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遗传变异与华裔糖尿病患者发生终末期肾病有关

据2010年8月25日刊载在《美国医学会杂志》上的一项研究披露,对某个参与细胞信号转导的基因的检查发现,该基因的4种常见的变异体与罹患II型糖尿病的华裔病人产生终末期肾脏疾病有关。

 
肾脏衰竭是罹患II型糖尿病患者的一种重要的死亡原因。根据文章的背景资料,亚洲人群似乎特别具有发生糖尿病性肾病(DKD)的风险;他们与白人相比,亚裔病人发生终末期肾病(ESRD)的风险要更高。蛋白激酶C-β (PKC-β) 是一种参与细胞信号转导的分子,它与糖尿病并发症的发生有关。

(PKC及相关信号通路在糖尿病肾病中的关系)

中国香港特别行政区新界沙田的威尔士王子医院及香港中文大学的Ronald C. W. Ma, M.B., B.Chir.(Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China)及其同事对蛋白激酶C-β 1(PRKCB1)基因的变异是否与一组罹患II型糖尿病的华裔病人的新发终末期肾病(ESRD)有关进行了调查。他们在1172名华裔患者(他们于1995-1998年期间被纳入此项研究)中开展了遗传学分析,这些患者在本研究开始的时候尚无肾脏疾病。一个验证组还另外包括了1049名早发糖尿病患者,这些人是在1998年后被纳入此项研究的,他们在基线水平没有肾脏疾病。在过了平均7.9年之后,有90位患者(占7.7%)进展成为终末期肾病(ESRD)。
 
分析表明,4种常见的遗传性变异在不同的模型中可预测终末期肾病(ESRD)的发生,而发生终末期肾病(ESRD)的可能性则会随着风险等位基因(某基因的一个另类形式)数目的增多而增加。具有4个风险等位基因的患者与有着0或1个风险等位基因者相比,其校正后的发生终末期肾病(ESRD)的风险大约会增高6倍。
 
文章的作者写道:“在这项对II型糖尿病的华裔患者所做的为期8年的随访中,我们发现,蛋白激酶C-β 1(PRKCB1)基因的遗传变异体与独立于其它已知风险因子的伴发终末期肾病(ESRD)有关,而赋予风险的等位基因则有着联合效应。即使在得到视网膜病、白蛋白尿 [ 尿中存在过多的蛋白]、肾功能、风险因子控制以及药物(包括在基线状态时使用血管紧张素转换酶[ACE]抑制剂)使用等的校正后,这种相关性也一直持续存在。”
 
“此外,我们在另外一个有着相对较短随访期的II型糖尿病华裔患者的组群中获得了蛋白激酶C-β 1(PRKCB1)基因中的遗传变异体在慢性肾病的发展中起着作用的进一步的支持性证据。我们的前后一致的结果因而表明,蛋白激酶C-β 1(PRKCB1)基因中的遗传变异是在华裔II型糖尿病患者中发生糖尿病性肾病(DKD)风险的一个重要的决定因素。”


附英文原文摘要:


文献标题:Genetic variants of the protein kinase C-beta 1 gene and development of end-stage renal disease in patients with type 2 diabetes.
来源期刊:JAMA : the journal of the American Medical Association.2010-08-25;304(8):881-9.
期刊影响因子:28.899
PMID:20736472

Abstract

 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.


PMID: 20736472 《美国医学会杂志》. 2010;304[8]:881-889 

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