Sequence variant on 9p21 is associated with the presence of abdominal aortic aneurysm disease but does not have an impact on aneurysmal expansion

Department of Cardiovascular Genetics, Rayne Building, UCL, UK.
European journal of human genetics: EJHG (Impact Factor: 4.23). 11/2008; 17(3):391-4. DOI: 10.1038/ejhg.2008.196
Source: PubMed

ABSTRACT Abdominal aortic aneurysm (AAA) is among a number of vascular disorders to be recently associated with a common allelic variant situated on chromosome 9p21. To further assess the significance of this region of the genome in AAA development, we genotyped the sequence variation tagged by rs10757278 in two geographically independent cohorts of patients and compared them to matched controls. We also assessed the impact of this variant on AAA growth rate in cohorts with a median surveillance period of 3.2 and 4.5 years. Using meta-analysis to combine the findings of both cohorts, we found a significant association between rs10757278-G and the presence of AAA (OR (95%CI) 1.38 (1.04-1.82) P=0.03), an effect size completely consistent with that originally reported. rs10757278 was not significantly associated with altered AAA growth rate in either cohort.

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    ABSTRACT: The 9p21.3 locus was the first to yield to genome-wide association studies (GWAS) seeking common genetic variants predisposing to increased risk of coronary artery atherosclerotic disease (CAD). The 59 single nucleotide polymorphisms that show highest association with CAD are clustered in a region 100,000 to 150,000 base pairs 5' to the cyclin-dependent kinase inhibitors CDKN2B (coding for p15(ink4b)) and CDKN2A (coding for p16(ink4a) and p14(ARF)). This region also covers the 3' end of a long noncoding RNA transcribed antisense to CDKN2B (CDKN2BAS, aka ANRIL for antisense noncoding RNA at the ink4 locus) whose expression has been linked to chromatin remodeling at the locus. Despite intensive investigation over the past 7 years, the functional significance of the 9p21.3 locus remains elusive. Other variants at this locus have been associated with glaucoma, glioma, and type 2 diabetes mellitus, diseases that implicate tissue-resident macrophages. Here, we review the evidence that genetic variants at 9p21.3 disrupt tissue-specific enhancers and propose new insights to guide future studies.
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a prevalent and potentially life-threatening disease. Early detection by screening programs and subsequent surveillance has been shown to be effective at reducing the risk of mortality due to aneurysm rupture. The aim of this review is to summarize the developments in the literature concerning the latest biomarkers (from 2008 to date) and their potential screening and therapeutic values. Our search included human studies in English and found numerous novel biomarkers under research, which were categorized in 6 groups. Most of these studies are either experimental or hampered by their low numbers of patients. We concluded that currently no specific laboratory markers allow screeing for the disease and monitoring its progression or the results of treatment. Further studies and studies in larger patient groups are required in order to validate biomarkers as cost-effective tools in the AAA disease.
    BioMed Research International 05/2014; 2014:925840. DOI:10.1155/2014/925840 · 2.71 Impact Factor
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    ABSTRACT: Several studies have reported that polymorphisms on chromosome 9p21.3, near the CDKN2A/2B gene, are strongly associated with increased susceptibility to abdominal aortic aneurysm (AAA). However, no convincing data has been reported on a relationship between AAA and these variants in the Chinese Han population. The aim of this study was to evaluate the role of rs10757278 and rs1333049 in determining genetic susceptibility to AAA. A total of 155 AAA patients and 310 controls, comparable in age and gender, were enrolled in this study. DNA samples were genotyped for rs10757278 and rs1333049 using the MassArray system. The association between these two single nucleotide polymorphisms and AAAs was tested using multivariate logistic regression. Stratified analysis was also performed by clinical and laboratory features. Single nucleotide polymorphisms rs10757278 and rs1333049 were significantly associated with increased risk of AAA. The frequencies of rs10757278-G and rs1333049-C in AAA patients were significantly higher than in control subjects (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.11-2.11; P = .01, and OR, 1.48; 95% CI, 1.07-2.05; P = .02). Multiple logistic regression analysis indicated that, after adjusting for smoking habits, drinking habits, and histories of other chronic diseases, homozygosity of the risk allele for rs10758278-G and rs1333049-C also increased the likelihood of AAA (OR, 2.31; 95% CI, 1.22-4.36, and OR, 2.14; 95% CI, 1.13-4.05). The frequency of the GC haplotype was significantly higher in AAA patients than in control subjects (OR, 1.44; P = .038). Stratification analysis of clinical and laboratory features revealed no association between polymorphisms and aortic diameters in AAA patients. There was a significantly high frequency of the rs10757278 GG genotype in AAA patients with high serum total homocysteine compared with those control subjects with high serum total homocysteine (OR, 2.71; 95% CI, 1.12-6.58; P = .03) indicating that the genotype GG of rs10757278 might interact with the homocysteine biological pathway to stimulate the presence of AAA. Present data demonstrate that rs10757278 and rs1333049 on chromosome 9p21.3 are significantly associated with increased risk of AAA in the Chinese population and emphasize the need to further study the role of these markers in AAA.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 12/2013; 59(4). DOI:10.1016/j.jvs.2013.10.095 · 2.98 Impact Factor

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