Study On The Association Between The Rs5516 And The Insertion/deletion Polymorphism Of The Angiotensin-converting Enzyme Gene And Aortic Aneurysm And Atherosclerotic Stenosis Based On Atherosclerosis

Part One:Are the single nucleotide polymorphism of rs5516 and the insertion/deletion polymorphism of the angiotensin-converting enzyme gene involved in differential development of aortic aneurysm and atherosclerotic stenosis based on atherosclerosis?Aortic aneurysm(AA)and atherosclerotic stenosis(AS)are complex disorders in which environmental and genetic factors play a role.Their basic pathological change is atherosclerosis,and several studies suggest that both the kallikrein 1(KLK1)and the angiotensin-converting enzyme(ACE)genes are associated with AA;in addition,the ACE is associated with AS.KLK1 and ACE are the key molecules of the kallikrein kinin system(KKS)and the renin-angiotensin system(RAS),which are the primary systems that maintain the balance and stability of the circulatory system.There is a significant association between ACE and atherosclerosis.Whether RAS and KKS or the single nucleotide polymorphism(SNP)rs5516 and the I/D polymorphism of the ACE are involved in the differential development of AA and AS based on atherosclerosis is unclear.If they are,then we would like to determine the mechanism.A case-control study was performed on a subject group from China(n=1248),of which 168 had an abdominal aortic aneurysm,240 had a thoracic aortic aneurysm,432 had atherosclerotic stenosis and 408 controls.We found that there was a significant association between CG/GG genotypes and the patients with AA compared with AS patients in a dominant model(P=0.0003,OR=0.578).The rs5516 minor(G)allele was significantly associated with AA(P=0.013,OR=0.323)and AS(P=0.00009,OR=0.200)compared with controls in a recessive model.This followed for the ID/DD genotypes using a dominant model(P=0.005,OR=0.639),and the D allele as well(P<0.001,OR=0.269 and P<0.001,OR=0.278).GG(P=0.00006,OR=0)and DD(P=0.0003,OR=0.486)genotypes were synergistic with hypertension in patients with AA but not AS.This study suggests that changes in KLK1 and ACE activity may be relevant for AA and AS progression.Patients with fewer D or G alleles and hypertension have a larger risk of developing AA,while more D or G alleles but without hypertension contribute to the risk of developing AS.Part Two:Is expression of rs5516 different in abdominal versus thoracic aortic aneurysmsAbdominal aortic aneurysm(AAA)and thoracic aortic aneurysm(TAA)are complex disorders in which environmental and genetic factors play a role in pathogenesis.A gene encoding kallikrein 1(KLK1)is located on chromosome 19q13,and the single nucleotide polymorphism(SNP)rs5516 has been previously shown to lead to structural changes in the KLK1 transcription regulatory region.One study suggests this genetic polymorphism in KILK1 may contribute to the risk of developing late-stage AAA.However,there is little information about the relationship between rs5516 and TAA.The aim of this study was to investigate whether there is difference of the expression of this SNP between these two diseases in a Chinese population.A case-control study was performed on a subject group from China(n=1224),of which 336 had an AAA and 480 had a TAA.Furthermore,we analysed RNA extracted from blood samples of 46patients who had AAA,26 patients who had TAA and 46 controls.We found that the G allele of the rs5516 polymorphism was associated with TAA(P=0.00003,OR=0.184)but not AAA using a recessive model in Chinese subjects.The association between hypertension and TAA(P<0.005,OR=0.458)was significantly higher than that between hypertension and AAA,meanwhile,GG genotype were synergistic with hypertension in patients with TAA(P=0.006,OR=0.304).The mRNA short splice variant of KLK1 was up-regulated within both TAA(P<0.001)and AAA(P<0.001)compared to control samples.This study suggests that rs5516 in KLK1 may contribute to the risk of developing later stage TAA.