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This version published online on November 4, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-1067
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Submitted on May 20, 2009
Accepted on September 23, 2009

Association of Polymorphism in the Receptor for Advanced Glycation End Products (RAGE) Gene with Circulating RAGE Levels

Katrien H. J. Gaens, Isabel Ferreira, Carla J. H. van der Kallen, Marleen M. J. van Greevenbroek, Ellen E. Blaak, Edith J. M. Feskens, Jacqueline M. Dekker, Giel Nijpels, Robert J. Heine, Leen M. 't Hart, Philip G. de Groot, Coen D. A. Stehouwer, and Casper G. Schalkwijk*

Departments of Internal Medicine (K.H.J.G., I.F., C.J.H.v.d.K., M.M.J.v.G., C.D.A.S., C.G.S.), Clinical Epidemiology and Medical Technology Assessment (I.F.), and Human Biology (E.E.B.), Cardiovascular Research Institute Maastricht (K.H.J.G., I.F., C.J.H.v.d.K., M.M.J.v.G., C.D.A.S., C.G.S.), Nutrition and Toxicology Research Institute Maastricht (E.E.B.), Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; Division of Human Nutrition (E.J.M.F.), Section Nutrition and Epidemiology, Wageningen University, 6701 BH Wageningen, The Netherlands; Institute for Health and Care Research (J.M.D., G.N., R.J.H.) and Department of Epidemiology and Biostatistics (J.M.D.), Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands; Department of Molecular Cell Biology (L.M.t.H.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Department of Clinical Chemistry and Haematology (P.G.d.G.), University Medical Center, 3508 GA Utrecht, The Netherlands

* To whom correspondence should be addressed. E-mail: c.schalkwijk{at}intmed.unimaas.nl.

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.






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