Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Abstract

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Migraine prevalence in patients with unruptured intracranial aneurysms: A case–control study

“…Also, endothelial dysfunction has been suggested in patients with migraine ( Lee et al., 2008; Yetkin, Ozisik, Ozcan, Aksoy, & Turhan 2006; Yetkin, Ozisik, Ozcan, Aksoy, & Turhan, 2007). Furthermore, genetic studies showed that a SNP in the LRP1 protein, that plays a role in vascular wall integrity, increases the risk of both migraine without aura and abdominal aneurysms (Bown et al., 2011; Freilinger, Anttila, De Vries, & Malik, 2013). The association between LRP1 and intracranial aneurysms has to our knowledge not been studied yet.…”

Candidate Gene Analysis of Arteriovenous Fistula Failure in Hemodialysis Patients

“…Moreover, LRP1 was shown to be essential for the maintenance of vascular wall integrity mediated through plateletderived growth factor receptor b and Smad signaling (29). Interestingly, in our study, patients carrying the variant A allele had a higher risk of developing AVF failure, whereas in the above-mentioned study (20), the wild-type allele was the risk allele. Whether this opposite effect indicates that AVF failure is mediated through a lack of vascular expansion, which is necessary for AVF maturation, or that another function LRP1 is involved in AVF failure is unclear.…”

“…In 2011, this SNP was identified in a genome-wide association study on abdominal aortic aneurysms and that this SNP has a possible functional role in LRP1 expression (20). The mechanism by which LRP1 could influence vascular remodeling leading to aneurysm formation, was suggested to involve regulation of MMP9 expression (20,28).…”

“…Furthermore, we also selected SNPs that were associated with coronary restenosis (13,17,18) and vascular aneurysm formation (19,20), because underlying mechanisms of these diseases are thought to overlap. A MEDLINE search using keywords including "hemodialysis," "arteriovenous access failure," and "single nucleotide polymorphism" identified six genes previously associated with AV access failure: TNF-a (21), klotho (22), fibrinogen-b (FGB) (23), factor V (24), and matrix metallopeptidase 1 (MMP1) (25).…”

Alcohol Consumption as a Risk Factor for Abdominal Aortic Aneurysm

“…Subsequent degradation of the extracellular matrix by proteases, with vascular smooth muscle cell apoptosis eventually leads to gradual dilatation of the abdominal aorta and formation of AAA [4]. Although there is likely to be a genetic component to AAA [5], aside from family history, the key clinical risk factors of increasing age, hypertension and smoking are the most widely established contributors affecting aneurysm development and growth [6][7][8][9][10]. Notwithstanding, women have an increased risk of AAA rupture [11].…”