Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 619-627 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 89 |
| Issue number | 5 |
| DOIs | |
| State | Published - 11 Nov 2011 |
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In: American Journal of Human Genetics, Vol. 89, No. 5, 11.11.2011, p. 619-627.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1
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N1 - Funding Information: This study was funded by the Wellcome Trust (number 084695). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk . Funding for the WTCCC project was provided by the Wellcome Trust under award 076113 and 085475. Further funding was provided by the Higher Education Funding Council for England (M.J.B.), Health Research Council of New Zealand (08/075) (Vascular Research Consortium of New Zealand), National Health Medical Research Council (NHMRC) and the Office of Health and Medical Research (J.G.); Swedish Research Council, Swedish Heart-Lung foundation, the European Commission (FAD, Health-F2-2008-200647), a donation by Fredrik Lundberg (for the expression study); National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' National Health Service (NHS) Foundation Trust (R.C.), NHMRC (Australia), The Dunhill Medical Trust (Leicester), and the Garfield Weston Trust for Medical Research into Heart Surgery (Leeds) (provided additional funding for source cohorts); the European Community's Seventh Framework Programme (FP7/2007-2013); Fighting Aneurysmal Disease Project grant agreement HEALTH-F2-2008-200647 (provided replication data sets from Iceland and Netherlands); St George's Hospital NHS Trust Special Trustees and the Peter and Sonia Field Charitable Trust (A.H.C.); British Heart Foundation Clinical Training Fellowship (FS/11/16/28696) (S.E.H.); British Heart Foundation (RG2008/08) (S.E.H., A.J.S., J.P.); Netherlands Heart Foundation (2009T001) (A.F.B.); British Heart Foundation chairs (S.E.H and N.J.S.); and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease (M.J.B., R.D.S. and N.J.S.). deCODE genetics is a biotechnology company, and authors employed by deCODE own stock or stock options in the company.
PY - 2011/11/11
Y1 - 2011/11/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84945173643&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.10.002
DO - 10.1016/j.ajhg.2011.10.002
M3 - Article
AN - SCOPUS:84945173643
SN - 0002-9297
VL - 89
SP - 619
EP - 627
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -