Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Matthew J Bown; Gregory T Jones; Seamus C Harrison; Benjamin J Wright; Suzannah Bumpstead; Annette F Baas; Solveig Gretarsdottir; Stephen A Badger; Declan T Bradley; Kevin Burnand; Anne H Child; Rachel E Clough; Gillian Cockerill; Hany Hafez; D Julian A Scott; Simon Futers; Anne Johnson; Soroush Sohrabi; Alberto Smith; Matthew M Thompson; Frank M van Bockxmeer; Matthew Waltham; Stefan E Matthiasson; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Jan D Blankensteijn; Joep A W Teijink; Cisca Wijmenga; Jacqueline de Graaf; Lambertus A Kiemeney; Themistocles L Assimes; Ruth McPherson; Lasse Westergaard Folkersen; Anders Franco-Cereceda; Jutta Palmen; Frank Andrew Smith; Nicolas Sylvius; John B Wild; Mette Refstrup; Sarah Edkins; Rhian Gwilliam; Sarah E Hunt; Simon Potter; Jes S. Lindholt; Ruth Frikke-Schmidt; Anne Tybjærg-Hansen; Anne E Hughes; Jonathan Golledge; Paul E Norman; Andre van Rij; CARDIoGRAM Consortium

doi:http://dx.doi.org/10.1016/j.ajhg.2011.10.002

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Matthew J Bown, Gregory T Jones, Seamus C Harrison, Benjamin J Wright, Suzannah Bumpstead, Annette F Baas, Solveig Gretarsdottir, Stephen A Badger, Declan T Bradley, Kevin Burnand, Anne H Child, Rachel E Clough, Gillian Cockerill, Hany Hafez, D Julian A Scott, Simon Futers, Anne Johnson, Soroush Sohrabi, Alberto Smith, Matthew M ThompsonFrank M van Bockxmeer, Matthew Waltham, Stefan E Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D Blankensteijn, Joep A W Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A Kiemeney, Themistocles L Assimes, Ruth McPherson, Lasse Westergaard Folkersen, Anders Franco-Cereceda, Jutta Palmen, Frank Andrew Smith, Nicolas Sylvius, John B Wild, Mette Refstrup, Sarah Edkins, Rhian Gwilliam, Sarah E Hunt, Simon Potter, Jes S. Lindholt, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen, Anne E Hughes, Jonathan Golledge, Paul E Norman, Andre van Rij, CARDIoGRAM Consortium

119 Citations (Scopus)

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
Journal	American Journal of Human Genetics
Volume	89
Issue number	5
Pages (from-to)	619-27
Number of pages	9
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2011.10.002
Publication status	Published - 11 Nov 2011

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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. A., Futers, S., Johnson, A., Sohrabi, S., Smith, A., ... CARDIoGRAM Consortium (2011). Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1. American Journal of Human Genetics, 89(5), 619-27. https://doi.org/10.1016/j.ajhg.2011.10.002

Bown, MJ, Jones, GT, Harrison, SC, Wright, BJ, Bumpstead, S, Baas, AF, Gretarsdottir, S, Badger, SA, Bradley, DT, Burnand, K, Child, AH, Clough, RE, Cockerill, G, Hafez, H, Scott, DJA, Futers, S, Johnson, A, Sohrabi, S, Smith, A, Thompson, MM, van Bockxmeer, FM, Waltham, M, Matthiasson, SE, Thorleifsson, G, Thorsteinsdottir, U, Blankensteijn, JD, Teijink, JAW, Wijmenga, C, de Graaf, J, Kiemeney, LA, Assimes, TL, McPherson, R, Folkersen, LW, Franco-Cereceda, A, Palmen, J, Smith, FA, Sylvius, N, Wild, JB, Refstrup, M, Edkins, S, Gwilliam, R, Hunt, SE, Potter, S, Lindholt, JS, Frikke-Schmidt, R, Tybjærg-Hansen, A, Hughes, AE, Golledge, J, Norman, PE, van Rij, A & CARDIoGRAM Consortium 2011, 'Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1', American Journal of Human Genetics, vol. 89, no. 5, pp. 619-27. https://doi.org/10.1016/j.ajhg.2011.10.002

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title = "Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1",

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.",

author = "Bown, {Matthew J} and Jones, {Gregory T} and Harrison, {Seamus C} and Wright, {Benjamin J} and Suzannah Bumpstead and Baas, {Annette F} and Solveig Gretarsdottir and Badger, {Stephen A} and Bradley, {Declan T} and Kevin Burnand and Child, {Anne H} and Clough, {Rachel E} and Gillian Cockerill and Hany Hafez and Scott, {D Julian A} and Simon Futers and Anne Johnson and Soroush Sohrabi and Alberto Smith and Thompson, {Matthew M} and {van Bockxmeer}, {Frank M} and Matthew Waltham and Matthiasson, {Stefan E} and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Blankensteijn, {Jan D} and Teijink, {Joep A W} and Cisca Wijmenga and {de Graaf}, Jacqueline and Kiemeney, {Lambertus A} and Assimes, {Themistocles L} and Ruth McPherson and Folkersen, {Lasse Westergaard} and Anders Franco-Cereceda and Jutta Palmen and Smith, {Frank Andrew} and Nicolas Sylvius and Wild, {John B} and Mette Refstrup and Sarah Edkins and Rhian Gwilliam and Hunt, {Sarah E} and Simon Potter and Lindholt, {Jes S.} and Ruth Frikke-Schmidt and Anne Tybj{\ae}rg-Hansen and Hughes, {Anne E} and Jonathan Golledge and Norman, {Paul E} and {van Rij}, Andre and Anne Tybj{\ae}rg-Hansen",

year = "2011",

month = nov,

day = "11",

doi = "http://dx.doi.org/10.1016/j.ajhg.2011.10.002",

language = "English",

volume = "89",

pages = "619--27",

journal = "American Journal of Human Genetics",

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publisher = "Cell Press",

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TY - JOUR

T1 - Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

AU - Bown, Matthew J

AU - Jones, Gregory T

AU - Harrison, Seamus C

AU - Wright, Benjamin J

AU - Bumpstead, Suzannah

AU - Baas, Annette F

AU - Gretarsdottir, Solveig

AU - Badger, Stephen A

AU - Bradley, Declan T

AU - Burnand, Kevin

AU - Child, Anne H

AU - Clough, Rachel E

AU - Cockerill, Gillian

AU - Hafez, Hany

AU - Scott, D Julian A

AU - Futers, Simon

AU - Johnson, Anne

AU - Sohrabi, Soroush

AU - Smith, Alberto

AU - Thompson, Matthew M

AU - van Bockxmeer, Frank M

AU - Waltham, Matthew

AU - Matthiasson, Stefan E

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Blankensteijn, Jan D

AU - Teijink, Joep A W

AU - Wijmenga, Cisca

AU - de Graaf, Jacqueline

AU - Kiemeney, Lambertus A

AU - Assimes, Themistocles L

AU - McPherson, Ruth

AU - Folkersen, Lasse Westergaard

AU - Franco-Cereceda, Anders

AU - Palmen, Jutta

AU - Smith, Frank Andrew

AU - Sylvius, Nicolas

AU - Wild, John B

AU - Refstrup, Mette

AU - Edkins, Sarah

AU - Gwilliam, Rhian

AU - Hunt, Sarah E

AU - Potter, Simon

AU - Lindholt, Jes S.

AU - Frikke-Schmidt, Ruth

AU - Tybjærg-Hansen, Anne

AU - Hughes, Anne E

AU - Golledge, Jonathan

AU - Norman, Paul E

AU - van Rij, Andre

AU - CARDIoGRAM Consortium

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.

U2 - http://dx.doi.org/10.1016/j.ajhg.2011.10.002

DO - http://dx.doi.org/10.1016/j.ajhg.2011.10.002

M3 - Journal article

SN - 0002-9297

VL - 89

SP - 619

EP - 627

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abstract

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