A Variant in LDLR is Associated with Abdominal Aortic Aneurysm

Declan T Bradley; Anne E Hughes; Stephen A Badger; Gregory T Jones; Seamus C Harrison; Benjamin J Wright; Suzannah Bumpstead; Annette F Baas; Solveig Gretarsdottir; Kevin Burnand; Anne H Child; Rachel Clough; Gillian Cockerill; Hany Hafez; D Julian A Scott; Robert A S Ariëns; 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; John B Wild; Sarah Edkins; Rhian Gwilliam; Sarah E Hunt; Simon Potter; Jes S Lindholt; Jonathan Golledge; Paul E Norman; Andre van Rij; Janet T Powell; Per Eriksson; Kari Stefansson; John R Thompson; Steve E Humphries; Robert D Sayers; Panos Deloukas; Nilesh J Samani; Matthew J Bown

doi:10.1161/CIRCGENETICS.113.000165

A Variant in LDLR is Associated with Abdominal Aortic Aneurysm

Declan T Bradley, Anne E Hughes, Stephen A Badger, Gregory T Jones, Seamus C Harrison, Benjamin J Wright, Suzannah Bumpstead, Annette F Baas, Solveig Gretarsdottir, Kevin Burnand, Anne H Child, Rachel Clough, Gillian Cockerill, Hany Hafez, D Julian A Scott, Robert A S Ariëns, 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, John B Wild, Sarah Edkins, Rhian Gwilliam, Sarah E Hunt, Simon Potter, Jes S Lindholt, Jonathan Golledge, Paul E Norman, Andre van Rij, Janet T Powell, Per Eriksson, Kari Stefansson, John R Thompson, Steve E Humphries, Robert D Sayers, Panos Deloukas, Nilesh J Samani, Matthew J Bown

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Abstract

Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.

Methods and Results—A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10−4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83; P=2.08×10−10).

Conclusions—LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

Original language	English
Article number	N/A
Pages (from-to)	498-504
Number of pages	7
Journal	Circulation-Cardiovascular Genetics
Volume	6
Issue number	5
DOIs	https://doi.org/10.1161/CIRCGENETICS.113.000165
Publication status	E-pub ahead of print - Oct 2013

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10.1161/CIRCGENETICS.113.000165

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Bradley, D. T., Hughes, A. E., Badger, S. A., Jones, G. T., Harrison, S. C., Wright, B. J., Bumpstead, S., Baas, A. F., Gretarsdottir, S., Burnand, K., Child, A. H., Clough, R., Cockerill, G., Hafez, H., Scott, D. J. A., Ariëns, R. A. S., Johnson, A., Sohrabi, S., Smith, A., ... Bown, M. J. (2013). A Variant in LDLR is Associated with Abdominal Aortic Aneurysm. Circulation-Cardiovascular Genetics, 6(5), 498-504. Article N/A. Advance online publication. https://doi.org/10.1161/CIRCGENETICS.113.000165

@article{2302372fef5b494bb37c5534fed47f7e,

title = "A Variant in LDLR is Associated with Abdominal Aortic Aneurysm",

abstract = "Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.Methods and Results—A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10−4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83; P=2.08×10−10).Conclusions—LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.",

author = "Bradley, {Declan T} and Hughes, {Anne E} and Badger, {Stephen A} and Jones, {Gregory T} and Harrison, {Seamus C} and Wright, {Benjamin J} and Suzannah Bumpstead and Baas, {Annette F} and Solveig Gretarsdottir and Kevin Burnand and Child, {Anne H} and Rachel Clough and Gillian Cockerill and Hany Hafez and Scott, {D Julian A} and Ari{\"e}ns, {Robert A S} 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 Wild, {John B} and Sarah Edkins and Rhian Gwilliam and Hunt, {Sarah E} and Simon Potter and Lindholt, {Jes S} and Jonathan Golledge and Norman, {Paul E} and {van Rij}, Andre and Powell, {Janet T} and Per Eriksson and Kari Stefansson and Thompson, {John R} and Humphries, {Steve E} and Sayers, {Robert D} and Panos Deloukas and Samani, {Nilesh J} and Bown, {Matthew J}",

year = "2013",

month = oct,

doi = "10.1161/CIRCGENETICS.113.000165",

language = "English",

volume = "6",

pages = "498--504",

journal = "Circulation-Cardiovascular Genetics",

issn = "1942-325X",

publisher = "American Heart Association, Inc.",

number = "5",

}

Bradley, DT, Hughes, AE, Badger, SA, Jones, GT, Harrison, SC, Wright, BJ, Bumpstead, S, Baas, AF, Gretarsdottir, S, Burnand, K, Child, AH, Clough, R, Cockerill, G, Hafez, H, Scott, DJA, Ariëns, RAS, 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, Wild, JB, Edkins, S, Gwilliam, R, Hunt, SE, Potter, S, Lindholt, JS, Golledge, J, Norman, PE, van Rij, A, Powell, JT, Eriksson, P, Stefansson, K, Thompson, JR, Humphries, SE, Sayers, RD, Deloukas, P, Samani, NJ & Bown, MJ 2013, 'A Variant in LDLR is Associated with Abdominal Aortic Aneurysm', Circulation-Cardiovascular Genetics, vol. 6, no. 5, N/A, pp. 498-504. https://doi.org/10.1161/CIRCGENETICS.113.000165

TY - JOUR

T1 - A Variant in LDLR is Associated with Abdominal Aortic Aneurysm

AU - Bradley, Declan T

AU - Hughes, Anne E

AU - Badger, Stephen A

AU - Jones, Gregory T

AU - Harrison, Seamus C

AU - Wright, Benjamin J

AU - Bumpstead, Suzannah

AU - Baas, Annette F

AU - Gretarsdottir, Solveig

AU - Burnand, Kevin

AU - Child, Anne H

AU - Clough, Rachel

AU - Cockerill, Gillian

AU - Hafez, Hany

AU - Scott, D Julian A

AU - Ariëns, Robert A S

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 - Wild, John B

AU - Edkins, Sarah

AU - Gwilliam, Rhian

AU - Hunt, Sarah E

AU - Potter, Simon

AU - Lindholt, Jes S

AU - Golledge, Jonathan

AU - Norman, Paul E

AU - van Rij, Andre

AU - Powell, Janet T

AU - Eriksson, Per

AU - Stefansson, Kari

AU - Thompson, John R

AU - Humphries, Steve E

AU - Sayers, Robert D

AU - Deloukas, Panos

AU - Samani, Nilesh J

AU - Bown, Matthew J

PY - 2013/10

Y1 - 2013/10

N2 - Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.Methods and Results—A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10−4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83; P=2.08×10−10).Conclusions—LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

AB - Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.Methods and Results—A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10−4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83; P=2.08×10−10).Conclusions—LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

U2 - 10.1161/CIRCGENETICS.113.000165

DO - 10.1161/CIRCGENETICS.113.000165

M3 - Article

C2 - 24046328

SN - 1942-325X

VL - 6

SP - 498

EP - 504

JO - Circulation-Cardiovascular Genetics

JF - Circulation-Cardiovascular Genetics

IS - 5

M1 - N/A

ER -

A Variant in LDLR is Associated with Abdominal Aortic Aneurysm

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