title: 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.
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.
authors.affiliation: Diabetes Centre, Khoo Teck Puat Hospital, Singapore.|Department of Medicine, Khoo Teck Puat Hospital, Singapore.
authors.forename: Su Chi
authors.initials: SC
authors.lastname: Lim
authors.affiliation: Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Dorajoo
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Su Fen
authors.initials: SF
authors.lastname: Ang
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Clara Si Hua
authors.initials: CSH
authors.lastname: Tan
authors.affiliation: Department of Medicine, Khoo Teck Puat Hospital, Singapore.
authors.forename: Lee Ying
authors.initials: LY
authors.lastname: Yeoh
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Xiao Wei
authors.initials: XW
authors.lastname: Ng
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Chang
authors.initials: C
authors.lastname: Su
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Liu
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Melvin D S
authors.initials: MDS
authors.lastname: Wong
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Kiat Mun Serena
authors.initials: KMS
authors.lastname: Low
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Amy Ou
authors.initials: AO
authors.lastname: Yao
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Jeevith
authors.initials: J
authors.lastname: Babitha
authors.affiliation: Diabetes Centre, Khoo Teck Puat Hospital, Singapore.
authors.forename: Sharon
authors.initials: S
authors.lastname: Fun
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhou
authors.affiliation: National Healthcare Group Polyclinics, Singapore.
authors.forename: Simon Biing Ming
authors.initials: SBM
authors.lastname: Lee
authors.affiliation: National Healthcare Group Polyclinics, Singapore.
authors.forename: Wern Ee
authors.initials: WE
authors.lastname: Tang
authors.affiliation: Diabetes Centre, Khoo Teck Puat Hospital, Singapore.|Department of Medicine, Khoo Teck Puat Hospital, Singapore.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Tavintharan
authors.affiliation: Diabetes Centre, Khoo Teck Puat Hospital, Singapore.|Department of Medicine, Khoo Teck Puat Hospital, Singapore.
authors.forename: Chee Fang
authors.initials: CF
authors.lastname: Sum
authors.affiliation: Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D044466:Asian People / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
keywords: DKD; GWAS; RAGE gene; rs2070600; rs2071288; sRAGE level