Genetic Variants of the Protein Kinase C-β1 Gene and Development of End-Stage Renal Disease in Patients With Type 2 Diabetes

Context Protein kinase C-beta (PKC-beta) is a cell-signaling intermediate implicated in development of diabetic complications. Objective To examine the risk association of PKC-beta 1 gene (PRKCB1) polymorphisms and end-stage renal disease (ESRD) in an 8-year prospective cohort of Chinese patients with type 2 diabetes. Design, Setting, and Participants We genotyped 18 common tag single-nucleotide polymorphisms (SNPs) that span the PRKCB1 gene (r(2)=0.80) in 1172 Chinese patients (recruited 1995-1998) without renal disease at baseline. A validation cohort included an additional 1049 patients with early-onset diabetes who were free of renal disease at baseline and were recruited after 1998. Main Outcome Measures Associations of PRKCB1 polymorphisms under additive, dominant, and recessive genetic models with new onset of ESRD (defined as estimated glomerular filtration rate <15 mL/min/1.73 m(2) or dialysis or renal-related death) were assessed by Cox proportional hazard regression, adjusted for all conventional risk factors including use of medications. Results After a mean (SD) of 7.9 (1.9) years, 90 patients (7.7%) progressed to ESRD. Four common SNPs were associated with ESRD (P<.05). The closely linked T allele at rs3760106 and G allele rs2575390 (r(2)=0.98) showed the strongest association with ESRD (hazard ratio [HR], 2.25; 95% confidence interval [Cl], 1.31-3.87; P=.003, and HR, 2.26; 95% Cl, 1.31-3.88; P=.003, respectively). Four common variants predicted ESRD in separate models. The HR for ESRD increased with increasing number of risk alleles (P<.001) in the joint effect analysis. The adjusted risk for ESRD was 6.04 (95% Cl, 2.00-18.31) for patients with 4 risk alleles compared with patients with 0 or 1 risk allele. Incidence was 4.4 per 1000 person-years (95% Cl, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% Cl, 8.8-31.1) in those carrying 4 risk alleles (6.9% of the cohort). These results were validated in a separate prospective cohort of young-onset diabetic patients. Of 1049 patients in the validation cohort, 151 (14.3%) developed chronic kidney disease (CKD) during follow-up, and there were significant associations between both the T allele of rs3760106 and the G allele of rs2575390 and development of CKD (HR, 1.68; 95% Cl, 1.10-2.57; P=.02, and HR, 1.62; 95% Cl, 1.07-2.47; P=.02, respectively). Conclusion Genetic variants in the PRKCB1 gene were independently associated with development of ESRD in Chinese patients with type 2 diabetes. JAMA. 2010;304(8):881-889