title: Polymorphisms of genes involved in extracellular matrix remodeling and abdominal aortic aneurysm.
abstract: BACKGROUND
  Abdominal aortic aneurysm (AAA) has a multifactorial etiology and the relevance of genetic factors is getting increasing interest, in particular those related to the destructive remodeling of extracellular matrix.
  
  
  METHODS
  We performed a candidate gene association study of polymorphisms in genes coding matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and elastin (ELN) in AAA. DNA samples from 423 AAA patients and 423 controls were genotyped for 12 polymorphisms in 10 genes: MMP1 (-1607G/GG), MMP2 (-735C/T; -1306C/T; -1575 G/A), MMP3 (5A/6A), MMP9 (-1562C/T), MMP10 (A180G), MMP-12 (-82A/G), MMP-13 (-77A/G), TIMP1 (C434T), TIMP3 (-1296T/C), and ELN (G1355A).
  
  
  RESULTS
  Genotype distribution was significantly different between patients and controls for the following polymorphisms: -1306C/T MMP2; 5A/6A MMP3; -77A/G MMP-13; G1355A ELN; and C434T TIMP1. In a multivariable logistic regression analysis adjusted for traditional cardiovascular risk factors and chronic obstructive pulmonary disease, -1306C/T MMP2 (odds ratios [OR] = 0.55 [95% confidence interval, CI .34-.85], P < .007) and G1355A ELN (OR = 0.64 ([95% CI .41-.99], P = .046) polymorphisms resulted in independent protective factors for abdominal aortic aneurysm (AAA), whereas 5A/6A MMP3 (OR = 1.82 [95% CI 1.04-3.12], P = .034) and -77 A/G MMP-13 (OR = 2.14 [95% CI 1.18-3.86], P = .012) polymorphisms resulted in independent risk factors for AAA. In a multivariable logistic regression analysis adjusted for traditional cardiovascular factors and chronic obstructive pulmonary disease, the prevalence of the contemporary presence of three or four genetic risk conditions was a strong and independent determinant of AAA disease (OR = 2.96, 95% CI 1.67-5.24, P < .0001). For those polymorphisms independently associated with AAA in this study (-1306C/T MMP2, 5A/6A MMP3, -77A/G MMP-13, and G1355A ELN polymorphisms), we performed a meta-analysis of the available data (this paper and literature data). We found a significant association with an increased risk of AAA for MMP3 (AAA patients n = 1258, controls n = 1406: OR = 1.48 [95% CI = 1.23-1.78], I(2) = 0%) and MMP-13 (AAA patients n = 800, controls n = 843: OR = 1.37 [95% CI = 1.04-1.82], I(2) = 25%) polymorphisms and a trend that did not reach the statistical significance, toward a decreased risk of AAA for MMP2 (AAA patients n = 1090, controls n = 1077: OR = 0.83 [95% CI = .60-1.15], I(2) =7 1%) and ELN (AAA patients n = 904, controls n = 1069: OR = 0.79 [95% CI = .53-1.18], I(2) = 72%) polymorphisms.
  
  
  CONCLUSIONS
  These findings suggest that polymorphisms in MMP2, MMP3, MMP-13, and ELN genes may independently contribute to the pathogenesis of AAA.
authors.affiliation: Department of Medical and Surgical Critical Care, University of Florence, Atherothrombotic Diseases Center, Florence, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Saracini
authors.forename: Paola
authors.initials: P
authors.lastname: Bolli
authors.forename: Elena
authors.initials: E
authors.lastname: Sticchi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pratesi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Pulli
authors.forename: Francesco
authors.initials: F
authors.lastname: Sofi
authors.forename: Carlo
authors.initials: C
authors.lastname: Pratesi
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Gensini
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
mesh_terms: D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004549:Elastin / Q000235:genetics* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy; D016015:Logistic Models; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D004549:Elastin; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2