The Association Between Adominal Aortic Aneurysm And Polymorphisms Of Extracellular Matrix Degradation Pathway Ralated Genes And Serum MMP-2 Level

Object:One of the important pathological features of abdominal aortic aneurysm (AAA) is the degradation and reconstruction of extracellular matrix (ECM). The most closely associated enzymes are the matrix metalloproteinases (MMP) family. This study was to explore the association between the extracellular matrix degradation pathways related gene polymorphism loci and haplotypes and abdominal aortic aneurysm. This study also investigates the gene-gene and gene-environment complex interactions to abdominal aortic aneurysm. The association between serum level of MMP-2 and the development of AAA is also the object of this study.Methods:This study is a 1:2 frequency matched case-control study. The AAA case group was enrolled in the hospital (155 participants), While the control group was enrolled both in hospital and a community (310 participants). Through a standard questionnaire to collect the research object of general demographic data, medical history, and personal behavior factors. Physical examination and blood biochemical laboratory tests were also performed in both groups. The method of time of flight mass spectrometry (TOF MS) was applied to genotype 17 single nucleotide polymorphisms (SNP) of MMP2, MMP3, MMP9, MMP13, TIMP1 and TIMP2, ELN, COL5A1. The serum level of MMP-2 was tested. The influence of gene-gene and gene-environment interactions to abdominal aortic aneurysm were also calculated with generalized multifactor dimensionality reduction (GMDR) method.Results:(1) Smoking, hypertension and dyslipidemia can significantly increase the risk of the occurrence of AAA(OR=5.23,95%CI:2.44,11.23; OR=1.88,95%CI:1.12,3.18; OR=2.61,95%CI:1.45,4.70). There are correlations between AAA and high sensitive c-reactive protein and homocysteine levels, respectively (OR=2.43,95%CI: 1.37,4.31; OR=2.73,95%CI:1.61,4.65).(2) The MMP2 rs243865 allele distribution between AAA patients and controls have significant differences (Pcorr=5*10-4). Rs243865-T can increase the risk of abdominal aortic aneurysm under dominant, recessive and additive genetic model (dominant OR=1.76,95%CI:1.13,2.74; recessive OR=5.12,95%CI:1.77,14.81; additive OR=1.79,95%CI:1.25,2.57).(3) There exists weak linkage disequilibrium between MMP2 rs243865 and rs243866. After adjusting a variety of environmental risk factors there still found that AT haplotype can increase the risk of abdominal aortic aneurysm(OR=2.25,Pcorr =0.002; OR=2.48,Pcorr=0.01).(4) The association between serum level of MMP-2 and abdominal aortic aneurysm was not found (P>0.05). Serum level of MMP-2 negatively associated with abdominal aortic diameter (T-value<0, P<0.05), but the correlation intensity was low (Adj R2<0.2). A curve fitting of the serum concentration of MMP-2 and abdominal aortic diameter was performed, which found within 60 mm diameter, serum level of MMP-2 is steady; with the enlargement of the abdominal aorta diameter after, MMP-2 levels showed a trend of decline.(5) It is not found that the different genotypes and alleles of six SNP in MMP2 gene have significant difference between MMP-2 serum levels(P>0.05).(6) There exist interactions between rs243865 and rs243866, hyperlipidemia and rs243865, respectively, which can affect the incidence of abdominal aortic aneurysm. But this effect disappeared after adjustment of demographic factors.Conclusion:This study found that smoking, high blood pressure and dyslipidemia is AAA environmental risk factors; MMP2 rs243865 -t and rs243866 AT haplotype may be composed of genetic risk factors for abdominal aortic aneurysm; Gene-gene and gene-environment interaction may be associated with abdominal aortic aneurysm. Further exploration is needed.