Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
JAMA. 2010 Aug 25;304(8):881-9. doi: 10.1001/jama.2010.1191.
Protein kinase C-beta (PKC-beta) is a cell-signaling intermediate implicated in development of diabetic complications.
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.
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.
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).
Genetic variants in the PRKCB1 gene were independently associated with development of ESRD in Chinese patients with type 2 diabetes.
蛋白激酶 C-β（PKC-β）是一种细胞信号转导中介物，与糖尿病并发症的发生有关。
在一项对中国 2 型糖尿病患者进行的 8 年前瞻性队列研究中，检查 PKC-β1 基因（PRKCB1）多态性与终末期肾脏疾病（ESRD）的风险关联。
设计、地点和参与者：我们对基线时无肾脏疾病的 1172 名中国患者（招募于 1995-1998 年）的 PRKCB1 基因（r²=0.80）上的 18 个常见标签单核苷酸多态性（SNP）进行了基因分型。验证队列包括另外 1049 名基线时无肾脏疾病且于 1998 年后招募的早发糖尿病患者。
通过 Cox 比例风险回归评估 PRKCB1 多态性在加性、显性和隐性遗传模型下与新发 ESRD（定义为估计肾小球滤过率<15mL/min/1.73m²或透析或与肾脏相关的死亡）的关联，调整了包括药物使用在内的所有常规风险因素。
平均（标准差）随访 7.9（1.9）年后，90 名患者（7.7%）进展为 ESRD。4 个常见 SNP 与 ESRD 相关（P<.05）。rs3760106 的紧密连锁 T 等位基因和 rs2575390 的 G 等位基因（r²=0.98）与 ESRD 相关性最强（危险比[HR]，2.25；95%置信区间[CI]，1.31-3.87；P=.003，和 HR，2.26；95% CI，1.31-3.88；P=.003）。4 种常见变异分别在单独模型中预测 ESRD。在联合效应分析中，ESRD 的 HR 随风险等位基因数量的增加而增加（P<.001）。与 0 或 1 个风险等位基因的患者相比，4 个风险等位基因的患者 ESRD 的调整风险为 6.04（95% CI，2.00-18.31）（P<.001）。与 0 或 1 个风险等位基因的个体相比，携带 4 个风险等位基因的个体的发病率为 4.4/1000 人年（95% CI，0.5-8.2），而携带 4 个风险等位基因的个体为 20.0/1000 人年（95% CI，8.8-31.1）（队列的 6.9%）。这些结果在一个独立的年轻起病的糖尿病患者前瞻性队列中得到了验证。在验证队列的 1049 名患者中，151 名（14.3%）在随访期间发生慢性肾脏病（CKD），rs3760106 的 T 等位基因和 rs2575390 的 G 等位基因与 CKD 的发生均有显著关联（HR，1.68；95% CI，1.10-2.57；P=.02，和 HR，1.62；95% CI，1.07-2.47；P=.02）。
中国 2 型糖尿病患者 PRKCB1 基因中的遗传变异与 ESRD 的发生独立相关。
