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


BACKGROUND
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.


METHODS
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).


RESULTS
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).


CONCLUSIONS
LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.
Population Genomics, deCODE Genetics, Reykjavik, Iceland. annah@decode.is
Anna
A
Helgadottir
Solveig
S
Gretarsdottir
Gudmar
G
Thorleifsson
Hilma
H
Holm
Riyaz S
RS
Patel
Thorarinn
T
Gudnason
Gregory T
GT
Jones
Andre M
AM
van Rij
Danny J
DJ
Eapen
Annette F
AF
Baas
David-Alexandre
DA
Tregouet
Pierre-Emmanuel
PE
Morange
Joseph
J
Emmerich
Bengt
B
Lindblad
Anders
A
Gottsäter
Lambertus A
LA
Kiemeny
Jes S
JS
Lindholt
Natzi
N
Sakalihasan
Robert E
RE
Ferrell
David J
DJ
Carey
James R
JR
Elmore
Philip S
PS
Tsao
Niels
N
Grarup
Torben
T
Jørgensen
Daniel R
DR
Witte
Torben
T
Hansen
Oluf
O
Pedersen
Roberto
R
Pola
Eleonora
E
Gaetani
Hulda B
HB
Magnadottir
Cisca
C
Wijmenga
Gerard
G
Tromp
Antti
A
Ronkainen
Ynte M
YM
Ruigrok
Jan D
JD
Blankensteijn
Thomas
T
Mueller
Philip S
PS
Wells
Javier
J
Corral
Jose Manuel
JM
Soria
Juan Carlos
JC
Souto
John F
JF
Peden
Shapour
S
Jalilzadeh
Bongani M
BM
Mayosi
Bernard
B
Keavney
Rona J
RJ
Strawbridge
Maria
M
Sabater-Lleal
Karl
K
Gertow
Damiano
D
Baldassarre
Kristiina
K
Nyyssönen
Rainer
R
Rauramaa
Andries J
AJ
Smit
Elmo
E
Mannarino
Philippe
P
Giral
Elena
E
Tremoli
Ulf
U
de Faire
Steve E
SE
Humphries
Anders
A
Hamsten
Vilhelmina
V
Haraldsdottir
Isleifur
I
Olafsson
Magnus K
MK
Magnusson
Nilesh J
NJ
Samani
Allan I
AI
Levey
Hugh S
HS
Markus
Konstantinos
K
Kostulas
Martin
M
Dichgans
Klaus
K
Berger
Gregor
G
Kuhlenbäumer
E Bernd
EB
Ringelstein
Monika
M
Stoll
Udo
U
Seedorf
Peter M
PM
Rothwell
Janet T
JT
Powell
Helena
H
Kuivaniemi
Pall T
PT
Onundarson
Einar
E
Valdimarsson
Stefan E
SE
Matthiasson
Daniel F
DF
Gudbjartsson
Guðmundur
G
Thorgeirsson
Arshed A
AA
Quyyumi
Hugh
H
Watkins
Martin
M
Farrall
Unnur
U
Thorsteinsdottir
Kari
K
Stefansson
D001741:Black or African American / Q000235:genetics; D017668:Age of Onset; D000792:Angiography; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics; D001054:Apolipoproteins A / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D002545:Brain Ischemia / Q000235:genetics; D059168:Carotid Intima-Media Thickness; D003324:Coronary Artery Disease / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics; D016014:Linear Models; D016015:Logistic Models; D009203:Myocardial Infarction / Q000235:genetics; D016017:Odds Ratio; D058729:Peripheral Arterial Disease / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke / Q000235:genetics; D054556:Venous Thromboembolism / Q000235:genetics; D044465:White People / Q000235:genetics
D001054:Apolipoproteins A