Betty and Guy Beatty Center for Integrated Research, Inova Fairfax Medical Campus, Falls Church, Virginia, United States of America.
Center for the Study of Chronic Metabolic Diseases, George Mason University, Fairfax, Virginia, United States of America.
PLoS One. 2018 Jun 21;13(6):e0199294. doi: 10.1371/journal.pone.0199294. eCollection 2018.
Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and major cause of chronic liver disease in developed countries. Its prevalence is increasing in parallel with the prevalence of obesity and other components of the metabolic syndrome. As the liver is central to the clearance and catabolism of circulating advanced glycosylation end-products (AGEs), AGEs and their cognate receptors-RAGE (receptor for AGEs) system might be involved in NAFLD in obese patients. To examine this, we investigated four common polymorphisms of RAGE gene: 1704G/T (rs184003), G82S (rs2070600), -374T/A (rs1800624) and -429T/C (rs1800625) in 340 obese patients with metabolic syndrome. and protein levels of AGE and RAGE. This is the first study to describe association of 4 common polymorphisms with non-alcoholic steatohepatitis (NASH) as well as to examine protein levels of RAGE and AGE. Univariate analysis showed patients carrying the rs1800624 heterozygote genotype (AT) exhibited 2.36-fold increased risk of NASH (odds ratio (OR) = 2.36; 95% confidence interval (95% CI): 1.35-4.19) after adjusting for confounders. The minor allele -374 A has been shown to suppress the expression of RAGE protein. The protein levels of esRAGE, total sRAGE and AGE protein levels did not correlate with each other in obese patients with no liver disease, indicative of RAGE signaling playing an independent role in liver injury. In obese patients with non-NASH NAFLD and NASH respectively, esRAGE protein showed strong positive correlation with total sRAGE protein. Further, haplotype analysis of the 4 SNPs, indicated that haplotype G-A-T-G was significantly associated with 2-fold increased risk for NASH (OR = 2.08; 95% CI: 1.21-3.5; P = 0.006) after adjusting for confounders. In conclusion, the presented data indicate that the G-A-T-G haplotype containing minor allele at position -374 A and major allele at position -429T, 1704G, and G82S G could be regarded as a marker for NASH.
非酒精性脂肪性肝病（NAFLD）是代谢综合征的肝脏表现，也是发达国家慢性肝病的主要原因。随着肥胖症和代谢综合征其他成分的流行，其发病率也在不断增加。由于肝脏是循环晚期糖基化终产物（AGEs）清除和分解代谢的中心，因此 AGEs 及其同源受体 RAGE（AGE 受体）系统可能参与肥胖患者的 NAFLD。为了研究这一点，我们在 340 名患有代谢综合征的肥胖患者中研究了 RAGE 基因的四个常见多态性：1704G/T（rs184003），G82S（rs2070600），-374T/A（rs1800624）和-429T/C（rs1800625）。以及 AGE 和 RAGE 的蛋白水平。这是第一项描述 4 种常见多态性与非酒精性脂肪性肝炎（NASH）之间关联的研究，也是首次研究 RAGE 和 AGE 蛋白水平的研究。单变量分析表明，在调整混杂因素后，携带 rs1800624 杂合基因型（AT）的患者患 NASH 的风险增加了 2.36 倍（优势比（OR）=2.36；95％置信区间（95％CI）：1.35-4.19）。已显示较小的等位基因-374 A 可抑制 RAGE 蛋白的表达。在没有肝脏疾病的肥胖患者中，esRAGE，总 sRAGE 和 AGE 蛋白水平彼此之间没有相关性，表明 RAGE 信号在肝损伤中起独立作用。在患有非 NASH NAFLD 和 NASH 的肥胖患者中，esRAGE 蛋白与总 sRAGE 蛋白呈强烈正相关。此外，对这 4 个 SNP 的单体型分析表明，单体型 G-A-T-G 与 NASH 的风险增加 2 倍显着相关（OR = 2.08；95％CI：1.21-3.5；P = 0.006），调整混杂因素后。总之，所提供的数据表明，包含位置-374 A 的较小等位基因和位置-429T，1704G 和 G82S G 的主要等位基因的 G-A-T-G 单体型可能被视为 NASH 的标志物。
