Association of polymorphism in the receptor for advanced glycation end products (RAGE) gene with circulating RAGE levels.

OBJECTIVE The receptor for advanced glycation end products (RAGE)-ligand interaction has been linked to vascular complications. The family of soluble forms of RAGE (sRAGE) consists of splice variants and proteolytically cleaved and shed forms of RAGE. sRAGE may be a reflection of cell-bound RAGE. Because genetic variation in the RAGE gene may be associated with individual differences in sRAGE concentration and outcome, we investigated whether RAGE single-nucleotide polymorphisms (SNPs) were associated with circulating levels of sRAGE. METHODS Nine SNPs, covering the common RAGE gene variation, were genotyped in a Dutch cohort of subjects with normal glucose metabolism (n = 301), impaired glucose metabolism (n = 127), and type 2 diabetes mellitus (n = 146). We used linear regression analyses adjusted for age, sex, and glucose metabolism status to compare sRAGE levels across genotypes. RESULTS SNP rs2060700 (Gly82Ser) showed an association with sRAGE levels. Specifically, after adjustments for age, sex, and glucose metabolism, subjects with CT genotype had -527 pg/ml (95% confidence interval -724 to -330, P < 0.001) lower sRAGE levels compared with the CC genotype (age, sex, and glucose metabolism adjusted mean +/- SE values of 836 +/- 99 and 1369 +/- 26 pg/ml, respectively, P < 0.001). These results were confirmed in a subsample of a second cohort study of subjects with CT (n = 37) and CC genotype (n = 37). Immunoblotting using antibodies against amino acids 39-55 and 100-116 of RAGE also showed a similar decrease of sRAGE levels in the CT genotypes. No other SNPs showed an association with sRAGE levels. In addition, no associations between SNPs and the advanced glycation end products N(epsilon)-(carboxymethyl)lysine and N(epsilon)-(carboxyethyl)lysine were found. CONCLUSION The CC genotype of SNP rs2070600 (Gly82Ser) was strongly associated with higher sRAGE levels in a Dutch population. The mechanism by which Gly82Ser polymorphism alters the sRAGE levels remains to be elucidated.

[1]  E. Feskens,et al.  Polymorphisms in glyoxalase 1 gene are not associated with vascular complications: the Hoorn and CoDAM studies , 2009, Journal of hypertension.

[2]  E. Feskens,et al.  Low‐grade inflammation can partly explain the association between the metabolic syndrome and either coronary artery disease or severity of peripheral arterial disease: the CODAM study , 2009, European journal of clinical investigation.

[3]  J. H. Lee,et al.  G allele at RAGE SNP82 is associated with proinflammatory markers in obese subjects. , 2009, Nutrition research.

[4]  M. Prins,et al.  Levels of soluble receptor for AGE are cross-sectionally associated with cardiovascular disease in type 1 diabetes, and this association is partially mediated by endothelial and renal dysfunction and by low-grade inflammation: the EURODIAB Prospective Complications Study , 2009, Diabetologia.

[5]  E. Kojro,et al.  Receptor for Advanced Glycation End Products Is Subjected to Protein Ectodomain Shedding by Metalloproteinases* , 2008, Journal of Biological Chemistry.

[6]  P. Saftig,et al.  A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane‐bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10) , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  M. Zorzetto,et al.  The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma2 gene is associated with plasma levels of soluble RAGE (Receptor for Advanced Glycation Endproducts) and the presence of peripheral arterial disease. , 2008, Clinical biochemistry.

[8]  A. Carter,et al.  Identification, classification, and expression of RAGE gene splice variants , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  T. Imaizumi,et al.  Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes. , 2008, Microvascular research.

[10]  E. Feskens,et al.  Receptor for Advanced Glycation End Product Polymorphisms and Type 2 Diabetes , 2008, Annals of the New York Academy of Sciences.

[11]  G. Basta.  Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications. , 2008, Atherosclerosis.

[12]  Hiroshi Yamamoto,et al.  De-N-glycosylation or G82S mutation of RAGE sensitizes its interaction with advanced glycation endproducts. , 2007, Biochimica et biophysica acta.

[13]  Takafumi Yoshida,et al.  Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease , 2007, Diabetes/metabolism research and reviews.

[14]  B. Oh,et al.  Association of RAGE gene polymorphisms with coronary artery disease in the Korean population , 2007, Coronary artery disease.

[15]  J. H. Lee,et al.  Association of the Gly82Ser polymorphism in the receptor for advanced glycation end products (RAGE) gene with circulating levels of soluble RAGE and inflammatory markers in nondiabetic and nonobese Koreans. , 2007, Metabolism: clinical and experimental.

[16]  T. Imaizumi,et al.  Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects. , 2006, Metabolism: clinical and experimental.

[17]  P. Gregersen,et al.  The RAGE Gly82Ser polymorphism is not associated with cardiovascular disease in the Framingham offspring study. , 2005, Atherosclerosis.

[18]  D. Stern,et al.  Understanding RAGE, the receptor for advanced glycation end products , 2005, Journal of Molecular Medicine.

[19]  T. Yoshikawa,et al.  Relation between polymorphisms G1704T and G82S of rage gene and diabetic retinopathy in Japanese type 2 diabetic patients. , 2005, Internal medicine.

[20]  T. Imaizumi,et al.  Advanced glycation end products (AGEs) and diabetic vascular complications. , 2005, Current diabetes reviews.

[21]  C. Schalkwijk,et al.  Measurement of Nε-(Carboxymethyl)lysine and Nε-(Carboxyethyl)lysine in Human Plasma Protein by Stable-Isotope-Dilution Tandem Mass Spectrometry , 2004 .

[22]  S. Takasawa,et al.  Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. , 2003, The Biochemical journal.

[23]  T. Sharma,et al.  Association of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy in type II diabetic Asian Indian patients. , 2002, Journal of diabetes and its complications.

[24]  P. Gregersen,et al.  RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response , 2002, Genes and Immunity.

[25]  P. Grant,et al.  Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy. , 2001, Diabetes.

[26]  H. Parving,et al.  Polymorphism screening of four genes encoding advanced glycation end-product putative receptors. Association study with nephropathy in type 1 diabetic patients. , 2001, Diabetes.

[27]  P. Grant,et al.  Identification of polymorphisms in the receptor for advanced glycation end products (RAGE) gene: prevalence in type 2 diabetes and ethnic groups. , 1998, Diabetes.

[28]  J. Spaan,et al.  Coronary circulation : from basic mechanisms to clinical implications , 1987 .