A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm

Jones, Gregory T., Brown, Matthew J., Gretarsdottir, Solveig, Romaine, Simon P.R., Helgadottir, Anna, Yu, Grace, Tromp, Gerard, Norman, Paul E., Jin, Cao, Baas, Annette F., Blankensteijn, Jan D., Kullo, Iftikhar J., Phillips, L. Victoria, Williams, Michael J.A., Topless, Ruth, Merriman, Tony R., Vasudevan, Thodor M., Lewis, David R., Blair, Ross D., Hill, Andrew A., Sayers, Robert D., Powell, Janet T., Deloukas, Panagiotis, Thorleifsson, Gudmar, Matthiasson, Stefan E., Thorsteinsdottir, Unnur, Golledge, Jonathan, Ariens, Robert A., Johnson, Anne, Sohrabi, Soroush, Scott, D. Julian, Carey, David J., Erdman, Robert, Elmore, James R., Kuivaniemi, Helena, Samani, Nilesh J., Stefansson, Kari, and van Rij, Andre M. (2013) A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm. Human Molecular Genetics, 22 (14). pp. 2941-2947.

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Abstract

Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76–0.85, P = 7.2 × 10⁻¹⁴). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case–control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.

Item ID: 27256
Item Type: Article (Research - C1)
ISSN: 1460-2083
Date Deposited: 31 May 2013 02:51
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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