TY - JOUR
T1 - A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm
AU - Jones, Gregory T.
AU - Bown, Matthew J.
AU - Gretarsdottir, Solveig
AU - Romaine, Simon P.R.
AU - Helgadottir, Anna
AU - Yu, Grace
AU - Tromp, Gerard
AU - Norman, Paul E.
AU - Jin, Cao
AU - Baas, Annette F.
AU - Blankensteijn, Jan D.
AU - Kullo, Iftikhar J.
AU - Victoria Phillips, L.
AU - Williams, Michael J.A.
AU - Topless, Ruth
AU - Merriman, Tony R.
AU - Vasudevan, Thodor M.
AU - Lewis, David R.
AU - Blair, Ross D.
AU - Hill, Andrew A.
AU - Sayers, Robert D.
AU - Powell, Janet T.
AU - Deloukas, Panagiotis
AU - Thorleifsson, Gudmar
AU - Matthiasson, Stefan E.
AU - Thorsteinsdottir, Unnur
AU - Golledge, Jonathan
AU - Ariëns, Robert A.
AU - Johnson, Anne
AU - Sohrabi, Soroush
AU - Julian Scott, D.
AU - Carey, David J.
AU - Erdman, Robert
AU - Elmore, James R.
AU - Kuivaniemi, Helena
AU - Samani, Nilesh J.
AU - Stefansson, Kari
AU - van Rij, Andre M.
N1 - Funding Information:
Funding for the New Zealand project was provided by the Health Research Council of New Zealand (08/075). The WTCCC project was funded by the Wellcome Trust under awards 076113, 085475 and 084695. The collection of samples and genotyping at Geisinger Clinic was supported by a grant from the Pennsylvania Commonwealth Universal Research Enhancement Program (to D.J.C.); and a Grant-In-Aid from the American Heart Association (to D.J.C.). The Geisinger MyCodew Project was funded in part by a grant from the Ben Franklin Technology Development Fund of Pennsylvania. The deCODE study was funded in part through grants from the European Community’s Seventh Framework Programme (FP7/2007–2013), FAD project grant agreement; HEALTH-F2–2008-200647 and ENGAGE project, grant agreement HEALTH-F4-2007-201413. The Netherland cohort was funded by the Netherlands Heart Foundation (2009T001). LEADS (Leeds Aneurysm Development Study) is supported by the Garfield Weston Trust for Medical Research into Diseases of the Heart. The Health In Men Study (Western Australia) was funded by National Health and Medical Research Project Grant 303232. J.G. holds a Practitioner Fellowship from the National Health and Medical Research Council, Australia (1019921) and a Senior Clinical Research Fellowship from the Queensland Government. The Mayo eMERGE study was supported by the grant U01-HG04599 from the National Human Genome Research Institute. The Belgian and Canadian sample collections were funded in part by the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL045996 and HL06410 to H.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2013/7
Y1 - 2013/7
N2 - 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 5 7.2 3 10214). 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.
AB - 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 5 7.2 3 10214). 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.
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U2 - 10.1093/hmg/ddt141
DO - 10.1093/hmg/ddt141
M3 - Article
C2 - 23535823
AN - SCOPUS:84880305065
SN - 0964-6906
VL - 22
SP - 2941
EP - 2947
JO - Human molecular genetics
JF - Human molecular genetics
IS - 14
M1 - ddt141
ER -