Lim Su Chi, Dorajoo Rajkumar, Zhang Xiao, Wang Ling, Ang Su Fen, Tan Clara Si Hua, Yeoh Lee Ying, Ng Xiao Wei, Li Na, Su Chang, Liu Sylvia, Wong Melvin D S, Low Kiat Mun Serena, Yao Amy Ou, Babitha Jeevith, Fun Sharon, Zhou Shiyi, Lee Simon Biing Ming, Tang Wern Ee, Tavintharan Subramaniam, Sum Chee Fang, Liu Jian-Jun
Diabetes Centre, Khoo Teck Puat Hospital, Singapore.
Department of Medicine, Khoo Teck Puat Hospital, Singapore.
Nephrol Dial Transplant. 2017 Oct 1;32(10):1697-1704. doi: 10.1093/ndt/gfw263.
The soluble receptor for advanced glycation end products (sRAGE) has been shown to play an important role in diabetic complications. We conducted genome-wide association study (GWAS) of sRAGE in Asian type 2 diabetes mellitus (T2DM) patient and validated the association in an independent cohort of T2DM.
GWAS for sRAGE was performed in 2058 T2DM patients. Associations between single-nucleotide polymorphisms (SNPs) and plasma sRAGE level were analyzed in an additive model using a linear mixed model. To validate the associations, we performed de novo genotyping in an independent cohort (n = 1984). We selected the top SNP for assessment with diabetic kidney disease (DKD).
The strongest SNP, rs2070600C>T (P = 1.21 × 10-52), was a genotyped, missense SNP located on chromosome 6, corresponding to the RAGE (AGER) gene locus, the gene encoding RAGE. Conditioning analysis on rs2070600 revealed that rs2071288C>T was the top genotyped independent SNP (P = 8.36 × 10-10). Both SNPs were strongly and dose-dependently correlated with sRAGE level (TT = 399.6 pg/mL, CT = 737.0 pg/mL and CC = 967.0 pg/mL, P < 0.001 for rs2070600; TT = 687.9 pg/mL, CT = 737.6 pg/mL and CC = 904.7 pg/mL, P < 0.001 for rs2072188). Both SNPs were robustly replicated in the independent cohort, especially among Chinese patients (P = 9.02 × 10-72 for rs2070600; P = 1.13 × 10-9 for rs2071288). Log-transformed sRAGE was associated with DKD after adjustment for age, gender and ethnicity in pooled cohorts [odds ratio 2.536 (95% confidence interval 1.864-3.450), P < 0.001]. However, we did not observe any significant association between rs2070600 and DKD.
Common variants in RAGE are strongly associated with plasma sRAGE level, which is associated with DKD. However, we did not find a causal link between sRAGE and renal function by Mendelian randomization.
晚期糖基化终末产物可溶性受体（sRAGE）已被证明在糖尿病并发症中起重要作用。我们对亚洲2型糖尿病（T2DM）患者进行了sRAGE的全基因组关联研究（GWAS），并在一个独立的T2DM队列中验证了这种关联。
对2058例T2DM患者进行sRAGE的GWAS。使用线性混合模型在加性模型中分析单核苷酸多态性（SNP）与血浆sRAGE水平之间的关联。为了验证这种关联，我们在一个独立队列（n = 1984）中进行了从头基因分型。我们选择了排名最靠前的SNP用于评估糖尿病肾病（DKD）。
最强的SNP，rs2070600C>T（P = 1.21×10-52），是一个位于6号染色体上的已分型错义SNP，对应于RAGE（AGER）基因座，即编码RAGE的基因。对rs2070600进行条件分析发现，rs2071288C>T是排名最靠前的已分型独立SNP（P = 8.36×10-10）。这两个SNP均与sRAGE水平呈强剂量依赖性相关（rs2070600：TT = 399.6 pg/mL，CT = 737.0 pg/mL，CC = 967.0 pg/mL，P < 0.001；rs2072188：TT = 687.9 pg/mL，CT = 737.6 pg/mL，CC = 904.7 pg/mL，P < 0.001）。这两个SNP在独立队列中均得到了有力验证，尤其是在中国患者中（rs2070600：P = 9.02×10-72；rs2071288：P = 1.13×10-9）。在合并队列中，调整年龄、性别和种族后，对数转换后的sRAGE与DKD相关[比值比2.536（95%置信区间1.864 - 3.450），P < 0.001]。然而，我们未观察到rs2070600与DKD之间存在任何显著关联。
RAGE中的常见变异与血浆sRAGE水平密切相关，而血浆sRAGE水平与DKD相关。然而，我们通过孟德尔随机化未发现sRAGE与肾功能之间存在因果联系。
