Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive MD3, 117597 Singapore, Republic of Singapore.
Diabetologia. 2012 Sep;55(9):2402-6. doi: 10.1007/s00125-012-2602-5. Epub 2012 Jun 14.
AIMS/HYPOTHESIS: A Japanese study had earlier reported that KCNQ1 single-nucleotide polymorphisms (SNPs) may be associated with diabetic nephropathy. To further investigate this finding, we analysed three SNPs, rs2237895, rs2237897 and rs2283228, within the KCNQ1 locus for association with albuminuria among Chinese type 2 diabetic patients residing in Singapore. Albuminuria was analysed as both categorical (micro- and macroalbuminuria) and continuous traits (log(e) albumin/creatinine ratio [ACR]).
A total of 752 Chinese patients with type 2 diabetes were included in the study. Albuminuria was determined by ACR using spot urine samples, and renal function was approximated using estimated GFR. Genotyping was performed using invader and Taqman assays as appropriate. Multivariate regression analyses were used to analyse the associations between SNPs and renal traits.
Significant associations were detected between rs2283228 and macroalbuminuria (p < 0.001, corrected p < 0.01), as well as log(e) ACR (p = 0.004, corrected p = 0.036) after multiple hypothesis testing and adjustment for potential confounding. A trend of increasing OR was observed with increasing severity of diabetic nephropathy (low and high microalbuminuria, macroalbuminuria). rs2237897, previously implicated in the earlier Japanese study, was also associated with macroalbuminuria, but this finding did not remain significant after correction for multiple testing. Meta-analyses of the Chinese and Japanese studies revealed both SNPs to be significantly associated with macroalbuminuria.
CONCLUSIONS/INTERPRETATION: Together with the previous Japanese study, our findings support the hypothesis that, in addition to KCNQ1 being an established type 2 diabetes gene, genetic variation in this gene may contribute to susceptibility to diabetic nephropathy in East Asians.
目的/假设：一项日本研究此前报告称，KCNQ1 单核苷酸多态性（SNP）可能与糖尿病肾病有关。为了进一步研究这一发现，我们分析了位于 KCNQ1 基因座内的三个 SNP（rs2237895、rs2237897 和 rs2283228）与新加坡华裔 2 型糖尿病患者蛋白尿之间的关联。蛋白尿分析为分类（微量和大量白蛋白尿）和连续特征（log(e)白蛋白/肌酐比值[ACR]）。
本研究共纳入 752 例华裔 2 型糖尿病患者。使用即时尿液样本通过 ACR 确定蛋白尿，使用估计的肾小球滤过率（eGFR）近似肾功能。使用合适的入侵酶和 Taqman 检测法进行基因分型。使用多元回归分析来分析 SNP 与肾脏特征之间的关联。
rs2283228 与大量白蛋白尿（p < 0.001，校正后 p < 0.01）以及 log(e)ACR（p = 0.004，校正后 p = 0.036）之间存在显著关联，这在进行了多次假设检验和调整潜在混杂因素后仍成立。随着糖尿病肾病严重程度的增加（低和高微量白蛋白尿、大量白蛋白尿），OR 呈上升趋势。先前在日本研究中涉及的 rs2237897 也与大量白蛋白尿有关，但在进行多次检验校正后，这一发现不再具有统计学意义。对中国和日本研究的荟萃分析显示，这两个 SNP 均与大量白蛋白尿显著相关。
结论/解释：结合之前的日本研究，我们的研究结果支持了这样一种假说，即除了 KCNQ1 是已确立的 2 型糖尿病基因之外，该基因的遗传变异可能导致东亚人易患糖尿病肾病。
