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Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms.

ABSTRACT: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs.DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects.Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P = .0047; rs2070584, P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (chi 2 P = .014 and empirical P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 ( P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN ( P = .0169) and TIMP3 ( P = .0023) in cases with a family history of AAA.These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease.Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.

SUBMITTER: Ogata T

PROVIDER: S-EPMC1249499 | biostudies-literature | 2005 Jun

REPOSITORIES: biostudies-literature

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Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms.

Ogata Toru T Shibamura Hidenori H Tromp Gerard G Sinha Moumita M Goddard Katrina A B KA Sakalihasan Natzi N Limet Raymond R MacKean Gerald L GL Arthur Claudette C Sueda Taijiro T Land Susan S Kuivaniemi Helena H

Journal of vascular surgery 20050601 6

<h4>Background</h4>Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothe ...[more]

PMID: 15944607

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Project description:BACKGROUND:The natural history of abdominal aortic aneurysms (AAAs) suggests that some remain slow in growth rate whereas many develop a more accelerated growth rate and reach a threshold for intervention. We hypothesized that different mechanisms are responsible for AAAs that remain slow growing and never become actionable vs the aggressive AAAs that require intervention and may be reflected by distinct associations with genetic polymorphisms. METHODS:AAA growth rate was determined from serial imaging data in 168 control and 141 AAA patients with ultrasound or computed tomography imaging studies covering ?5 years. Genetic polymorphisms all previously reported as showing a significant correlation with AAA with functional effects on the expression or function were determined by analysis of the genomic DNA, including angiotensin 1 receptor (rs5186), interleukin-10 (IL-10; rs1800896), methyl-tetrahydrofolate reductase (rs1801133), low-density lipoprotein receptor-related protein 1 (LRP1; rs1466535), angiotensin-converting enzyme (rs1799752), and several matrix metalloproteinase 9 (MMP-9) single nucleotide polymorphisms. RESULTS:Of the AAA patients, 81 were classified as slow AAA growth rate (<3.25 mm/y) vs 60 with aggressive AAA growth rate (>3.25 mm/y, those presenting with a rupture, or those with maximal aortic diameter >5.5 cm [male] or >5.0 cm [female]). Discriminating confounds between the groups were identified by logistic regression. Analyses identified MMP-9 p-2502 single nucleotide polymorphism (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.31-0.94; P = .029) as a significant confound discriminating between control vs slow-growth AAA, MMP-9 D165N (OR, 0.49; 95% CI, 0.26-0.95; P = .035) and LRP1 (OR, 4.99; 95% CI, 1.13-22.1; P = .034) between control vs aggressive-growth AAAs, and methyltetrahydrofolate reductase (OR, 2.99; 95% CI, 1.01-8.86; P = .048), MMP-9 p-2502 (OR, 2.19; 95% CI, 1.05-4.58; P = .037), and LRP1 (OR, 4.96; 95% CI, 1.03-23.9; P = .046) as the statistically significant confounds distinguishing slow-growth AAAs vs aggressive-growth AAAs. CONCLUSIONS:Logistic regression identified different genetic confounds for the slow-growth and aggressive-growth AAAs, indicating a potential for different genetic influences on AAAs of distinct aggressiveness. Future logistic regression studies investigating for potential genetic or clinical confounds for this disease should take into account the growth rate and size of the AAA to better identify confounds likely to be associated with aggressive AAAs likely to require intervention.

Project description:Abdominal aortic aneurysm (AAA) is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM) database.Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22) were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies.Several SNPs were nominally associated with AAA (p < 0.05). The SNPs with most significant p-values were located near the CCAAT enhancer binding protein (CEBPG), peptidase D (PEPD), and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP) database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non-aneurysmal tissue samples.Association testing of the functional positional candidate genes on the AAA1 locus on chromosome 19q13 demonstrated nominal association in three genes. PEPD and CD22 were considered the most promising candidate genes for altering AAA risk, based on gene function, association evidence, gene expression, and protein expression.

Project description:BACKGROUND:An abdominal aortic aneurysm (AAA) is an abnormal ballooning of the major abdominal artery. Some AAAs present as emergencies and require surgery; others remain asymptomatic. Treatment of asymptomatic AAAs depends on many factors but an important one is size of the aneurysm, as risk of rupture increases with aneurysm size. Large asymptomatic AAAs (> 5.5 cm in diameter) are usually operated on; very small AAAs (< 4.0 cm diameter) are monitored with ultrasonography. The optimal timing of surgery would benefit from further evidence. OBJECTIVES:This review compared long-term survival in patients with AAAs of diameter 4.0 to 5.5 cm who received immediate repair versus routine ultrasound surveillance. SEARCH METHODS:For this update the Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (February 2012) and CENTRAL (2012, Issue 1). Reference lists of relevant articles were checked for additional studies and the searches were supplemented by handsearches of recent conference proceedings and information from experts in the field. SELECTION CRITERIA:Randomised controlled trials in which men and women with asymptomatic AAAs of diameter 4.0 to 5.5 cm were randomly allocated to immediate repair or imaging-based surveillance at least every six months. Outcomes had to include mortality or survival. DATA COLLECTION AND ANALYSIS:Two authors (GF, MAMM) abstracted the data, which were cross-checked by the other authors (DJB, JTP). Due to the small number of trials, formal tests of heterogeneity and sensitivity analyses were not conducted. MAIN RESULTS:Four trials with a combined total of 3314 patients, the UK Small Aneurysm Trial (UKSAT), the Aneurysm Detection and Management (ADAM) trial, the Comparison of Surveillance Versus Aortic Endografting for Small Aneurysm Repair (CAESAR), and the Positive Impact of Endovascular Options for treating Aneurysms Early (PIVOTAL) fulfilled the inclusion criteria. The four trials showed an early survival benefit in the surveillance group (due to 30-day operative mortality with surgery) but no significant differences in long-term survival (adjusted hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.75 to 1.02, mean follow up 10 years (UKSAT); HR 1.21, 95% CI 0.95 to 1.54, mean follow up 4.9 years (ADAM); HR 0.76, 95% CI 0.30 to 1.93, median follow up 32.4 months (CAESAR); HR 1.01, 95% CI 0.49 to 2.07, mean follow up 20 months (PIVOTAL)). The meta analyses of mortality at one year (CAESAR and PIVOTAL only) and six years (UKSAT and ADAM only) revealed a non-significant association (Peto odds ratio at one year 1.15, 95% CI 0.59 to 2.25; Peto odds ratio at six years 1.11, 95% CI 0.91 to 1.34). AUTHORS' CONCLUSIONS:The results from the four trials to date demonstrate no advantage to early repair (via open or endovascular surgery) for small AAA (4.0 to 5.5 cm) and suggest that 'best care' for these patients favours surveillance. Furthermore, the more recent trials focused on the efficacy of endovascular aneurysm repair and still failed to show benefit. Thus, both open and endovascular repair of small AAAs are not supported by currently available evidence.

Dataset Information

Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms.

Publications

Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms.

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