晚期糖基化终产物受体（RAGE）基因多态性与循环 RAGE 水平的关系。

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

机构信息

Department of Internal Medicine, Maastricht University Medical Center, Debeyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.

出版信息

J Clin Endocrinol Metab. 2009 Dec;94(12):5174-80. doi: 10.1210/jc.2009-1067. Epub 2009 Nov 4.

DOI:10.1210/jc.2009-1067

PMID:19890027

Abstract

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.

摘要

目的

晚期糖基化终产物（RAGE）受体-配体相互作用与血管并发症有关。RAGE 的可溶性形式（sRAGE）家族由剪接变异体和蛋白水解切割及脱落形式的 RAGE 组成。sRAGE 可能反映细胞结合的 RAGE。由于 RAGE 基因的遗传变异可能与 sRAGE 浓度和结果的个体差异有关，我们研究了 RAGE 单核苷酸多态性（SNP）是否与循环 sRAGE 水平相关。

方法

在荷兰正常葡萄糖代谢（n = 301）、葡萄糖代谢受损（n = 127）和 2 型糖尿病（n = 146）患者的队列中，对 9 个涵盖常见 RAGE 基因变异的 SNP 进行了基因分型。我们使用线性回归分析调整年龄、性别和葡萄糖代谢状态，比较基因型之间 sRAGE 水平的差异。

结果

SNP rs2060700（Gly82Ser）与 sRAGE 水平相关。具体而言，在调整年龄、性别和葡萄糖代谢后，CT 基因型患者的 sRAGE 水平比 CC 基因型患者低-527 pg/ml（95%置信区间 -724 至 -330，P < 0.001）（年龄、性别和葡萄糖代谢调整后平均 +/- SE 值分别为 836 +/- 99 和 1369 +/- 26 pg/ml，P < 0.001）。这些结果在第二个队列研究的 CT（n = 37）和 CC 基因型（n = 37）亚组中得到了证实。使用针对 RAGE 氨基酸 39-55 和 100-116 的抗体进行免疫印迹也显示 CT 基因型的 sRAGE 水平相似下降。其他 SNP 与 sRAGE 水平无关。此外，没有发现 SNP 与晚期糖基化终产物 N(epsilon)-(羧甲基)赖氨酸和 N(epsilon)-(羧乙基)赖氨酸之间存在关联。