Association of Polymorphism in the Receptor for Advanced Glycation End Products (RAGE) Gene with Circulating RAGE Levels
Association of Polymorphism in the Receptor for Advanced Glycation End Products (RAGE) Gene with Circulating RAGE Levels
复制标题
DOI：
10.1210/jc.2009-1067
复制
发表时间：
2009-12-01
影响因子：
5.8
通讯作者：
Schalkwijk, Casper G.
中科院分区：
文献类型：
--
作者：
Gaens, Katrien H. J.;Ferreira, Isabel;Schalkwijk, Casper G.
目的：晚期糖基化终末产物受体（Receptor for Advanced Glycation End Products，RECEPTOR）-配体相互作用与血管并发症有关。可溶性形式的β-淀粉样蛋白（β-淀粉样蛋白）家族由剪接变体和蛋白水解切割和脱落形式的β-淀粉样蛋白组成。细胞粘附可能是细胞结合粘附的反映。由于β-淀粉样蛋白基因的遗传变异可能与β-淀粉样蛋白浓度和结果的个体差异有关，我们研究了β-淀粉样蛋白单核苷酸多态性（SNP）是否与循环β-淀粉样蛋白水平有关。在一组荷兰受试者中对9个SNP进行基因分型，这些受试者包括葡萄糖代谢正常（n = 301），葡萄糖代谢受损（n = 127），2型糖尿病146例。我们使用线性回归分析调整年龄，性别和糖代谢状态，比较saponin水平跨genotype.Results：SNP rs 2060700（Gly 82 Ser）显示与saponin水平。具体而言，在调整年龄、性别和葡萄糖代谢后，CT基因型受试者的血糖水平为-527 pg/ml，（95%可信区间-724 ~-330，P < 0.001）与CC基因型相比，（年龄、性别和葡萄糖代谢调整的平均+/-SE值分别为836 +/- 99和1369 +/- 26 pg/ml，P < 0.001）。这些结果在具有CT（n = 37）和CC基因型（n = 37）的受试者的第二队列研究的子样本中得到证实。免疫印迹法使用的抗体对氨基酸39-55和100-116的saponin也显示了类似的降低水平的CT基因型。没有其他SNPs显示出与sodium水平相关。此外，SNPs与晚期糖基化终产物N-α-（羧甲基）赖氨酸和N-α-（羧乙基）赖氨酸之间没有关联。结论：在荷兰人群中，SNPs rs 2070600（Gly 82 Ser）的CC基因型与较高的糖化水平密切相关。Gly 82 Ser多态性改变sodium水平的机制仍有待阐明。（临床内分泌代谢杂志94：5174-5180，2009）
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. (J Clin Endocrinol Metab 94: 5174-5180, 2009)