Thrombosis Research 134 (2014) 426432

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Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Regular Article

Inuence of coronary artery disease-associated genetic variants on risk of

venous thromboembolism
Maria Bruzelius a,b,1, Rona J. Strawbridge b,1,, David-Alexandre Trgout c,d,m, Kerri L. Wiggins e, Karl Gertow b,
Maria Sabater-Lleal b, John hrvik b, Annica Bergendal f, Angela Silveira b, Anders Sundstrm f, Helle Kieler f,
Ann-Christine Syvnen g, Nicholas L. Smith h,i,j, Pierre-Emmanuel Morange k,
Jacob Odeberg a,b,l, Anders Hamsten b
a

Coagulation Unit, Hematology Centre, Karolinska University Hospital Solna, Sweden

Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
c
INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, F-75013, Paris, France
d
ICAN Institute for Cardiometabolism and Nutrition, F-75013, Paris, France
e
Department of Medicine, University of Washington, Seattle WA USA
f
Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
g
Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
h
Department of Epidemiology, University of Washington, Seattle WA USA
i
Group Health Research Institute, Group Health Cooperative, Seattle WA USA
j
Seattle Epidemiologic Research and Information Center, Veterans Affairs Ofce of Research and Development, Seattle WA 98101, USA
k
Inserm UMR 1062, Marseille, Aix-Marseille Universit, Marseille, France
l
Science for Life Laboratory Stockholm, Department of Proteomics, School of Biotechnology, KTH, Solna, Sweden
m
Sorbonne Universits, UPMC Univ Paris 06, UMR_S 1166, F-75013, Paris, France
b

a r t i c l e

i n f o

Article history:
Received 22 January 2014
Received in revised form 11 March 2014
Accepted 31 March 2014
Available online 4 April 2014
Keywords:
Venous thromboembolism
Coronary artery disease
ANRIL
ABO
Genetics

a b s t r a c t
Introduction: We investigated whether genetic variations robustly associated with coronary artery disease
are also associated with risk of venous thromboembolism in a well-dened, female casecontrol study
(n = 2753) from Sweden.
Materials and Methods: 39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in
genome-wide association studies were identied in a literature search and genotyped in the ThromboEmbolism
Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression.
Results: Only rs579459 in the ABO locus demonstrated a signicant association with VTE. A tentative association
between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts
(total n = 7181).
Conclusions: It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.
2014 Elsevier Ltd. All rights reserved.

Introduction

Abbreviations: BMI, body mass index; CAD, Coronary artery disease; DVT, deep vein
thrombosis; PE, pulmonary embolism; SNP, single nucleotide polymorphism; VTE, venous
thromboembolism; TEHS, The ThromboEmbolism Hormone Study; FARIVE, The Facteurs
de risque et de rcidive de la maladie thromboembolique veineuse study; HVH, The
Heart and Vascular Health Study; MARTHA, The Marseille Thrombosis Association
study; EOVT, The Early Onset of Venous Thrombosis study.
Corresponding author at: Atherosclerosis Research Unit, Centre for Molecular
Medicine, Building L8:03, Karolinska University Hospital Solna, S-17176 Stockholm,
Sweden. Tel.: +46 8 51770305.
E-mail address: rona.strawbridge@ki.se (R.J. Strawbridge).
1
Contributed equally.

http://dx.doi.org/10.1016/j.thromres.2014.03.054
0049-3848/ 2014 Elsevier Ltd. All rights reserved.

A plausible causal link between arterial and venous thrombosis has

been advocated [1,2], and a large meta-analysis indicates an impact of
established risk factors for atherosclerosis on both disease entities [3].
Several studies have reported increased risks of cardiovascular disease
amongst patients previously diagnosed with venous thromboembolism
(VTE) suggesting that VTE is a predictor of subsequent arterial thrombosis [4,5]. Similarly, patients with atherosclerosis and manifest cardiovascular disease have been reported to be at an increased risk of developing
VTE [6,7]. In addition, arterial and venous thrombosis is inuenced by
common mechanisms, i.e. ABO blood group [8,9] activation of blood coagulation [1012], hypobrinolysis [13,14] and inammation [15,16].
Recent studies have highlighted that risk of VTE is reduced in subjects

M. Bruzelius et al. / Thrombosis Research 134 (2014) 426432

treated with statins or antiplatelet drugs, which today are established

regimens for primary and secondary prevention of cardiovascular complications in atherosclerotic disease [17,18].
Despite these epidemiological ndings, arterial and venous thromboses have been considered as two separate entities, with different
pathophysiology and treatment. Indeed, two large prospective population studies have refuted an impact of atherosclerosis on risk of VTE
[19,20]. However, controversy remains whether this conclusion is
valid [1]. Increasing age and body mass index (BMI) remain the
only cardiovascular risk factors with robust inuences on VTE risk in
prospective population studies, whereas for smoking, hyperlipidemia,
hypertension and diabetes mellitus the observed associations are inconsistent [2123].
In terms of genetic predisposition, it is known that common variants
in the ABO [24], factor V (F5) [25], prothrombin (F2) [26], brinogen
-chain (FGG) [27] and factor XI (F11) [28] genes inuence risk of VTE.
However, no study has systematically investigated whether known
coronary artery disease (CAD)-associated SNPs that have emerged
through genome-wide association (GWA) studies of CAD also increase
the risk of VTE. Here, we investigated the genetic variants which have
been robustly associated with CAD, in a well-dened, Swedish female
casecontrol study of VTE, with the aim of clarifying whether there is
a common genetic predisposition for CAD and VTE.
Materials and Methods
Discovery Cohort
The ThromboEmbolism Hormone Study (TEHS) is a casecontrol
study of VTE in women initiated by the Medical Product Agency (MPA)
in Uppsala and conducted through the Centre for Pharmacoepidemiology
at Karolinska Institutet in Stockholm. TEHS was designed to investigate how environmental and genetic factors affect the risk of VTE,
with a particular focus on women taking different combined hormonal contraceptives or hormone replacement therapy [9]. In brief,
a total of 1433 cases and 1402 controls, aged between 18 and 65,
who contributed DNA samples, were recruited between 2003 and
2009. Cases were out- and in-patients, recruited from 43 hospitals
across Sweden, with rst time, incident deep vein thrombosis (DVT) in
lower limbs and/or pulmonary embolism (PE). All cases of VTE were

427

objectively conrmed with established diagnostic imaging methods,

and treatment with anticoagulants was initiated. Exclusion criteria
were previous VTE, current malignancy or pregnancy. Women who
had previously been diagnosed with cancer were included only if treatment had been completed at least ve years before the VTE diagnosis. Female controls were selected randomly from the population register held
by the National Board of Taxation and matched to birth year of the cases.
Extensive information was obtained through telephone interviews, precluding participation of non-Swedish-speaking women. Table 1 reports
the characteristics of the population studied. Informed written consent
was obtained in accordance with the Declaration of Helsinki. The study
was approved by the regional research ethics committees.
SNP Selection and Genotyping
After a literature survey (May 2011), 32 loci were selected (Supplementary Table 1). In a number of loci, 2 signals appear to be independent so both signals were included; thus, a total of 39 SNPs robustly
associated with CAD and/or MI (having attained conventional genomewide signicance (P b 5 108) in large genome-wide or candidate
gene meta-analyses) were included (Supplementary Table 1). Established
genetic variants predisposing to VTE were also genotyped, including
those tagging ABO phenotypes (rs514659 tagging non-O blood group;
rs8176704, rs512770 and rs8176749) [29], F5 (rs6025), F2 (rs1799963),
FGG (rs2066285) and F11 (rs2036914). It has been reported that the following SNPs are able to discriminate between; rs514659, O versus non-O;
rs8176704, A1 versus A2; rs512770, O1 versus O1v/O2; rs8176749, A1
versus B [29].
Forty-four SNPs were assayed using the Illumina Goldengate
platform, and genotypes were read and analysed using the Illumina
BeadXpress and Illumina GenomeStudio 2011.1 software, respectively,
at the SNP&SEQ Technology Platform, Uppsala, Sweden. Rs6025
and rs1799963 were genotyped by Pyrosequencing technology (ISO
standard 2004) at the Royal Institute of Technology, Stockholm,
Sweden. Rs512770 was genotyped with a Taqman SNP genotyping
assay (C__997884_20, Applied Biosystems) and analyzed using StepOne
software v2.1. Standard quality control procedures were performed,
with SNP exclusion due to call rate (b 95%) and/or deviation from
Hardy-Weinberg equilibrium (p b 0.005). Subjects with a low call rate
(b90%) were excluded. Genotyping was performed on plates containing

Table 1
Characteristics of TEHS.
Cases
mean
Pulmonary embolism
Deep venous thrombosis
PE + DVT
Women
Age (years)
18-49
50-64
BMI (kg/m2)
BMI 30 or more
Current smoking
Hypertension
Hyperlipidaemia
Diabetes Mellitus
Cardiovascular disease
Contraceptives
Combined oestrogen and progesterone
Progesterone only
Menopausal replacement therapy
Positive family history of VTE

Controls
N
1426
457
997
28
1426

freq.

mean

freq.

p-value

1395
0.32
0.70
0.02
1.00

46

1395

1.00

692
703

0.50
0.50

47
746
680

0.52
0.48

351
377
303
167
61
74

0.25
0.26
0.21
0.12
0.04
0.05

176
303
285
174
38
43

0.13
0.22
0.20
0.13
0.03
0.03

b0.001
b0.001
0.005
NA
NA
0.026
0.005

326
143
195
376

0.44*
0.21*
0.29
0.27

109
180
120
205

0.16*
0.26*
0.17
0.15

b0.001
NA
b0.001
b0.001

27

25

Where: PE, pulmonary embolism; DVT, deep vein thrombosis; BMI, body mass index; Cardiovascular disease, including previous myocardial infarction, angina pectoris, peripheral artery
disease, transient ischemic attack and stroke; Hornome replacement therapy dened as per oral or patch application; * frequency of women age 1849 and frequency of women age 50;
p-value calculated by T-test. NA, not associated.

428

M. Bruzelius et al. / Thrombosis Research 134 (2014) 426432

a mixture of cases and controls and was completed in one stage each for
the Illumina and Taqman platforms. In all, 2821 subjects (1426 cases
and 1395 controls, 99.5% of the total sample) and 47 SNPs were available for analysis.
Statistical Analysis
Logistic regression was carried out in PLINK [30]. For the primary
analysis of the 39 CAD-associated SNPs in TEHS, logistic regression
was performed with adjustment for age assuming an additive genetic
model. Multiple logistic regression was used to assess the impact of covariates on the relationship between SNPs and VTE risk and Chi squared
tests were performed to determine whether there was signicant variation in allele frequencies between cohorts. Both analyses were performed using STATA (StataCorp, Texas, USA). Haplotype analysis was
carried out using TEHSIAS software [31].
By adjusting for the risk factors common to cardiovascular disease
and VTE (age and BMI) as well as VTE-associated genetic variants, we
aimed to explore the possibility of common genetic background of the
two conditions, independent of these known factors. Thus in secondary
analysis, models including different adjustments were explored; Model
A: age, BMI and genetic variants in the ABO (rs514659, rs8176704 and
rs8176749), F5 (rs6025) and F2 (s1799963) loci; and Model B: age,
BMI and the 5 SNPs with the strongest associations with VTE according
to the current literature (ABO (rs514659), F5 (rs6025), F2 (rs1799963),
FGG (rs2066865) and F11 (rs2036914)) [32]. As the replication cohorts
consisted of both male and female subjects, sex was also included in the
models.
Of 47 SNPs genotyped, 8 were included as covariates. SNPs were
included in the study because of previous associations with cardiovascular disease and thus VTE-relevant biological mechanisms, we used
Bonferroni correction for multiple testing of 39 independent SNPs
in 32 loci, which gave statistical signicance at a p-value 0.0013
(=0.05/39) Models including a variety of covariates were used to assess
robustness only, thus these tests were not corrected for. Haplotypes at
the ABO locus were constructed in PLINK.

subjects from the SUVIMAX study were used as controls [33,35]. In

EOVT, genotyping was performed using the IlluminaSentrix
HumanHap300 Beadchip.
MARTHA: The Marseille Thrombosis Association study, includes
1542 cases of a rst-time VTE (66% females) without known strong
risk factors, recruited from 1994 to 2005 at the Timone Hospital,
Marseille in France. The controls comprise 1110 healthy individuals
(69% females), randomly chosen from the 3C study, with an age over
65 years [36]. In MARTHA, genotyping was carried out using the Illumina
Human 610-Quad and Illumina Human 660 W-Quad Beadchips. In
the 3C study, genotyping was conducted using the Illumina Human
610-Quad Beadchip.
In the genotyping arrays performed on EOVT and MARTHA,
rs1333049 was not available but according to HapMap was in strong
linkage disequilibrium (r2 = 0.81, D' = 0.91) with rs10116272. The
latter was then used as a proxy for rs1333049 in EOVT and MARTHA.
Clinical characteristics of the replication cohorts are shown in Supplementary Table 2. BMI measurements were only available in FARIVE
and HVH (but not in EOVT or MARTHA). Thus, meta-analyses were conducted using the models described above, except for meta-analyses including all 4 cohorts, where BMI was dropped from the models.
Power Calculation for Replication of the ANRIL Locus
The available power for the range of ORs and risk allele frequencies
of SNPs in the one stage discovery analysis in TEHS are presented in
Supplementary Table 3. For the replication analysis, power calculations
indicated that using the two-stage association study design based
on TEHS and the replication studies (3400 cases and 4000 controls),
we had 99% power to detect an OR of b0.85 or N1.18 (as observed in
the discovery cohort) for a SNP with a MAF of 50%, assuming a VTE incidence of 0.0015 (reecting that observed in European populations)
[37]. All power calculations were carried out using CaTS (CaTS power
calculator [38].
Results

Replication Cohorts

Subject Characteristics

FARIVE: The Facteurs de risque et de rcidive de la maladie

thromboembolique veineuse study is a French hospital-based multicentre
casecontrol study with recruitment on-going since 2003. At present, it
includes a total of 606 cases with a rst episode of VTE and 606 matched
controls. The controls are composed of in- and out-patients, eligible
only if free from personal and family history of venous and arterial
thrombosis [33]. In FARIVE, genotyping was carried out using Taqman
assays (Applied Biosystems, Foster City, CA). Genotypes were available
for 496 cases (62% females) and 524 controls (59% females).
HVH: The Heart and Vascular Health (HVH) Study is a populationbased, casecontrol study of MI, stroke, atrial brillation, and VTE.
For this analysis, the participants were European-ancestry female VTE
cases and controls from 40 to 89 years old who were members of
Group Health Cooperative, a large integrated health care system in
western Washington State, USA. Cases had a rst incident DVT or PE between 1995 and 2006, and were alive at the time of study recruitment.
The controls had no prior VTE and were frequency matched by age
(within decade), sex, treated hypertension status, and calendar-year
of identication to MI cases (largest group) [34]. Genotyping was
carried out using the Illumina370CNV (subset 1000G1) and Omni
Beadchips (subset 1000G2). There were 848 cases and 1128 controls
included in this analysis.
EOVT: The Early Onset of Venous Thrombosis study is a French case
control study composed of 411 (44% females) cases and 1228 controls
(70% females). Cases of a rst-time unprovoked VTE were recruited
from four French centres between 1999 and 2006 and are under
50 years of age without known strong genetic risk factors. Healthy

The clinical characteristics of TEHS are presented in Table 1. The

study contained 2821 female participants, of whom 1426 were cases
(30% PE, 68% DVT and 2% with both DVT and PE) and 1395 were controls. Occurrence of known risk factors for VTE such as obesity, use of
combined hormonal contraceptives, menopausal replacement therapy
and positive family history of VTE was more frequent in cases than
controls. This was also the case for cardiovascular risk factors such as
smoking, diabetes mellitus and previous cardiovascular events.
CAD SNPs in VTE
Table 2 shows the associations (age adjusted) between all the 39
CAD SNPs and VTE in TEHS. In this analysis, rs579459, located in the
ABO cluster on 9q34.2, was the only SNP reaching our pre-set level of
statistical signicance (P 0.0013). Next, we included common CAD
and VTE clinical risk factors (age and BMI) together with, SNPs in ABO,
F5 and F2 in Model A and the ve most strongly VTE-associated genetic
variants [32] in Model B. When adjusting for all ABO blood group SNPs
(Model A), rs579459 was no longer signicant, whereas it remained
statistically signicant in Model B when adjusting only for non-O
blood group-tagging SNP. In contrast, these adjustments increased the
strength of associations between rs1333049 in ANRIL on 9q21 and
VTE. Of note, the SNPs in the ABO locus demonstrated no LD with
rs1333049 (Supplementary Fig. 1). Whilst not reaching our formal
signicance threshold, the rs1333049 SNP was taken forward for
further investigation in meta-analysis as this SNP is the most robust
marker for CAD and has been associated with diverse cardiovascular

M. Bruzelius et al. / Thrombosis Research 134 (2014) 426432

Table 2
Results of the discovery analysis.
Age-adjusted
CHR

SNP

Allele

MAF

OR (95%CI)

p-value

1
1
1
1
1
2
2
3
3
5
6
6
6
6
6
7
7
8
9
9
10
10
10
10
10
10
11
11
12
12
13
14
15
15
17
17
17
19
21

rs599839
rs646776
rs17114036
rs11206510
rs17465637
rs4299376
rs6725887
rs9818870
rs2306374
rs2706399
rs17609940
rs12526453
rs12190287
rs3798220
rs10455872
rs10953541
rs11556924
rs17321515
rs1333049
rs579459
rs2505083
rs1746048
rs501120
rs2246942
rs1412444
rs12413409
rs974819
rs964184
rs3184504
rs11065987
rs4773144
rs2895811
rs4380028
rs3825807
rs12936587
rs216172
rs46522
rs1122608
rs9982601

G/A
C/T
G/A
C/T
A/G
G/T
C/T
T/C
C/T
G/A
C/G
G/C
G/C
C/T
G/A
T/C
T/C
G/A
C/G
C/T
C/T
T/C
C/T
G/A
T/C
A/G
T/C
G/C
T/C
G/A
G/A
C/T
T/C
G/A
A/G
C/G
C/T
T/G
T/C

0.24
0.23
0.08
0.18
0.27
0.27
0.12
0.14
0.14
0.49
0.23
0.31
0.37
0.01
0.07
0.25
0.36
0.49
0.46
0.28
0.42
0.14
0.14
0.38
0.36
0.10
0.26
0.13
0.46
0.40
0.40
0.44
0.38
0.42
0.46
0.37
0.48
0.23
0.14

0.96 (0.85-1.09)
0.96 (0.84-1.09)
1.01 (0.83-1.22)
1.00 (0.87-1.15)
1.08 (0.96-1.21)
0.96 (0.85-1.08)
0.95 (0.82-1.12)
0.99 (0.86-1.15)
1.00 (0.86-1.16)
0.99 (0.89-1.10)
1.05 (0.92-1.19)
0.99 (0.88-1.11)
1.00 (0.89-1.11)
0.59 (0.36-0.95)
1.00 (0.81-1.24)
0.92 (0.81-1.04)
1.00 (0.90-1.11)
1.06 (0.96-1.18)
0.87 (0.79-0.97)
1.57 (1.39-1.78)
0.95 (0.85-1.05)
0.93 (0.80-1.09)
0.95 (0.82-1.11)
1.04 (0.93-1.16)
1.03 (0.92-1.15)
1.06 (0.89-1.26)
0.99 (0.88-1.11)
0.94 (0.80-1.10)
0.98 (0.89-1.10)
1.01 (0.91-1.12)
0.96 (0.86-1.07)
1.04 (0.94-1.16)
0.99 (0.89-1.10)
1.06 (0.95-1.18)
1.01 (0.91-1.12)
1.04 (0.93-1.15)
1.03 (0.92-1.14)
0.98 (0.87-1.12)
0.92 (0.80-1.07)

0.54
0.50
0.95
0.98
0.23
0.51
0.56
0.93
0.98
0.82
0.50
0.84
0.96
0.03
0.97
0.16
0.98
0.25
0.01
6.43E-13
0.30
0.39
0.53
0.51
0.64
0.54
0.86
0.45
0.78
0.88
0.47
0.43
0.79
0.30
0.91
0.53
0.61
0.79
0.29

Where: Allele, effect/non-effect allele; MAF, minor (effect) allele frequency; OR, odds ratio;
signicant p-values (b0.0013) in bold and nominal signicant p-values (b0.05) in italics.

traits (carotid plaque formation, stroke and intra-abdominal aneurysm [39]). The results of the association between VTE and rs579459
and rs1333049 are presented in Table 3. The association between
rs1333049 and VTE is unexpected, but cannot be accounted for by case
vs control deviation from Hardy Weinberg equilibrium (p = 0.2819
and p = 0.9129 respectively) or by differences in call rate (99.4% and
99.5%, respectively). Thus, we believe that technical aspects are not
responsible for the association between rs1333049 and VTE.
ABO SNPs in VTE
Supplementary Fig. 1 demonstrates the LD between the SNPs in ABO
as well as between the ABO locus and the ANRIL locus. It is interesting
to note that in Models A and B (Table 3), the associations between
rs579459 and VTE were dependent upon which other SNPs within the

429

ABO region were included in the model, despite the low LD between
the SNPs. Indeed, ABO haplotypes demonstrate different associations
with VTE; The ABO haplotypes tagging the ABO blood group A1 and B
had an OR of 1.69 and 1.54 compared to ABO O and A2. (Supplementary
Table 4). This analysis also indicated that the genotype for ABO blood
group A1 in exon 6 and rs579459 in intron 1 correlated very well.
Conditional analysis indicated that SNPs in ABO are inter-dependent
(Supplementary Table 5). Rs579459 behaves as a proxy for genotype
blood group A1 in these analyses, and explains why the association
with VTE in model A and B varied from the age-adjusted model. Including the three (rs8176704, rs514659, rs8176749) captures the
ABO locus with respect to phenotype whereas including only one
SNP (rs514659) does not. The strongest confounder in the model is
rs8176749 (Beta 0.088). Rs579459 is in LD with rs2519093 (r2 = 0.96
in 1000 Genomes CEU population), which has previously been associated
with VTE [40]. Thus, this SNP was not taken forward to replication.
ANRIL SNP: Replication and Meta-analysis
Characteristics of the replication cohorts are given in Supplementary
Table 2. Replication and meta-analysis of rs1333049 were rst attempted
in HVH and FARIVE (n = 2891), using models consistent with those
used in the analysis of TEHS (Table 4 top). Secondly, the four replication
cohorts were combined (n = 7181). EOVT and MARTHA lack BMI
measurements; hence, the statistical models used for these analyses
excluded BMI, but were otherwise as previously described (Table 4
bottom). It is worth noting that genotyping of rs1799963 (F2) was not
available in HVH, however sensitivity analysis in both TEHS and FARIVE
indicate that exclusion of this SNP from the model has negligible impact.
A women-only meta-analysis of subjects from the HVH and FARIVE
cohorts (n = 2524) was also non-signicant (p N 0.526 for all models),
indicating that lack of replication is unlikely to be due to a femalespecic effect.
Trans-European Variation in rs1333049 Minor Allele
The MAF of rs1333049 was close to 50% in all cohorts (Table 5), and
because it is a CG SNPs, it can be problematic to ensure that the same
allele was assessed. Thorough checks were carried out on all cohort
data, and a proxy (T/G alleles so easier to assign strands) was also tested
(rs10116277). The minor allele in TEHS and FARIVE was the C allele,
whereas in MARTHA and EOVT it was the G allele when using
rs10116272 as proxy (Table 5). It is worth noting that only HVH imputed some of the data included here (1000G1, imputed rs1333049,
oevar = 0.84; 1000G2, imputed rs10116277 oevar 0.99 and rs1333049
oevar = 0.81), whilst all other cohorts directly genotyped these SNPs.
The European populations in the HapMap project showed a similar difference, with the minor allele in the CEU population (north and western
European descent) being the C allele, whereas in the Italian population,
the minor allele was the G allele. This pattern was also conrmed in two
European multi-centre studies, IMPROVE [41] and PROCARDIS [42]
(Table 5).The MAF in the HVH study of subjects were comparable to
the European cohorts. Chi squared tests indicate that the differences
in allele frequencies across Europe were not statistically signicant
(all cohorts/countries p 0.2241 compared to TEHS, Table 5).

Table 3
The inuence of SNPs with VTE risk in TEHS.
Age adjusted

Model A

Model B

Chr.

SNP

allele

MAF

OR

(95%CI)

p-value

OR

(95%CI)

p-value

OR

(95%CI)

p-value

9
9

rs1333049
rs579459

C/G
C/T

0.46
0.28

0.87
1.57

(0.79-0.97)
(1.39-1.78)

0.01
6.43E-13

0.85
1.24

(0.75-0.95)
(0.80-1.93)

0.004
0.33

0.84
1.32

(0.75-0.94)
(1.12-1.55)

0.003
0.001

Where: minor (effect) allele is underlined, MAF, minor (effect) allele frequency; OR, odds ratio; Model A: age, BMI and genetic variants in the ABO (rs514659, rs8176704 and rs8176749),
F5 (rs6025) and F2 (s1799963); Model B: age, BMI and the 5 SNPs with the strongest associations with VTE; ABO (rs514659), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11
(rs2036914); signicant p-values (b0.0013) in bold and nominal signicant p-values (b0.05) in italics.

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M. Bruzelius et al. / Thrombosis Research 134 (2014) 426432

Table 4
Rs1333049 replication meta-analyses of FARIVE and HVH (top) or FARIVE, HVH, EOVT and MARTHA (bottom).
Model

Alleles

EAF

OR (95%CI)

P-value

Het_p

I2

Effect

age, bmi, sex

A: age, bmi, sex, 3abo, f2, f5
B: age, bmi, sex, top5

C/G
C/G
C/G

0.50
0.50
0.50

0.96 (0.85-1.09)
0.98 (0.87-1.10)
0.98 (0.87-1.11)

0.5569
0.7434
0.7485

0.5068
0.6784
0.5710

0
0
0

2891
2883
2883

0
0
+

Model

Alleles

EAF

OR (95%CI)

P-value

Het_p

I2

Effect

age, sex
A: age, sex, 3abo, f2, f5
B: age, sex, top5

C/G
C/G
C/G

0.53
0.53
0.53

0.90 (0.91-1.07)
0.99 (0.91-1.07)
0.99 (0.91-1.07)

0.7526
0.7468
0.7696

0.8717
0.9500
0.9052

0
0
0

7181
7173
7173

-+
+
0 +

Where: minor (effect) allele is underlined, MAF, minor (effect) allele frequency; OR, odds ratio; Het-p, p-value for signicant hetrogenity between cohorts; N, number of participants in
the analysis; Effect, direction of effect of the minor allele; Model A, adjusted also for ABO (rs514659, rs8176704 and rs8176749), F5 (rs6025) and F2 (s1799963); Model B, adjusted also for
ABO (rs514659), F5 (rs6025),F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914), signicant p-values (b0.05) in bold.

Discussion
In this study we investigated the effect of common genetic CADassociated variants on VTE risk. We found a robust association between
rs579459 in the ABO locus and risk of VTE, but little evidence for association with other loci. This is in line with a report that family history
of coronary heart disease or stroke differs from that of VTE which concluded that shared disease-causing variants are unlikely [43,44]. Some
evidence of a novel association between rs1333049 in the ANRIL locus
and VTE in our Swedish female TEHS cohort was identied but a
meta-analysis of 4 independent cohorts, rs1333049 did not replicate
the association with VTE.
The ABO blood group is a well established risk factor for CAD
and VTE. The mechanism for association appears to involve the von
Willebrand factor (vWF) which carries factor VIII (FVIII) and protects
it from degradation. The antigens A, B and H (O) are determinants for
ABO blood group which exist as complex carbohydrate structures and
are expressed on red blood cells, platelets and vascular endothelium.
ABH(O) antigens are believed to have an effect on proteolysis and clearance of vWF, but the mechanism is still unknown. It has been shown
that levels of vWF and FVIII are 25 to 30 per cent lower in carriers for
blood group ABO O and A2 genotype, which may partly explain the
lower risk of VTE and CAD for these individuals compared to A1 and B.
[45,46]. However, it has been suggested that the effect of ABO genotype
is not limited to its impact on vWF and FVIII levels [47]. Rs579459 in
ABO, reported here, has been associated with other diseases and traits.
In the original CAD study, rs579459 was both associated with CAD and
levels of LDL- and HDL levels, but no adjustment was made for the
ABO genotype [48]. In a previous study in women, rs507666 (high LD
(r2 = 0.96) with rs579459 (r2 = 1.00 in the 1000 Genomes CEU

population)), was associated with sICAM-1 concentration, a risk predictor for CAD [49]. In this study this variant was used to tag ABO blood
group A1 [49]. We found that rs2519093 in intron 1 of ABO, reported
to be associated with VTE [40], is also in perfect LD with rs579459
(r2 = 0.96 in the 1000 Genomes CEU population). Heit et al. reported
that rs2519093 was independent of the non-O ABO genotype and demonstrated a stronger association with VTE than the non-O blood group
[40]. In TEHS the low LD between the ABO tagging SNPs and rs579459
would suggest that they are independent, but the haplotype analysis
clearly indicated that rs579459 is a good proxy for rs8176704 (blood
group A1 genotype) (Supplementary Fig. 1 and Supplementary Tables 4
and 5). It is unfortunate that in TEHS ABO phenotyping is not possible,
but ABO genotype has been reported to correspond well with phenotype [50]. Whether the SNP in intron 1 in the ABO-locus has a regulatory
effect on ABO or nearby genes remains to be elucidated.
The association between rs1333049 in ANRIL on 9q21 and VTE risk
encountered in TEHS is interesting, as this region has shown the strongest association with CAD in multiple studies and it appears to be
independent of traditional atherosclerotic risk factors such as BMI, hyperlipidemia, hypertension, diabetes mellitus, smoking and obesity
[51]. The lack of replication indicates that this is most likely a spurious
nding. Indeed, that the VTE risk-increasing allele is the one which is
associated with decreased risk for CAD is counterintuitive.
The VTE association of ANRIL did not replicate in the replication
meta-analysis. One reason, and a limitation of our study, is the heterogeneity across cohorts. For example, the selection criteria for the control
groups are inconsistent. For FARIVE, the controls consist of in- and outpatients with a high prevalence of hypertension, diabetes mellitus and
smoking, whereas EOVT and MARTHA used population-based controls
from other studies who were older compared to the cases. Also, the

Table 5
Variation in minor allele and minor allele frequency across European ancestry populations.
Cohort

TEHS
FARIVE
HVH
EOVT
MARTHA
IMPROVE

PROCARDIS

Country

Swedish
French
USA*
French
French
Finnish
Swedish
Dutch
French
Italian
Swedish
German
British
Italian

Population

controls (female only)

controls
controls (female only)
controls
controls
high CAD-risk
high CAD-risk
high CAD-risk
high CAD-risk
high CAD-risk
controls
controls
controls
controls

rs1333049

rs10116277

Alleles

MAF

C/G
C/G
C/G

0.48
0.50
0.50

C/G
C/G
C/G
C/G
C/G

0.42
0.44
0.46
0.48
0.47

Alleles

MAF

p-value

T/G
T/G
T/G
T/G
T/G
T/G
T/G
T/G
T/G
T/G
T/G
T/G

0.49
0.45
0.46
0.42
0.42
0.44
0.44
0.41
0.42
0.45
0.50
0.43

0.0016
0.0016
0.0036
0.0023
0.0144
0.0064
0.0016
0.0000
0.0004
0.0144
0.0036
0.0016
0.0100

0.9681
0.9681
0.9520
0.9614
0.9044
0.9362
0.9681
1.0000
0.9840
0.9044
0.9521
0.9681
0.9203

Where: rs10116277 is a proxy for rs1333049 with LD of r2 = 0.81 and d = 0.91 in the HapMap CEU population; minor (effect) allele is underlined; MAF, minor (effect) allele frequency;
IMPROVE cohort includes persons with high risk for coronary artery disease the other cohorts are results from population controls. *Eurpoean ancestry. 2 test of allele frequencies in
comparison to TEHS (1 degree of freedom).

M. Bruzelius et al. / Thrombosis Research 134 (2014) 426432

inclusion of BMI in the models strengthened the association with VTE.

However, this information is lacking in EOVT and MARTHA and thus
was not included in the meta-analysis.
This study is the rst to systematically assess the impact of CADassociated variants on VTE. Other strengths include a large discovery cohort with age-matched controls and 4 independent replication cohorts.
A limitation for this study is that for the discovery analysis, when using
strict Bonferonni correction for number of loci, power was 80% for
SNPs with MAFs of 5-50% and OR of 1.58-1.28, respectively. The
range of MAFs, ORs and resulting power expected from literature is described in Supplementary Table 3. However, it should be noted that
these calculations are based on ORs reported for CAD, whereas it is plausible that the effects of these SNPs on VTE could be strikingly different
(either weaker or stronger). In addition, residual confounding may
have been introduced into models A and B (Table 3) as the SNPs used
as covariates are likely to have associations with VTE but not with
ANRIL. Whilst we have suboptimal power for some SNPs, we believe
that because TEHS is a very well dened, homogeneous cohort with
matched controls we would be able to identify the strongest signals to
take forward for replication.
Given that CAD and VTE appear to share limited genetic risk factors,
it is tempting to speculate that the commonality between the two
pathologies include epigenetic mechanisms. Indeed, with age and BMI
being the only consistent risk factors CAD and VTE have in common
[2123], a greater focus on these aspects would be of value. BMI (as a
marker of general metabolic dysregulation) is of particular interest, as
a risk factor that is easily measured and modiable by lifestyle changes.
In particular, central obesity has been shown to trigger changes in the
vascular bed and haemostasis leading to an increase in risk of thrombosis [52]. Understanding the impact of metabolic control and obesity on
CAD is the subject of much current research, whereas the impact on
VTE is little understood.
In conclusion, we can conrm the inuence of rs579459 in the ABO
cluster on VTE risk, but not its independence from the ABO genotype.
Overall, we cannot conrm a link between established CAD and MI genetic variants and VTE, and although ANRIL showed an intriguing association in discovery analysis, this was not replicated in a meta-analysis
of upwards of 7000 VTE cases and controls.
Authorship
A.B., H.K. and J.O. designed the core TEHS study. A.Su. and A.B. organized the phenotype database. M.B., K.G., J.O. and A.H. designed the
present investigation. M.B. and R.S. performed the statistical analyses.
R.S., A.Si. M.S-L and J.O. co-ordinated sample handling and genotyping,
and A-C.S. conducted the array-based genotyping, SNP reading and
quality control. D.T, P.M, KW and NS. performed the replication analyses. M.B., R.S., J.h and J.O. and A.H. participated in the writing of
the manuscript. All co-authors were involved in the editing of the
manuscript.
Conict of Interest Statement
The authors declare that no conicts of interest exist.
Acknowledgements
We acknowledge the contribution of all participants in the studies
included. All contributors to all of the included studies. Funding: TEHS
was funded by Janssen-Cilag, Novartis, Organon, Schering, Wyeth,
AFA, Centre for Gender Medicine and by the authors afliations. The
sponsors were not involved in the design and conduct of the study;
collection, management, analysis or interpretation of the data, and preparation, review, or approval of the manuscript. Work on this manuscript
was supported by the Swedish Heart-Lung Foundation, the Swedish
Research Council (8691), the Strategic Cardiovascular Program of

431

Karolinska Institutet and Stockholm County Council, the Foundation

for Strategic Research and the Stockholm County Council (560283).
R.S is supported by Swedish Heart-Lung Foundation (20120600),
the Tore Nilsson, Gamla Tjnarinnor and Fredrik and Ingrid Thurings
foundations. FARIVE was supported by grants from the Fondation pour
la Recherche Mdicale, the Programme Hospitalier pour la Recherche
Clinique (PHRC 2002, PHRC 2009 RENOVA-TV) and the Leducq Foundation. The MARTHA project was funded by a grant from the Programme
Hospitalier pour la Recherche Clinique. The Heart and Vascular Health
study is supported by the National Health Lung and Blood Institute
grants HL43201, HL60739, HL68986, HL73410, HL74745, HL85251, and
HL95080. The funding organization had no role in the present study or
analysis.
Appendix A. Supplementary Data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.thromres.2014.03.054.
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