Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism

Anna Helgadottir; Solveig Gretarsdottir; Gudmar Thorleifsson; Hilma Holm; Riyaz S Patel; Thorarinn Gudnason; Gregory T Jones; Andre M van Rij; Danny J Eapen; Annette F Baas; David-Alexandre Tregouet; Pierre-Emmanuel Morange; Joseph Emmerich; Bengt Lindblad; Anders Gottsäter; Lambertus A Kiemeny; Jes S. Lindholt; Natzi Sakalihasan; Robert E Ferrell; David J Carey; James R Elmore; Philip S Tsao; Niels Grarup; Torben Jørgensen; Daniel R Witte; Torben Hansen; Oluf Pedersen; Roberto Pola; Eleonora Gaetani; Hulda B Magnadottir; Cisca Wijmenga; Gerard Tromp; Antti Ronkainen; Ynte M Ruigrok; Jan D Blankensteijn; Thomas Mueller; Philip S Wells; Javier Corral; Jose Manuel Soria; Juan Carlos Souto; John F Peden; Shapour Jalilzadeh; Bongani M Mayosi; Bernard Keavney; Rona J Strawbridge; Maria Sabater-Lleal; Karl Gertow; Damiano Baldassarre; Kristiina Nyyssönen; Rainer Rauramaa; Andries J Smit; Elmo Mannarino; Philippe Giral; Elena Tremoli; Ulf de Faire; Steve E Humphries; Anders Hamsten; Vilhelmina Haraldsdottir; Isleifur Olafsson; Magnus K Magnusson; Nilesh J Samani; Allan I Levey; Hugh S Markus; Konstantinos Kostulas; Martin Dichgans; Klaus Berger; Gregor Kuhlenbäumer; E Bernd Ringelstein; Monika Stoll; Udo Seedorf; Peter M Rothwell; Janet T Powell; Helena Kuivaniemi; Pall T Onundarson; Einar Valdimarsson; Stefan E Matthiasson; Daniel F Gudbjartsson; Guðmundur Thorgeirsson; Arshed A Quyyumi; Hugh Watkins; Martin Farrall; Unnur Thorsteinsdottir; Kari Stefansson

doi:10.1016/j.jacc.2012.01.078

Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism

Anna Helgadottir, Solveig Gretarsdottir, Gudmar Thorleifsson, Hilma Holm, Riyaz S Patel, Thorarinn Gudnason, Gregory T Jones, Andre M van Rij, Danny J Eapen, Annette F Baas, David-Alexandre Tregouet, Pierre-Emmanuel Morange, Joseph Emmerich, Bengt Lindblad, Anders Gottsäter, Lambertus A Kiemeny, Jes S. Lindholt, Natzi Sakalihasan, Robert E Ferrell, David J CareyJames R Elmore, Philip S Tsao, Niels Grarup, Torben Jørgensen, Daniel R Witte, Torben Hansen, Oluf Pedersen, Roberto Pola, Eleonora Gaetani, Hulda B Magnadottir, Cisca Wijmenga, Gerard Tromp, Antti Ronkainen, Ynte M Ruigrok, Jan D Blankensteijn, Thomas Mueller, Philip S Wells, Javier Corral, Jose Manuel Soria, Juan Carlos Souto, John F Peden, Shapour Jalilzadeh, Bongani M Mayosi, Bernard Keavney, Rona J Strawbridge, Maria Sabater-Lleal, Karl Gertow, Damiano Baldassarre, Kristiina Nyyssönen, Rainer Rauramaa, Andries J Smit, Elmo Mannarino, Philippe Giral, Elena Tremoli, Ulf de Faire, Steve E Humphries, Anders Hamsten, Vilhelmina Haraldsdottir, Isleifur Olafsson, Magnus K Magnusson, Nilesh J Samani, Allan I Levey, Hugh S Markus, Konstantinos Kostulas, Martin Dichgans, Klaus Berger, Gregor Kuhlenbäumer, E Bernd Ringelstein, Monika Stoll, Udo Seedorf, Peter M Rothwell, Janet T Powell, Helena Kuivaniemi, Pall T Onundarson, Einar Valdimarsson, Stefan E Matthiasson, Daniel F Gudbjartsson, Guðmundur Thorgeirsson, Arshed A Quyyumi, Hugh Watkins, Martin Farrall, Unnur Thorsteinsdottir, Kari Stefansson

109 Citations (Scopus)

Abstract

The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n _e] = 9,396); peripheral arterial disease (n _e = 5,215); abdominal aortic aneurysm (n _e = 4,572); venous thromboembolism (n _e = 4,607); intracranial aneurysm (n _e = 1,328); CAD (n _e = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10 ⁴), peripheral artery disease (OR: 1.47; p = 2.9 × 10 ¹⁴), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10 ⁵), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10 ¹²). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (1.58 years/allele; p = 8.2 × 10 ⁸) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

Original language	English
Journal	Journal of the American College of Cardiology
Volume	60
Issue number	8
Pages (from-to)	722-9
Number of pages	8
DOIs	https://doi.org/10.1016/j.jacc.2012.01.078
Publication status	Published - 21 Aug 2012

Keywords

African Americans
Age of Onset
Angiography
Aortic Aneurysm, Abdominal
Apolipoproteins A
Atherosclerosis
Brain Ischemia
Carotid Intima-Media Thickness
Coronary Artery Disease
European Continental Ancestry Group
Genetic Predisposition to Disease
Humans
Intracranial Aneurysm
Linear Models
Logistic Models
Myocardial Infarction
Odds Ratio
Peripheral Arterial Disease
Polymorphism, Single Nucleotide
Risk Factors
Severity of Illness Index
Stroke
Venous Thromboembolism

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10.1016/j.jacc.2012.01.078

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Helgadottir, A., Gretarsdottir, S., Thorleifsson, G., Holm, H., Patel, R. S., Gudnason, T., Jones, G. T., van Rij, A. M., Eapen, D. J., Baas, A. F., Tregouet, D.-A., Morange, P.-E., Emmerich, J., Lindblad, B., Gottsäter, A., Kiemeny, L. A., Lindholt, J. S., Sakalihasan, N., Ferrell, R. E., ... Stefansson, K. (2012). Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. Journal of the American College of Cardiology, 60(8), 722-9. https://doi.org/10.1016/j.jacc.2012.01.078

Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. / Helgadottir, Anna; Gretarsdottir, Solveig; Thorleifsson, Gudmar et al.
In: Journal of the American College of Cardiology, Vol. 60, No. 8, 21.08.2012, p. 722-9.

Research output: Contribution to journal › Journal article › Research › peer-review

Helgadottir, A, Gretarsdottir, S, Thorleifsson, G, Holm, H, Patel, RS, Gudnason, T, Jones, GT, van Rij, AM, Eapen, DJ, Baas, AF, Tregouet, D-A, Morange, P-E, Emmerich, J, Lindblad, B, Gottsäter, A, Kiemeny, LA, Lindholt, JS, Sakalihasan, N, Ferrell, RE, Carey, DJ, Elmore, JR, Tsao, PS, Grarup, N, Jørgensen, T, Witte, DR, Hansen, T , Pedersen, O, Pola, R, Gaetani, E, Magnadottir, HB, Wijmenga, C, Tromp, G, Ronkainen, A, Ruigrok, YM, Blankensteijn, JD, Mueller, T, Wells, PS, Corral, J, Soria, JM, Souto, JC, Peden, JF, Jalilzadeh, S, Mayosi, BM, Keavney, B, Strawbridge, RJ, Sabater-Lleal, M, Gertow, K, Baldassarre, D, Nyyssönen, K, Rauramaa, R, Smit, AJ, Mannarino, E, Giral, P, Tremoli, E, de Faire, U, Humphries, SE, Hamsten, A, Haraldsdottir, V, Olafsson, I, Magnusson, MK, Samani, NJ, Levey, AI, Markus, HS, Kostulas, K, Dichgans, M, Berger, K, Kuhlenbäumer, G, Ringelstein, EB, Stoll, M, Seedorf, U, Rothwell, PM, Powell, JT, Kuivaniemi, H, Onundarson, PT, Valdimarsson, E, Matthiasson, SE, Gudbjartsson, DF, Thorgeirsson, G, Quyyumi, AA, Watkins, H, Farrall, M, Thorsteinsdottir, U & Stefansson, K 2012, 'Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism', Journal of the American College of Cardiology, vol. 60, no. 8, pp. 722-9. https://doi.org/10.1016/j.jacc.2012.01.078

@article{13c8a2ca6021405ea6db62e1981ed855,

title = "Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism",

abstract = "The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n e] = 9,396); peripheral arterial disease (n e = 5,215); abdominal aortic aneurysm (n e = 4,572); venous thromboembolism (n e = 4,607); intracranial aneurysm (n e = 1,328); CAD (n e = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10 4), peripheral artery disease (OR: 1.47; p = 2.9 × 10 14), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10 5), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10 12). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (1.58 years/allele; p = 8.2 × 10 8) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.",

keywords = "African Americans, Age of Onset, Angiography, Aortic Aneurysm, Abdominal, Apolipoproteins A, Atherosclerosis, Brain Ischemia, Carotid Intima-Media Thickness, Coronary Artery Disease, European Continental Ancestry Group, Genetic Predisposition to Disease, Humans, Intracranial Aneurysm, Linear Models, Logistic Models, Myocardial Infarction, Odds Ratio, Peripheral Arterial Disease, Polymorphism, Single Nucleotide, Risk Factors, Severity of Illness Index, Stroke, Venous Thromboembolism",

author = "Anna Helgadottir and Solveig Gretarsdottir and Gudmar Thorleifsson and Hilma Holm and Patel, {Riyaz S} and Thorarinn Gudnason and Jones, {Gregory T} and {van Rij}, {Andre M} and Eapen, {Danny J} and Baas, {Annette F} and David-Alexandre Tregouet and Pierre-Emmanuel Morange and Joseph Emmerich and Bengt Lindblad and Anders Gotts{\"a}ter and Kiemeny, {Lambertus A} and Lindholt, {Jes S.} and Natzi Sakalihasan and Ferrell, {Robert E} and Carey, {David J} and Elmore, {James R} and Tsao, {Philip S} and Niels Grarup and Torben J{\o}rgensen and Witte, {Daniel R} and Torben Hansen and Oluf Pedersen and Roberto Pola and Eleonora Gaetani and Magnadottir, {Hulda B} and Cisca Wijmenga and Gerard Tromp and Antti Ronkainen and Ruigrok, {Ynte M} and Blankensteijn, {Jan D} and Thomas Mueller and Wells, {Philip S} and Javier Corral and Soria, {Jose Manuel} and Souto, {Juan Carlos} and Peden, {John F} and Shapour Jalilzadeh and Mayosi, {Bongani M} and Bernard Keavney and Strawbridge, {Rona J} and Maria Sabater-Lleal and Karl Gertow and Damiano Baldassarre and Kristiina Nyyss{\"o}nen and Rainer Rauramaa and Smit, {Andries J} and Elmo Mannarino and Philippe Giral and Elena Tremoli and {de Faire}, Ulf and Humphries, {Steve E} and Anders Hamsten and Vilhelmina Haraldsdottir and Isleifur Olafsson and Magnusson, {Magnus K} and Samani, {Nilesh J} and Levey, {Allan I} and Markus, {Hugh S} and Konstantinos Kostulas and Martin Dichgans and Klaus Berger and Gregor Kuhlenb{\"a}umer and Ringelstein, {E Bernd} and Monika Stoll and Udo Seedorf and Rothwell, {Peter M} and Powell, {Janet T} and Helena Kuivaniemi and Onundarson, {Pall T} and Einar Valdimarsson and Matthiasson, {Stefan E} and Gudbjartsson, {Daniel F} and Gu{\dh}mundur Thorgeirsson and Quyyumi, {Arshed A} and Hugh Watkins and Martin Farrall and Unnur Thorsteinsdottir and Kari Stefansson",

year = "2012",

month = aug,

day = "21",

doi = "10.1016/j.jacc.2012.01.078",

language = "English",

volume = "60",

pages = "722--9",

journal = "Journal of the American College of Cardiology",

issn = "1558-3597",

publisher = "Elsevier",

number = "8",

}

TY - JOUR

T1 - Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism

AU - Helgadottir, Anna

AU - Gretarsdottir, Solveig

AU - Thorleifsson, Gudmar

AU - Holm, Hilma

AU - Patel, Riyaz S

AU - Gudnason, Thorarinn

AU - Jones, Gregory T

AU - van Rij, Andre M

AU - Eapen, Danny J

AU - Baas, Annette F

AU - Tregouet, David-Alexandre

AU - Morange, Pierre-Emmanuel

AU - Emmerich, Joseph

AU - Lindblad, Bengt

AU - Gottsäter, Anders

AU - Kiemeny, Lambertus A

AU - Lindholt, Jes S.

AU - Sakalihasan, Natzi

AU - Ferrell, Robert E

AU - Carey, David J

AU - Elmore, James R

AU - Tsao, Philip S

AU - Grarup, Niels

AU - Jørgensen, Torben

AU - Witte, Daniel R

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Pola, Roberto

AU - Gaetani, Eleonora

AU - Magnadottir, Hulda B

AU - Wijmenga, Cisca

AU - Tromp, Gerard

AU - Ronkainen, Antti

AU - Ruigrok, Ynte M

AU - Blankensteijn, Jan D

AU - Mueller, Thomas

AU - Wells, Philip S

AU - Corral, Javier

AU - Soria, Jose Manuel

AU - Souto, Juan Carlos

AU - Peden, John F

AU - Jalilzadeh, Shapour

AU - Mayosi, Bongani M

AU - Keavney, Bernard

AU - Strawbridge, Rona J

AU - Sabater-Lleal, Maria

AU - Gertow, Karl

AU - Baldassarre, Damiano

AU - Nyyssönen, Kristiina

AU - Rauramaa, Rainer

AU - Smit, Andries J

AU - Mannarino, Elmo

AU - Giral, Philippe

AU - Tremoli, Elena

AU - de Faire, Ulf

AU - Humphries, Steve E

AU - Hamsten, Anders

AU - Haraldsdottir, Vilhelmina

AU - Olafsson, Isleifur

AU - Magnusson, Magnus K

AU - Samani, Nilesh J

AU - Levey, Allan I

AU - Markus, Hugh S

AU - Kostulas, Konstantinos

AU - Dichgans, Martin

AU - Berger, Klaus

AU - Kuhlenbäumer, Gregor

AU - Ringelstein, E Bernd

AU - Stoll, Monika

AU - Seedorf, Udo

AU - Rothwell, Peter M

AU - Powell, Janet T

AU - Kuivaniemi, Helena

AU - Onundarson, Pall T

AU - Valdimarsson, Einar

AU - Matthiasson, Stefan E

AU - Gudbjartsson, Daniel F

AU - Thorgeirsson, Guðmundur

AU - Quyyumi, Arshed A

AU - Watkins, Hugh

AU - Farrall, Martin

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

PY - 2012/8/21

Y1 - 2012/8/21

N2 - The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n e] = 9,396); peripheral arterial disease (n e = 5,215); abdominal aortic aneurysm (n e = 4,572); venous thromboembolism (n e = 4,607); intracranial aneurysm (n e = 1,328); CAD (n e = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10 4), peripheral artery disease (OR: 1.47; p = 2.9 × 10 14), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10 5), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10 12). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (1.58 years/allele; p = 8.2 × 10 8) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

AB - The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n e] = 9,396); peripheral arterial disease (n e = 5,215); abdominal aortic aneurysm (n e = 4,572); venous thromboembolism (n e = 4,607); intracranial aneurysm (n e = 1,328); CAD (n e = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10 4), peripheral artery disease (OR: 1.47; p = 2.9 × 10 14), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10 5), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10 12). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (1.58 years/allele; p = 8.2 × 10 8) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

KW - African Americans

KW - Age of Onset

KW - Angiography

KW - Aortic Aneurysm, Abdominal

KW - Apolipoproteins A

KW - Atherosclerosis

KW - Brain Ischemia

KW - Carotid Intima-Media Thickness

KW - Coronary Artery Disease

KW - European Continental Ancestry Group

KW - Genetic Predisposition to Disease

KW - Humans

KW - Intracranial Aneurysm

KW - Linear Models

KW - Logistic Models

KW - Myocardial Infarction

KW - Odds Ratio

KW - Peripheral Arterial Disease

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Severity of Illness Index

KW - Stroke

KW - Venous Thromboembolism

U2 - 10.1016/j.jacc.2012.01.078

DO - 10.1016/j.jacc.2012.01.078

M3 - Journal article

C2 - 22898070

SN - 1558-3597

VL - 60

SP - 722

EP - 729

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 8

ER -

Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism

Abstract

Keywords

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