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. 2017 Oct 1;32(10):1697-1704.
doi: 10.1093/ndt/gfw263.

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study

Su Chi Lim  1   2 , Rajkumar Dorajoo  3 , Xiao Zhang  4 , Ling Wang  3 , Su Fen Ang  4 , Clara Si Hua Tan  4 , Lee Ying Yeoh  2 , Xiao Wei Ng  4 , Na Li  4 , Chang Su  4 , Sylvia Liu  4 , Melvin D S Wong  4 , Kiat Mun Serena Low  4 , Amy Ou Yao  4 , Jeevith Babitha  4 , Sharon Fun  1 , Shiyi Zhou  4 , Simon Biing Ming Lee  5 , Wern Ee Tang  5 , Subramaniam Tavintharan  1   2 , Chee Fang Sum  1   2 , Jian-Jun Liu  3
Affiliations

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study

Su Chi Lim et al. Nephrol Dial Transplant. .

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: DKD; GWAS; RAGE gene; rs2070600; rs2071288; sRAGE level.

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