Abdominal aortic aneurysm is a multifactorial disorder with multiple genetic and environmental risk factors. The disorder may occur as part of a heritable syndrome or in isolation (summary by Kuivaniemi et al., 2003).
- Genetic Heterogeneity ... Abdominal aortic aneurysm is a multifactorial disorder with multiple genetic and environmental risk factors. The disorder may occur as part of a heritable syndrome or in isolation (summary by Kuivaniemi et al., 2003). - Genetic Heterogeneity of Abdominal Aortic Aneurysm Other mapped loci for abdominal aortic aneurysm include AAA2 (609782) on chromosome 4q31; AAA3 (611891) on chromosome 9p21; and AAA4 (614375) on chromosome 12q13.3.
Loosemore et al. (1988) described 2 brothers with abdominal aortic aneurysm at ages 58 and 62 years, whose father died of ruptured abdominal aortic aneurysm at the age of 72 years. Four other sibs died of myocardial infarction ... Loosemore et al. (1988) described 2 brothers with abdominal aortic aneurysm at ages 58 and 62 years, whose father died of ruptured abdominal aortic aneurysm at the age of 72 years. Four other sibs died of myocardial infarction at ages 47 to 61 years. Loosemore et al. (1988) suggested that a deficiency of type III collagen (see 120180) might be the basis for the aneurysm formation. The proportion of type III collagen in forearm skin biopsies was cited as accurately reflective of the proportion in the aorta and was said to have been low in the brothers. Ward (1992) looked for association of dilated peripheral arteries with aortic aneurysmal disease by measuring the diameters of the common femoral, popliteal, brachial, common carotid, internal carotid, and external carotid arteries by color-flow duplex scan in 30 control subjects and 36 patients with aortic aneurysm matched for age, sex, smoking habits, and hypertension. Mean peripheral artery diameter was significantly greater in patients with aortic aneurysms than in controls at all measurement sites. Peripheral artery dilatation was identified at sites that are seldom, if ever, involved in atherosclerosis. Ward (1992) concluded that there is a generalized dilating diathesis in aortic aneurysmal disease that may be unrelated to atherosclerosis. In the study of Verloes et al. (1995), familial male cases showed a significantly earlier age at rupture and a greater rupture rate as compared with sporadic male cases, as well as a tendency (p less than 0.05) towards earlier age of diagnosis. AAA occurs among approximately 1.5% of the male population older than 50 years of age. Several studies have indicated an increased frequency among first-degree relatives of patients with AAA. Aneurysms of the peripheral arteries (femoral, popliteal, and isolated iliac) are less common than aortic aneurysms (Lawrence et al., 1995), and arteriomegaly (diffuse aneurysmal disease) is even less common (Hollier et al., 1983). Peripheral aneurysms and arteriomegaly carry a high risk for complications such as rupture, embolism, or thrombosis.
Yoon et al. (1999) performed association studies using polymorphisms in the MMP3 (185250), MMP9 (120361), and PAI1 (173360) genes and DNA isolated from 47 AAA patients, 57 intracranial aneurysm (IA) patients, and ... - Associations Pending Confirmation Yoon et al. (1999) performed association studies using polymorphisms in the MMP3 (185250), MMP9 (120361), and PAI1 (173360) genes and DNA isolated from 47 AAA patients, 57 intracranial aneurysm (IA) patients, and 174 controls, all from Finland. The frequency of the 5A MMP3 allele (185250.0001) was somewhat higher in the AAA than in the control group (corrected p = 0.0609), whereas the MMP3 allele frequencies in the IA group did not differ from those of the controls. These findings suggested that the transcriptionally more active 5A MMP3 allele might be a genetic risk factor for AAA among Finns. The findings were in agreement with previous studies demonstrating higher levels of MMP3 expression in AAA than in control tissues. Yoon et al. (1999) found that PAI1 and MMP9 genotypes, including the PAI1 4G/5G polymorphism (173360.0002), did not associate with aneurysms. Noting that the 5G variant of the PAI1 4G/5G polymorphism is associated with less inhibition of the plasminogen activators and, consequently, increased conversion of plasminogen to plasmin and increased activation of MMPs, Rossaak et al. (2000) studied the ratios of the 4G:5G genotypes in 190 patients with AAA, including 39 patients with strong family histories, and 163 controls, and found that 26% of patients with familial AAA were homozygous 5G compared with 13% of the control population. The 4G allele frequency was 0.47 in the familial AAAs, compared with 0.62 in the nonfamilial patients (P = 0.02) and 0.61 in the control population (p = 0.03). Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells (Steinmetz et al., 2003). Ogata et al. (2005) hypothesized that genes involved in these events could harbor changes and make individuals more susceptible to aneurysms. They analyzed 387 Caucasian individuals with AAA and 425 controls for 14 polymorphisms in 13 candidate genes, and found significant association between variation in the TIMP1 gene (305370) and AAA in males without a family history (p = 0.0047 for nt+434 and p = 0.015 for dbSNP rs2070584). Baas et al. (2010) performed an association study of SNPs in the TGF-beta receptor genes TGFBR1 (190181) and TGFBR2 (190182) and AAA in a Dutch population. In the stage 1 analysis of 376 cases and 648 controls, 3 of the 4 TGFBR1 SNPs and 9 of the 28 TGFBR2 SNPs had a p value of less than 0.07. Genotyping of these SNPs in an independent cohort of 360 cases and 376 controls in stage 2 confirmed association (p less than 0.05) for the same allele of 1 SNP in TGFBR1 and 2 SNPs in TGFBR2. Joint analysis of the 736 cases and 1,024 controls showed statistically significant associations of these SNPs, which sustained after proper correction for multiple testing (TGFBR1 dbSNP rs1626340, OR = 1.32, 95% CI 1.11-1.56, p = 0.001; TGFBR2 dbSNP rs1036095, OR = 1.32, 95% CI 1.12-1.54, p = 0.001; dbSNP rs4522809, OR = 1.28, 95% CI 1.12-1.46, p = 0.0004). Baas et al. (2010) concluded that genetic variation in TGFBR1 and TGFBR2 associate with AAA in the Dutch population.