients clinically diagnosed as having type 2 diabetes according to the WHO criteria [14] provided multiple 24-h urine samples for assessment of urinary AER and eGFR.…”