Bradley Declan T, Hughes Anne E, Badger Stephen A, Jones Gregory T, Harrison Seamus C, Wright Benjamin J, Bumpstead Suzannah, Baas Annette F, Grétarsdóttir Sólveig, 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, Matthíasson Stefán E, Thorleifsson Gudmar, Thorsteinsdottir Unnur, Blankensteijn Jan D, 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, Stefánsson Kári, Thompson John R, Humphries Steve E, Sayers Robert D, Deloukas Panos, Samani Nilesh J, Bown Matthew J
Circ Cardiovasc Genet. 2013 Oct;6(5):498-504. doi: 10.1161/CIRCGENETICS.113.000165. Epub 2013 Sep 17.
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.
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)).
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.
腹主动脉瘤（AAA）是老年人中常见的心血管疾病，具有显著的遗传易感性。与其他类似的复杂疾病相比，已证实的与AAA相关的基因关联相对较少。我们重新分析了我们的全基因组研究，并在较低的显著性水平上进行了提示性发现关联的验证。
使用来自英国、新西兰和澳大利亚的1830例肾下腹主动脉直径≥30mm或AAA破裂患者以及来自1958年出生队列和惠康信托病例对照研究联盟国家血液服务队列的5435例未筛查对照进行全基因组关联研究。对8个P<1×10(-4)的提示性关联在1292例AAA病例和30503例对照中进行了电子复制验证。在电子研究中，一个经Bonferroni校正后P<0.05的单核苷酸多态性进行了进一步验证（来自英国的706例AAA病例和1063例对照、来自丹麦的507例AAA病例和199例对照以及来自新西兰的885例AAA病例和1000例对照）。低密度脂蛋白受体（LDLR）rs6511720 A在总体以及5项个体复制研究中的3项中显著相关。完整研究显示该关联达到全基因组显著性水平（优势比，0.76；95%置信区间，0.70-0.83；P=2.08×10(-10)）。
LDLR rs6511720与AAA相关。这一发现与该变体对冠状动脉疾病的既定影响一致。与其他心血管疾病共享的因果途径可能为AAA的预防和治疗策略带来新的机遇。
