A variant in LDLR is associated with abdominal aortic aneurysm

Journal Publication ResearchOnline@JCU
Bradley, Declan T.;Hughes, Anne E.;Badger, Stephen A.;Jones, Gregory T.;Harrison, Seamus C.;Wright, Benjamin J.;Bumpstead, Suzannah;Baas, Annette F.;Gretarsdottir, Solveig;Burnand, Kevin;Child, Anne H.;Clough, Rachel E.;Cockerill, Gillian;Hafez, Hany;Scott, D. Julian A.;Ariëns, Robert A.S.;Johnson, Anne;Sohrabi, Soroush;Smith, Alberto;Thompson, Matthew M.;van Bockxmeer, Frank M.;Waltham, Matthew;Matthiasson, Stefan E.;Thorleifsson, Gudmar;Thorsteinsdottir, Unnur;Blankensteijn, Jan;Teijink, Joep A.W.;Wijmenga, Cisca;de Graaf, Jacqueline;Kiemeney, Lambertus A.;Wild, John B.;Edkins, Sarah;Gwilliam, Rhian;Hunt, Sarah E.;Potter, Simon;Lindholt, Jes S.;Golledge, Jonathan;Norman, Paul E.;Van Rij, Andre;Powell, Janet T.;Eriksson, Per;Stefansson, Kari;Thompson, John R.;Humphries, Steve E.;Sayers, Robert D.;Deloukas, Panos;Samani, Nilesh J.;Brown, Matthew J.
Jonathan Golledge
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<1x10⁻⁴ were carried through to in silico replication in 1292 AAA cases and 30503 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=2.08x10⁻¹⁰. 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.

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6

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1942-3268

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5

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7

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Lippincott, Williams & Wilkins

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DOI

10.1161/CIRCGENETICS.113.000165