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 [CI], 1.31-3.87; P = .003, and HR, 2.26; 95% CI, 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% CI, 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% CI, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% CI, 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% CI, 1.10-2.57; P = .02, and HR, 1.62; 95% CI, 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.
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 [CI], 1.31-3.87; P = .003, and HR, 2.26; 95% CI, 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% CI, 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% CI, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% CI, 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 diabeticpatients. 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% CI, 1.10-2.57; P = .02, and HR, 1.62; 95% CI, 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.
Authors: Spandan Shah; Andrew W Gibson; Chuanyi Ji; Eric Darrington; James Mobley; Kyoko Kojima; Jeffrey C Edberg; Robert P Kimberly Journal: J Leukoc Biol Date: 2016-09-14 Impact factor: 4.962
Authors: Eugene J Barrett; Zhenqi Liu; Mogher Khamaisi; George L King; Ronald Klein; Barbara E K Klein; Timothy M Hughes; Suzanne Craft; Barry I Freedman; Donald W Bowden; Aaron I Vinik; Carolina M Casellini Journal: J Clin Endocrinol Metab Date: 2017-12-01 Impact factor: 5.958
Authors: Alice P S Kong; Gang Xu; Nicola Brown; Wing-Yee So; Ronald C W Ma; Juliana C N Chan Journal: Nat Rev Endocrinol Date: 2013-05-28 Impact factor: 43.330