[SNP] with a p value <1×10−5) in 2,871 additional cases and 32,687 controls and performed further follow-up in 1,491 abdominal aortic aneurysms and 11,060 controls. “In the discovery study, nine loci demonstrated association with abdominal aortic aneurysms (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),” Bown said. “We confirmed the association of rs1466535 and abdominal aortic aneurysm in our follow-up study (p=0.035).
In a combined analysis (6,228 abdominal aortic aneurysms and 49,182 controls), rs1466535 had a consistent effect size and direction in all sample sets. 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 abdominal aortic aneurysms. “Our findings suggest a mechanism contributing to abdominal aortic aneurysm formation via the LRP1 pathway, and exploration of this mechanism could provide future therapeutic approaches to preventing the development and/or progression of abdominal aortic aneurysms,” Bown et al reported.
“This study identifies a biological process that could be altered using drugs and therefore treat aneurysms, either to prevent them completely or to prevent them growing,” Bown said. “The key challenges are to identify how the protein produced by this gene causes or protects against aneurysms and then work out ways to reduce or increase the activity of the protein or pathway that this protein is involved in. The next step is to find out how the protein produced by this gene is involved in the development of aneurysms,” he noted.
He concluded that the gene was aortic aneurysm specific and that it was biologically plausible. In the discussion after his study was presented, Martin Bjorck, Uppsala, Sweden, asked Bown about the possible interaction between the LRP1 gene and environmental factors. Bown said their data was limited and not powered to detect such an interaction. Janet Powell, London, UK, commented: “The reason why we white people get aneurysms must partly be because of our environment and partly because of our genes.”
The research, funded by The Wellcome Trust, was published in The American Journal of Human Genetics in November 2011.