• Su Chi Lim, Rajkumar Dorajoo, Xiao Zhang, Ling Wang, Su Fen Ang, Clara Si Hua Tan, Lee Ying Yeoh, Xiao Wei Ng, Na Li, Chang Su, Sylvia Liu, Melvin D S Wong, Kiat Mun Serena Low, Amy Ou Yao, Jeevith Babitha, Sharon Fun, Shiyi Zhou, Simon Biing Ming Lee, Wern Ee Tang, Subramaniam Tavintharan, Chee Fang Sum, and Jian-Jun Liu.
• Diabetes Centre, Khoo Teck Puat Hospital, Singapore.
• Nephrol. Dial. Transplant. 2017 Oct 1; 32 (10): 1697-1704.

BackgroundThe 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.MethodsGWAS 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).ResultsThe 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.ConclusionsCommon 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.© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

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