Correlation Between Advanced Glycation End Product Receptors And Their Gene Polymorphisms And Coronary Atherosclerotic Heart Disease

BACKGROUND:With the continuous development of our society and the economy,the prevalence and mortality of coronary atherosclerotic heart disease(CHD)is increasing year by year.Despite the different medications,PCI and surgery and other active treatment,the incidence of coronary heart disease and mortality rate has not been able to decline.This phenomenon requires us to re-examine the pathogenesis of coronary heart disease,to strive to find in addition to age,hyperglycemia,hypertension,hyperlipidemia,male,obesity,family history of coronary heart disease and other common cardiovascular risk factors other than the incidence,mechanism and risk factors.More and more studies have confirmed that atherosclerosis(AS)is actually a chronic inflammatory response disease in which a variety of inflammatory responses and immune responses are involved.A thorough research of some studies showed,the Receptor of Advanced Glycation End Products,RAGEs(RAGE)and advanced glycation end products(AGEs)ligands interaction plays an important role in the process of atherosclerosisAdvanced glycation end product receptor(RAGE)belongs to the cell surface of the immunoglobulin superfamily members of the transmembrane receptor,with a variety of ligand binding,It is the most important receptor for advanced glycation end products(AGEs).RAGE can also be combined with many other ligands,such as S100/Calcium family members,high mobility group box 1(HMGB1),etc?Studies have shown that advanced glycation end products(AGEs)and their receptors(RAGE)play an important role in the process of atherosclerosis?AGEs combined with RAGEaffect intracellular signaling,stimulate the release of cytokines,causing increased oxidative stress and inflammatory response,resulting in endothelial dysfunction,and coronary atherosclerotic heart disease(referred to as coronary heart disease)are closely related.Combination of S10012A-RAGE,through the intracellular signal transduction pathway to activate ROS,NF-?B,etc.,involved in a variety of gene transcription regulation,promote vascular adhesion molecule-1(VCAM-1),intercellular adhesion factor-1(ICAM-1),interleukin-1,6,8(IL-1,6,8)and so on,so that the adhesion between the cells and blood vessels increase,causing monocyte macrophage displacement,polysaccharide(LPS)invasion,leading to the occurrence and development of atherosclerosis.The soluble advanced glycation end product receptor(sRAGE)is one of the C-terminal parts of RAGE,which contains only the extracellular domain.SRAGE can be competitive to block the ligand and RAGE combined to inhibit the pathological effects of RAGE,coronary heart disease is a protective factor.Previous studies have found that RAGE is associated with coronary heart disease.RAGE expression in patients with coronary heart disease increased,and its serum sRAGE levels decreased.But the role of RAGE on coronary heart disease is still not fully understood,and so far there is little RAGE studies in elderly patients with coronary heart disease and its related mechanisms.OBJECTIVE:To study the relationship between advanced glycation end product receptors and patients with coronary heart disease at different ages,and to focus on their mechanism of action on coronary heart disease,especially in elderly patients with coronary heart diseaseMETHODS:All patients underwent percutaneous coronary angiography(CAG)with a definite diagnosis.According to the age of the patients they were divided in two groups,272 adult patient groups(aged<60 years)and 268 elderly people group(age?60 years).According to the results of coronary angiography,each group is divided into three subgroups:Coronary artery disease subgroup(anterior descending branch,circumflex artery,right at least one major vascular stenosis?50%),coronary atherosclerosis patients subgroup(coronary atherosclerotic plaque,but stenosis<50%)and normal coronary angiography subgroup.The collection of the general clinical data of each selected patient,understanding the combined disease and the current medication situation,each patient was enrolled in a two-dimensional echocardiogram after admission and the morning fasting venous blood samples 6ml,4ml and was collected and sent to the Jiangsu Provincal Hospital's depart of blood inspection.For biochemical and coagulation function;another 2ml of blood was taken for serum test.We collected the blood from coronary artery opening before and after PCI in CAD patients.The concentrations of sRAGE,S100A12 and VCAM-1 of venous blood and coronary blood were measured by enzyme-linked immunofluorescence assay(ELISA)with double antibody sandwich method.Gensini scores were assessed on the basis of the results of coronary angiography for each patient.This study aimed to investigate the correlation between sRAGE,S100A12 and VCAM-1 in different age groups,and to compare the differences of sRAGE,S100A12 and VCAM-1 in patients with coronary heart disease at different ages and study the correlation between these indexes and score,Correlation between S100A12 and VCAM-1 concentration and severity of coronary artery disease.At the same time to observe whether coronary angiography and PCI have an impact on the concentration of these indicators.RESULTS(1)Adults:Compared with normal subgroups of coronary angiography,serum sRAGE levels were significantly decreased(87.7±50.1ng/L vs 113.1±58.5 ng/L,P<0.05)S100A12 level was significantly increased(6.6±6.1 ug/L vs 5.9±5.0 ug/L,P<0.05)VCAM-1 levels were significantly increased(86.3±77.3 ug/L vs 77.2±62.5 ug/L,P<0.05),were statistically significant.The level of sRAGE in the coronary atherosclerosis subgroup was significantly decreased(94.7±60.5 ng/L vs 113.1±58.5 ng/L,P<0.05)VCAM-1 levels were significantly increased(84.1±58.6 ug/L vs 77.2±62.5 ug/L.P<0.05)Were statistically different,S100A12 levels were increased(6.2±4.9 ug/L vs 5.9±5.0 ug/L,P>0.05)But no statistically significant differences Compared with the coronary atherosclerosis subgroup,the level of sRAGE in the subgroup of coronary heart disease decreased(87.7±50.1 ng/L vs 94.7±60.5 ng/L,P>0.05)S100A12 level,(6.6±6.1 ug/L vs 6.2±4.9 ug/L,P>0.05),and the level of VCAM-(86.3±77.3 ug/L vs 84.1±58.6 ug/L,P>0.05)But no statistically significant differences(2)Old People group:Compared with normal subgroups of coronary angiography,serum sRAGE levels in the subgroup of coronary heart disease were significantly decreased.(76.6±56.1 ng/L vs 104.6±61.1 ng/L,P<0.05)?S100A12?VCAM-1 The level was significantly higher 7.3±6.9 ug/L vs 6.5±5.8 ug/L,P<0.05),96.4±78.0 ug/L vs 84.5±66.2 ug/L,P<0.05);The level of sRAGE in the coronary atherosclerosis subgroup was significantly decreased(79.5±78.5 ng/L vs 104.6±61.1 ng/L,P<0.05),S100A12,VCAM-1The level has also increased(6.9±6.3 ug/L vs 6.5±5.8 ug/L,P>0.05).(90.1±65.2 ug/L vs 84.5±66.2 ug/L,P>0.05)No statistical difference.Compared with atherosclerotic subgroups,The level of serum sRAGE in the subgroup of coronary heart disease was decreased(76.6± 56.1 ng/L vs 79.5±78,5 ng/L,P>0.05)S100A12(7.3± 6:9 ug/L vs 6.9±6.3 ug/L,P>0.05)VCAM-1(96.4±78.0 ug/L vs 90.1±65.2 ug/L,P>0.05)The content increased,but there was no significant difference(3)SRAGE was negatively correlated with Gensini(R=-0.305,P<0.01).There was a positive correlation between S100A12 and VCAM-1 and Gensini score(r=0.534,P<0.01),(r=0.619,P<0.01).(4)Compared with adult group,the level of sRAGE in elderly group decreased significantly(76.1±56.1 ng/L vs 87.7±50.1 ng/L,P<0.05),S100A12(7.3±6.9 ug/L vs 6.6±6.1 ug/L,P<0.05),VCAM-1(96.4±78.0 ug/L vs 86.3±77.3 ug/L,P<0.05),the difference was statistically significant.(5)Compared with preoperative PCI,both the adult group and the elderly group,patients with PCI after coronary artery blood sRAGE content decreased significantly(95.3±78.5 ng/L vs 112.4±72.9 ng/L,P<0.05),(83.8.3±53.1ng/L vs 94.1±45,5 ng/L,P<0.05).VCAM-1 levels were significantly increased(96.3± 92.5 ug/L vs 86.3±77.3 ug/L,P<0.05).S100A12 content(7.3± 6.9 ug/L vs 7.1±6.9 ug/L,P>0.05),(7.3±6.9 ug/L vs 7.1±6.9 ug/L,Increased,but no statistically significant difference.Conclusion:(1)RAGE was associated with the morbidity of coronary heart disease.The level of sRAGE in patients with coronary heart disease decreased,and the levels of S100A12 and VCAM-1 were increased.RAGE was correlated with the severity of coronary heart disease,and sRAGE was negatively correlated with Gensini.S100A12 and VCAM-1 were positively correlated with Gensini score.In patients with coronary heart disease,the pathological effect of RAGE was more obvious with the increase of age.Compared with adult group,the level of serum sRAGE in elderly patients with coronary heart disease decreased significantly,and the levels of S100A12 and VCAM-1 were significantly increased.(2)The levels of sRAGE in the blood of coronary artery were significantly decreased after PCI,and the level of VCAM-1 was significantly increased and the content of S100A12 was also increased in patients with coronary heart disease(CHD)after PCI.BACKGROUND:There are many risk factors of coronary heart disease,such as aging,male,hypertension,Diabetes,Hyperlipidemia,ect.Recently,studies had confirmed that atherosclerosis(AS)is a kind ofchronic inflammatory response disease.Various different mechanisms can cause inflammatory responses and immune responses.The Receptor of Advanced Glycation End Products,RAGEs(RAGE)and its ligands interaction play an very important role among those mechanisms.Advanced glycation end product receptor(RAGE)plays an important role in organism,specially for cardiovascular disease such as coronary heart disease.Because of the effect is related to its unique structural characteristics,RAGE gene polymorphism and its effect on genetic predisposition to disease have received more and moreattention,epecially in the cardiovascular field.RAGE-G82S is located in exon 3 of RAGE gene.Research found genetic susceptibility of many diseases such as coronary heart disease and diabetic retinopathy were related to RAGE-G82S(rs2070600)mutation.There is-429T/C(rs 1800625)polymorphism in promoter region of RAGE gene.This polymorphism is related to many diseases such as diabetic retinopathy and diabetic nephropathy.Recent researchs identified that gene polymorphism 2184A/G(rs3134940)locates in intron region of RAGE gene.More and more attention has been paid to the gene polymorphism 2184A/G(rs3134940).Numerous researchs pay attention to the association between these gene polymorphisms with coronary heart disease and the severity of coronary heart disease.But the results are not the same.Therefore,We need further study the association between RAGE gene polymorphisms and coronary heart disease in Chinese Han population.OBJECTIVE:To study the relationship between RAGE gene polymorphisms and coronary heart disease in Chinese Han population,and to observe the correlation of sRAGE with these polymorphisms.METHODS:All patients underwent percutaneous coronary angiography(CAG)with a definite diagnosis.According to the results the patients were divided in two groups,CAD groups and non-CAD group.We collected the general clinical data of each patient,the combined diseases and the current medication situation.All patients were enrolled in a two-dimensional echocardiogram.We collected the morning fasting venous blood samples,2ml was sent to the Jiangsu Provincal Hospital's depart of blood inspection.for biochemical test;another 2ml of blood was taken for serum test of sRAGE,another 2ml was taken for extraction of peripheral blood cells DNA.We designed the Primers for Multiple PCR reaction.We measured the gene polymorphisms by SnaPshot multiple single base extension reaction.RESULTS(1)RAGE 2184A/G(rs3134940)gene polymorphism:OR value of coronary heart disease with AG genotype is 1.23(0.61-2.50).After adjusting for age,sex,smoking and other factors,OR value is(0.60-3.11).There was no statistical significance(P>0.05).OR value of coronary heart disease with GG genotype is 2.66(0.93-7.65).After adjusting for multi factors,OR value is 1.80(0.58-5.61).There was also no statistical significance(P>0.05).OR value of coronary heart disease with AG+GG genotypes is 1.54(0.78-3.01),There was no statistical significance even after adjusting.(P>0.05).(2)RAGE G82S(rs2070600)gene polymorphism:OR value of coronary heart disease with AG genotype before and after adjusting are 0.62(0.30-1.28)and 0.81(0.35-1.87).There was no statistical significance(P>0.05).OR value of coronary heart disease with GG genotype before and after adjusting are 0.96(0.44-2.07)and 1.03(0.43-2.48).There was no statistical significance,too(P>0.05).OR value of coronary heart disease with AG+GG genotypes before and after adjusting are 0.66(0.34-1.30)and 0.83(0.38-1.82).There was also no statistical significance(P>0.05).(3)RAGE-429T/C(rs1800625)is a linkage gene of 2184A/G(rs3134940),RAGE-429T/C(rs1800625).There was no correlation between the incidence of coronary heart disease and TCgenotype,CCgenotype and TC+CC genotypes(P>0.05).(4)The level of sRAGE in CHD group was significantly higher than that in CHD group(58.04±5.35 ng/Lvs 41.18±3.44ng/L,P<0.01),the difference was statistically significant.Correlation analysis of sRAGE and RAGE gene polymorphism:Coronary heart disease group:Compared with rs3134940 AA genotype,There was no significant difference in serum sRAGE level between AG genotype and GG genotype(46.87 ±8.57 ng/L vs 38.24 ±3.83 ng/L,P>0.05)and(45.86±8.59 ng/L vs 38.24±3.83 ng/L,P>0.05).Compared with rs2070600 AA genotype,There was no significant difference in serum sRAGE level between AG genotype and GG genotype(37.07 ± 7.02 ng/L vs 42.13±4.07 ng/L,P>0.05)and(43.85±17.47 ng/L vs 42.13 ±4.07ng/L,P>0.05).In non CHD group,There was no significant difference in serum sRAGE level between AG genotype and GG genotype compared with rs3134940 AA genotype(56.52±13.79 ng/L vs 58.97±5.66 ng/L,P>0.05)and(35.29 ng/L vs 58.97±5.66 ng/L,P>0.05).There was no significant difference in serum sRAGE level between AG genotype and GG genotype compared with rs2070600 AA genotype(68.16± 10.0 ng/L vs 55.02±6.62 ng/L,P>0.05)?(36.57±15.60 ng/L vs 55.02±6.62 ng/L,P>0.05).Because rs1800625 is a linkage gene of rs3134940,the result is same with rs3134940.There was no correlation between RAGE and rs3134940 TC and CC genotypes.Conclusion:(1)RAGE G82S(rs2070600)gene polymorphism,RAGE 2184A/G(rs3134940)gene polymorphism,RAGE-429T/C(rs 1800625)gene polymorphism were not associated with coronary heart disease in Jiangsu Han population.(2)Although sRAGE has a protective effect on coronary heart disease,There was no correlation between sRAGE and G82S(rs2070600),2184A/G(rs3134940)and-429T/C(rs1800625)polymorphism of RAGE gene,Whether in coronary heart disease group or non coronary heart disease group.