Themistocles (Tim) Assimes

Publication Details

  • Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1 AMERICAN JOURNAL OF HUMAN GENETICS Bown, M. J., Jones, G. T., Harrison, S. C., Wright, B. J., Bumpstead, S., Baas, A. F., Gretarsdottir, S., Badger, S. A., Bradley, D. T., Burnand, K., Child, A. H., Clough, R. E., Cockerill, G., Hafez, H., Scott, D. J., Futers, S., Johnson, A., Sohrabi, S., Smith, A., Thompson, M. M., van Bockxmeer, F. M., Waltham, M., Matthiasson, S. E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J. D., Teijink, J. A., Wijmenga, C., de Graaf, J., Kiemeney, L. A., Assimes, T. L., McPherson, R., Folkersen, L., Franco-Cereceda, A., Palmen, J., Smith, A. J., Sylvius, N., Wild, J. B., Refstrup, M., Edkins, S., Gwilliam, R., Hunt, S. E., Potter, S., Lindholt, J. S., Frikke-Schmidt, R., Tybjaerg-Hansen, A., Hughes, A. E., Golledge, J., Norman, P. E., van Rij, A., Powel, J. T., Eriksson, P., Stefansson, K., Thompson, J. R., Humphries, S. E., Sayers, R. D., Deloukas, P., Samani, N. J. 2011; 89 (5): 619-627


    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.

    View details for DOI 10.1016/j.ajhg.2011.10.002

    View details for Web of Science ID 000297090100003

    View details for PubMedID 22055160

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