A Variant in LDLR is Associated with Abdominal Aortic Aneurysm

Declan T Bradley, Anne E Hughes, Stephen A Badger, Gregory T Jones, Seamus C Harrison, Benjamin J Wright, Suzannah Bumpstead, Annette F Baas, Solveig Gretarsdottir, Kevin Burnand, Anne H Child, Rachel Clough, Gillian Cockerill, Hany Hafez, D Julian A Scott, Robert A S Ariëns, Anne Johnson, Soroush Sohrabi, Alberto Smith, Matthew M ThompsonFrank M van Bockxmeer, Matthew Waltham, Stefan E Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D Blankensteijn, Joep A W Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A Kiemeney, John B Wild, Sarah Edkins, Rhian Gwilliam, Sarah E Hunt, Simon Potter, Jes S Lindholt, Jonathan Golledge, Paul E Norman, Andre van Rij, Janet T Powell, Per Eriksson, Kari Stefansson, John R Thompson, Steve E Humphries, Robert D Sayers, Panos Deloukas, Nilesh J Samani, Matthew J Bown

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

Abstract

Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.

Methods and Results—A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10−4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83; P=2.08×10−10).

Conclusions—LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.
Original languageEnglish
Article numberN/A
Pages (from-to)498-504
Number of pages7
JournalCirculation-Cardiovascular Genetics
Volume6
Issue number5
DOIs
Publication statusE-pub ahead of print - Oct 2013

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