Polymorphisms of the protein kinase C-beta gene (PRKCB1) accelerate kidney disease in type 2 diabetes without overt proteinuria.
OBJECTIVE
We investigated the contribution of PKC-beta gene (PRKCB1) polymorphisms to diabetic kidney disease in a prospective observational follow-up study.


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 (-1504C/T, -546C/G, -348A/G, -278C/T, and -238C/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 -1054 C/T and G allele at -546 C/G polymorphisms frequently showed transition to advanced stages of diabetic nephropathy (P = 0.015). The annual change rate in eGFR in the subjects with both alleles was also significantly higher than in others (-2.96 +/- 0.62 vs. -1.63 +/- 0.15 ml/min per 1.73 m(2)/year, P = 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 Delta eGFR (> or =3 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.
Araki
Shin-ichi
S
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan. araki@belle.shiga-med.ac.jp
Haneda
Masakazu
M
Sugimoto
Toshiro
T
Isono
Motohide
M
Isshiki
Keiji
K
Kashiwagi
Atsunori
A
Koya
Daisuke
D
D000419:Albuminuria; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000652:urine; D003928:Diabetic Nephropathies / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011493:Protein Kinase C / Q000235:genetics*; D064546:Protein Kinase C beta; D011507:Proteinuria
C579054:PRKCB protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta