A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm

Gregory T. Jones; Matthew J. Bown; Solveig Gretarsdottir; Simon P.R. Romaine; Anna Helgadottir; Grace Yu; Gerard Tromp; Paul E. Norman; Cao Jin; Annette F. Baas; Jan D. Blankensteijn; Iftikhar J. Kullo; L. Victoria Phillips; Michael J.A. Williams; Ruth Topless; Tony R. Merriman; Thodor M. Vasudevan; David R. Lewis; Ross D. Blair; Andrew A. Hill; Robert D. Sayers; Janet T. Powell; Panagiotis Deloukas; Gudmar Thorleifsson; Stefan E. Matthiasson; Unnur Thorsteinsdottir; Jonathan Golledge; Robert A. Ariëns; Anne Johnson; Soroush Sohrabi; D. Julian Scott; David J. Carey; Robert Erdman; James R. Elmore; Helena Kuivaniemi; Nilesh J. Samani; Kari Stefansson; Andre M. van Rij

doi:10.1093/hmg/ddt141

A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm

Gregory T. Jones
, Matthew J. Bown
, Solveig Gretarsdottir
, Simon P.R. Romaine
, Anna Helgadottir
, Grace Yu
, Gerard Tromp
, Paul E. Norman
, Cao Jin
, Annette F. Baas
, Jan D. Blankensteijn
, Iftikhar J. Kullo
, L. Victoria Phillips
, Michael J.A. Williams
, Ruth Topless
, Tony R. Merriman
, Thodor M. Vasudevan
, David R. Lewis
, Ross D. Blair
, Andrew A. Hill

Robert D. Sayers, Janet T. Powell, Panagiotis Deloukas, Gudmar Thorleifsson, Stefan E. Matthiasson, Unnur Thorsteinsdottir, Jonathan Golledge, Robert A. Ariëns, Anne Johnson, Soroush Sohrabi, D. Julian Scott, David J. Carey, Robert Erdman, James R. Elmore, Helena Kuivaniemi, Nilesh J. Samani, Kari Stefansson, Andre M. van Rij

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	ddt141
Pages (from-to)	2941-2947
Number of pages	7
Journal	Human molecular genetics
Volume	22
Issue number	14
DOIs	https://doi.org/10.1093/hmg/ddt141
Publication status	Published - Jul 2013

Bibliographical note

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.

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Cite this

Jones, G. T., Bown, M. J., Gretarsdottir, S., Romaine, S. P. R., Helgadottir, A., Yu, G., Tromp, G., Norman, P. E., Jin, C., Baas, A. F., Blankensteijn, J. D., Kullo, I. J., Victoria Phillips, L., Williams, M. J. A., Topless, R., Merriman, T. R., Vasudevan, T. M., Lewis, D. R., Blair, R. D., ... van Rij, A. M. (2013). A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm. Human molecular genetics, 22(14), 2941-2947. Article ddt141. https://doi.org/10.1093/hmg/ddt141

@article{2ff6cfd622e34d98bab24c720057bc3a,

title = "A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm",

abstract = "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.",

author = "Jones, \{Gregory T.\} and Bown, \{Matthew J.\} and Solveig Gretarsdottir and Romaine, \{Simon P.R.\} and Anna Helgadottir and Grace Yu and Gerard Tromp and Norman, \{Paul E.\} and Cao Jin and Baas, \{Annette F.\} and Blankensteijn, \{Jan D.\} and Kullo, \{Iftikhar J.\} and \{Victoria Phillips\}, L. and Williams, \{Michael J.A.\} and Ruth Topless and Merriman, \{Tony R.\} and Vasudevan, \{Thodor M.\} and Lewis, \{David R.\} and Blair, \{Ross D.\} and Hill, \{Andrew A.\} and Sayers, \{Robert D.\} and Powell, \{Janet T.\} and Panagiotis Deloukas and Gudmar Thorleifsson and Matthiasson, \{Stefan E.\} and Unnur Thorsteinsdottir and Jonathan Golledge and Ari{\"e}ns, \{Robert A.\} and Anne Johnson and Soroush Sohrabi and \{Julian Scott\}, D. and Carey, \{David J.\} and Robert Erdman and Elmore, \{James R.\} and Helena Kuivaniemi and Samani, \{Nilesh J.\} and Kari Stefansson and \{van Rij\}, \{Andre M.\}",

note = "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{\textquoteright}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.",

year = "2013",

month = jul,

doi = "10.1093/hmg/ddt141",

language = "English",

volume = "22",

pages = "2941--2947",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "14",

}

Jones, GT, Bown, MJ, Gretarsdottir, S, Romaine, SPR, Helgadottir, A, Yu, G, Tromp, G, Norman, PE, Jin, C, Baas, AF, Blankensteijn, JD, Kullo, IJ, Victoria Phillips, L, Williams, MJA, Topless, R, Merriman, TR, Vasudevan, TM, Lewis, DR, Blair, RD, Hill, AA, Sayers, RD, Powell, JT, Deloukas, P, Thorleifsson, G, Matthiasson, SE, Thorsteinsdottir, U, Golledge, J, Ariëns, RA, Johnson, A, Sohrabi, S, Julian Scott, D, Carey, DJ, Erdman, R, Elmore, JR, Kuivaniemi, H, Samani, NJ, Stefansson, K & van Rij, AM 2013, 'A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm', Human molecular genetics, vol. 22, no. 14, ddt141, pp. 2941-2947. https://doi.org/10.1093/hmg/ddt141

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.

UR - https://www.scopus.com/pages/publications/84880305065

U2 - 10.1093/hmg/ddt141

DO - 10.1093/hmg/ddt141

M3 - Article

C2 - 23535823

SN - 0964-6906

VL - 22

SP - 2941

EP - 2947

JO - Human molecular genetics

JF - Human molecular genetics

IS - 14

M1 - ddt141

ER -

A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm

Abstract

Bibliographical note

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