Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

被引：149

作者：

Bown, Matthew J. ^{[1
]}

Jones, Gregory T. ^{[2
]}

Harrison, Seamus C. ^{[3
]}

Wright, Benjamin J. ^{[1
]}

Bumpstead, Suzannah ^{[4
]}

Baas, Annette F. ^{[5
]}

Gretarsdottir, Solveig ^{[6
,7
]}

Badger, Stephen A. ^{[8
]}

Bradley, Declan T. ^{[8
]}

Burnand, Kevin ^{[9
]}

Child, Anne H. ^{[10
]}

Clough, Rachel E. ^{[9
]}

Cockerill, Gillian ^{[10
]}

Hafez, Hany ^{[11
]}

Scott, D. Julian A. ^{[12
]}

Futers, Simon ^{[12
]}

Johnson, Anne ^{[12
]}

Sohrabi, Soroush ^{[12
]}

Smith, Alberto ^{[9
]}

Thompson, Matthew M. ^{[10
]}

van Bockxmeer, Frank M. ^{[13
]}

Waltham, Matthew ^{[9
]}

Matthiasson, Stefan E. ^{[14
]}

Thorleifsson, Gudmar ^{[6
,7
]}

Thorsteinsdottir, Unnur ^{[6
,7
]}

Blankensteijn, Jan D. ^{[15
]}

Teijink, Joep A. W. ^{[16
]}

Wijmenga, Cisca ^{[17
]}

de Graaf, Jacqueline ^{[18
]}

Kiemeney, Lambertus A. ^{[18
]}

Assimes, Themistocles L. ^{[19
]}

McPherson, Ruth ^{[20
]}

Folkersen, Lasse ^{[21
]}

Franco-Cereceda, Anders ^{[21
]}

Palmen, Jutta ^{[3
]}

Smith, Andrew J. ^{[3
]}

Sylvius, Nicolas ^{[1
]}

Wild, John B. ^{[1
]}

Refstrup, Mette ^{[22
]}

Edkins, Sarah ^{[4
]}

Gwilliam, Rhian ^{[4
]}

Hunt, Sarah E. ^{[4
]}

Potter, Simon ^{[4
]}

Lindholt, Jes S. ^{[23
]}

Frikke-Schmidt, Ruth ^{[22
]}

Tybjaerg-Hansen, Anne ^{[22
]}

Hughes, Anne E. ^{[8
]}

Golledge, Jonathan ^{[24
]}

Norman, Paul E. ^{[13
]}

van Rij, Andre ^{[2
]}

机构：

[1] Univ Leicester, Dept Cardiovasc Sci, Leicester LE2 7LX, Leics, England

[2] Univ Otago, Dept Anat, Dunedin 9054, New Zealand

[3] UCL, London WC1E 6JF, England

[4] Wellcome Trust Sanger Inst, Genet Complex Traits Humans Grp, Cambridge CB10 1SA, England

[5] Univ Med Ctr Utrecht, Med Genet Res Sect, NL-3584 CG Utrecht, Netherlands

[6] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[7] deCODE Genet, IS-101 Reykjavik, Iceland

[8] Queens Univ, Sch Med, Belfast BT7 1NN, Antrim, North Ireland

[9] Kings Coll London, Dept Vasc Surg, London WC2R 2LS, England

[10] St Georges Univ London, Dept Vasc Surg, London SW17 0RE, England

[11] St Richards Hosp, Dept Vasc Surg, Chichester PO19 6SE, England

[12] Univ Leeds, Leeds Inst Genet Hlth & Tech, Leeds LS2 9JT, W Yorkshire, England

[13] Univ Western Australia, Dept Surg, Crawley, WA 6009, Australia

[14] Laekning Med Clin, IS-108 Reykjavik, Iceland

[15] Vrije Univ Amsterdam, Med Ctr, Dept Vasc Surg, NL-1007 MB Amsterdam, Netherlands

[16] Catharina Hosp, Dept Vasc Surg, NL-5623 EJ Eindhoven, Netherlands

[17] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[18] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands

[19] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[20] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON K1Y 4W7, Canada

[21] Karolinska Inst, SE-17177 Stockholm, Sweden

[22] Copenhagen Univ Hosp, Dept Clin Biochem, DK-2100 Copenhagen, Denmark

[23] Viborg Hosp, Dept Vasc Surg, DK-8800 Viborg, Denmark

[24] James Cook Univ, Vasc Biol Unit, Townsville, Qld 4811, Australia

[25] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London SW7 2AZ, England

[26] Univ Leicester, Dept Hlth Sci, Leicester LE2 7LX, Leics, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2011年 / 89卷 / 05期

基金：

英国惠康基金; 瑞典研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; SEQUENCE VARIANT; VASCULAR WALL; DISEASE; METALLOPROTEINASE; IDENTIFICATION; GELATINASE; EXPRESSION; MUTATIONS;

D O I：

10.1016/j.ajhg.2011.10.002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 x 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 x 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.

引用

页码：619 / 627

页数：9

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