Association of a matrix metallopeptidase 1 gene polymorphism with long-term outcome of thoracic aortic aneurysm

Abstract

Abstract. Although genetic variants are thought to contribute to the development of thoracic aortic aneurysm including dissection (TAA), it remains unclear whether gene polymorphisms are associated with the long-term outcome of TAA. The purpose of the present study was to identify genetic variants associated with the long-term outcome of medically treated patients with TAA. A total of 103 medically-treated patients with TAA (13 aneurysms and 90 dissections) were retrospectively studied for their outcomes (mean follow-up period, 24 months). The genotypes for 95 polymorphisms of 89 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the Chi-square test and subsequent multivariable logistic regression analysis with adjustment for covariates revealed that the -340A→G polymorphism (rs514921) of the matrix metallopeptidase 1 gene (MMP1) was significantly (P=0.0288) associated with the outcome of TAA, with the minor G allele being related to a favorable outcome. The aneurysm diameter was significantly (P=0.0167) smaller in the combined group of the AG and GG genotypes for this polymorphism than in subjects with the AA genotype. Kaplan-Meier survival curves constructed according to MMP1 genotypes showed a more favorable outcome of TAA (log-rank P=0.0146) in subjects with the G allele of rs514921. Determination of genotype for this polymorphism may prove informative for assessment of the long-term outcome of TAA. IntroductionThoracic aortic aneurysm including dissection (TAA) is a serious condition that results from aortic atherosclerosis and is a leading cause of mortality (1). Recent studies on the genetic basis of familial TAA have focused on its relation to systemic connective tissue disorders such as the Marfan syndrome (2) and the Ehlers-Danlos syndrome (3). However, up to 19% of individuals with non-syndromic TAA referred for surgery have been found to have affected first-degree relatives (4). In addition to conventional risk factors for TAA including age, arteriosclerosis, hypertension, and inflammatory or autoimmune diseases, genetic epidemiological studies have suggested that genetic variants contribute to the initiation and progression of this condition (5,6). It has remained unclear, however, whether gene polymorphisms are associated with the long-term outcome of TAA.Although computed tomography (7) parameters are currently applied to prediction of the risk for TAA rupture, only the relative, not the individual, rupture risk can be determined (8). The identification of gene polymorphisms related to the long-term outcome of medically-treated TAA may therefore lead to a better understanding of the factors relevant to the progression and rupture of TAA, and consequently may better inform the selection of patients as candidates for surgical therapy because of a higher risk of rupture.We have now performed an association study for 95 polymorphisms of 89 candidat...

Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants

“…Evaluation of genotype distributions by the Chi-square test and subsequent multivariable logistic regression analysis with adjustment for covariates revealed that the −340A → G polymorphism (rs514921) of MMP-1 gene was significantly (P = 0.0288) associated with the outcome of TAA, with the minor G allele being related to a favorable outcome [30].…”

The genetic architecture of non-syndromic thoracic aortic aneurysm

“…In a smaller study, it was suggested that patients with STAAD were five times more likely to have the G-allele of the MMP9 -8202A/G polymorphism compared with control subjects 53. Other studies have demonstrated associations with SNPs on 9p21 (near CDKN2B-AS1 ) and in MMP1 gene 54 55. Matrix metalloproteinases are enzymes involved in the breakdown of extracellular matrix.…”

Association between endothelial nitric oxide synthase intron 4a/b polymorphism and aortic dissection

“…[1,15,16] Previous studies have shown an association between ACE gene polymorphism and matrix metallopeptidase-1 gene polymorphism and AD. [12,13] To our knowledge, this is the first study investigating the relationship between AD and eNOS 4a/b polymorphism.…”

“…[6][7][8][9][10][11] Additionally, the eNOS gene polymorphism has been shown to be associated with HT. [12,13] In AD, formation of intimal tear and dissection represents the end point of chronic atherosclerotic and inflammatory changes in the aortic wall. It is possible that impaired metabolism of NO secondary to genetic predisposition may influence the aortic wall.…”