Clinical and genetic risk factors in acute coronary syndromes

106 Pages·2016·1.06 MB·English

by  Satu Vaara

Heart and Lung Center
Helsinki University Central Hospital
University of Helsinki
Helsinki, Finland

Doctoral Programme in Clinical Research, University of Helsinki
Helsinki, Finland

Clinical and genetic risk factors in acute coronary
syndromes

Satu Vaara

ACADEMIC DISSERTATION
To be presented with the permission of the Medical Faculty of the University of
Helsinki, for public examination in Meilahti Hospital, Lecture Hall 3, on January 27th
2017, at 12 noon.

Helsinki 2017
SUPERVISOR

Professor Juha Sinisalo
Heart and Lung Center
Helsinki University Central Hospital
University of Helsinki
Helsinki, Finland

REVIEWERS

Professor Ilkka Pörsti
Department of Internal Medicine
Tampere University Hospital
Tampere, Finland

Professor Katriina Aalto-Setälä
Heart Center
Tampere University Hospital
Tampere, Finland
and
BioMediTech
University of Tampere
Tampere, Finland

OFFICIAL OPPONENT

Docent Heikki Ukkonen
Heart Center
Turku University Hospital
University of Turku
Turku, Finland

ISBN 978-951-51-2820-1 (paperback)
ISBN 978-951-51-2821-8 (PDF)
http://ethesis.helsinki.fi

Unigrafia Oy
Helsinki 2017

Contents
List of original publications 7
Most important abbreviations 8
Abstract 10
1. Introduction 12
2. Review of the literature 14
2.1. Epidemiology of CAD and ACS 14
2.2. Classification and diagnosis of stable CAD and ACS 15
2.3. Pathophysiology 19
2.3.1. Formation and composition of an atherosclerotic plaque 19
2.3.2. Pathophysiology of ACS 20
2.4. Clinical risk factors of atherosclerosis and ACS 22
2.5. Treatment of stable CAD and ACS 24
2.6. Genetics of CAD 25
2.6.1. Revealed genetic risk variants for CAD 25
2.7. Differences in pathophysiology and clinical characteristics between STEMI
and NSTEMI 35
2.8. Prediction of CAD, MI and outcome 35
2.8.1. Traditional risk-prediction tools 35
2.8.2. Risk prediction using genetic information 38
2.9. Other manifestations of CVD 40
2.9.1. Peripheral artery disease 40
2.9.2. Stroke 41
3. Aims of the study 43
4. Methods 44
4.1. Design of the substudies 44
4.2. Study cohorts 45
4.2.1. Corogene (I-IV) 46
4.2.2. TACOS (III) 47
4.2.3 FINRISK (III-IV) 47
4.3 Definitions of study end-points 48
4.4 Genotyping 49
4.5. Statistical methods 50
4.5.1. Statistical tests 50
4.5.2. Calculation of GRS 51
5. Results 52
5.1. Overall patient characteristics in the Corogene cohort (I) 52
5.2. ACS patients (II) 55
5.2.1. Recurrent ACS during follow-up 55
5.2.2. Mortality of the ACS patients 56
5.2.3. Single SNP associations with outcome and with risk factors in ACS
patients 57
5.2.4. GRS associations with outcome in ACS patients 57
5.2.5. GRS associations with subtype of ACS and clinical factors 58
5.3. Differences between STEMI and NSTEMI patients (III) 59
5.3.1. Clinical characteristics 59
5.3.2. Genetic variants associated with NSTEMI in GWAS 60
5.3.3. Association of previously reported CAD/MI risk loci with NSTEMI and
STEMI (III) 62
5.4. Associations of variant rs656843 at 1p13.3 with cardiovascular risk factors,
adverse outcome, and other manifestations of atherosclerosis (IV) 62
5.4.1. Associations of rs656843 genotypes with clinical characteristics 62
5.4.2. Associations of rs656843 with outcome and other manifestations of CVD 63
6. Discussion 65
6.1. Cohort evaluation 65
6.2. Genetics affecting outcome of ACS patients 67
6.3. Differences between STEMI and NSTEMI patients 69
6.4. The new risk variant for NSTEMI predisposing to PAD? 70
6.5. Limitations of the study 71
6.6. Clinical implications and future perspectives 72
7. Conclusions 74
8. Acknowledgements 75
9. References 77
List of original publications
This thesis is based on the following publications:

I Vaara S, Nieminen MS, Lokki ML, Perola M, Pussinen PJ, Allonen J,
Parkkonen O, Sinisalo J. Cohort profile: The Corogene Study. Int J
Epidemiol. 2012 Oct;41(5):1265-71.

II Vaara S, Tikkanen E, Parkkonen O, Lokki ML, Ripatti S, Perola M,
Nieminen MS, Sinisalo J. Genetic risk scores predict recurrence of acute
coronary syndrome. Circ Cardiovasc Genet. 2016 Apr;9(2):172-8.

III Salo PP, Vaara S, Kettunen J, Pirinen M, Sarin AP, Huikuri H, Karhunen PJ,
Eskola M, Nikus K, Lokki ML, Ripatti S, Havulinna AS, Salomaa V, Palotie
A, Nieminen MS, Sinisalo J, Perola M. Genetic variants on chromosome
1p13.3 are associated with non-ST elevation myocardial infarction and the
expression of DRAM2 in the Finnish population. PLoS One. 2015 Oct
28;10(10):e0140576.

IV Vaara S, Salo P, Perola M, Parkkonen O, Lokki ML, Havulinna A, Salomaa
V, Nieminen MS, Sinisalo J. A risk locus for non-ST-elevation myocardial
infarction on chromosome 1p13.3 is also associated with peripheral artery
disease in patients with acute coronary syndrome. (Submitted to Scientific
Reports)

The publications are referred to in the text by their Roman numerals.

Additional information not published in these articles is included and cited as “S.V. et al.,
unpublished results”.

The original articles are reproduced with the permission of the respective copyright
holders (I-III).

7
Most important abbreviations
ABI ankle brachial index
ACS acute coronary syndrome
AMI acute myocardial infarction
ARIC Atherosclerosis Risk in Communities
ASAT aspartate aminotransferase
AUC area under the receiver operating characteristics curve
BMI body-mass index
CABG coronary artery by-pass grafting
CAD coronary artery disease
CCTA computed coronary tomography angiogram
CI confidence interval
CKMBm creatine kinase-MB-mass
CRP C-reactive protein
CVD cardiovascular disease
DNA deoxyribonucleic acid
DRAM2 damage-regulated autophagy modulator 2
ECG electrocardiogram
FDR false discovery rate
GFR glomerular filtration rate
GGT gammaglutamyltransferase
GRACE Global Registry of Acute Coronary Events
GRS genetic risk score
GTEx Genotype-Tissue Expression project
GUSTO Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries
GWAS genome-wide association study
EMMACE Evaluation of the Methods and Management of Acute
Coronary Events
HbA1c glycosylated hemoglobin A1c
HDL high-density lipoprotein
HR hazard ratio
IQR interquartile range
LDL low-density lipoprotein
LD linkage disequilibrium
MAF minor allele frequency
MDRD Modification of Diet in Renal Disease
MI myocardial infarction
MONICA Multinational MONItoring of trends and determinants in
CArdiovascular disease -Project
NSTEACS non-ST-elevation acute coronary syndrome
NSTEMI non-ST-elevation myocardial infarction
OR odds ratio
8
PAD peripheral artery disease
PCI percutaneous coronary intervention
proBNP Type B N-terminal natriuretic propeptide
PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor
Suppression Using Integrilin Therapy
ROC receiver operating characteristics
SD standard deviation
SMC smooth muscle cell
STEMI ST-elevation myocardial infarction
SNP single nucleotide polymorphism
SRI Simple Risk Index
TACOS Tampere Acute Coronary Syndrome Study
TIA transient ischemic attack
TIMI Thrombolysis in Myocardial Infarction Study Group
TnI cardiac troponin I
TnT cardiac troponin T
UAP unstable angina pectoris
9
Abstract

Aims
This study aimed to investigate how various genetic variants affect acute coronary
syndrome (ACS): its subtype and the prognosis. More precisely, its objectives were to
describe the characteristics of a Finnish cohort of consecutive angiography patients and to
evaluate the importance of clinical risk factors and genetic risk scores (GRS) in predicting
the ACS prognosis. Additionally, genetic differences were sought between patients with
non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial
infarction (STEMI). The newly discovered NSTEMI risk variant was studied for effects
on prognosis, clinical risk factors and other manifestations of atherosclerosis.

Material and methods
Studies I to IV are based on the Corogene cohort, consisting of 5 294 consecutive patients
who underwent coronary angiography between 2006 and 2008. The patients with ACS or
prior myocardial infarction (MI) were genotyped. Additionally, genotyped individuals
from Tampere Acute Coronary Syndrome Study (TACOS) (Study III) and FINRISK
cohorts (Studies III-IV) were included to further test the findings discovered of the
Corogene Study.
Study I was an observational cohort study of all the 5 294 consecutive coronary
angiography patients included in the Corogene Study. It described the risk factor profiles,
disease stability and severity, and the revascularization strategy of all these patients. Study
II elucidated the recurrence rate and the mortality from coronary artery disease (CAD) in
the 2 090 ACS patients during a median 5.5-year follow-up, and clinical factors affecting
their prognosis. The GRS of 47 previously known CAD risk variants was formed and
tested for association with recurrent ACS and CAD mortality. Clinical risk factors were
studied for association with the GRS47. Patients with MI were selected for Study III, a
genome-wide association study (GWAS), to discover new genetic variants conferring risk
specifically for NSTEMI or STEMI. The variants passing a pre-defined statistical
significance threshold were chosen for replication in the TACOS and FINRISK cohorts. In
Study IV, data of all the genotyped ACS patients served for analysis of clinical
characteristics and comorbidities associated with the variant discovered in the GWAS of
Study III, with special emphasis on the variant’s effect on the prognosis and on incidence
of peripheral artery disease (PAD).

Main results
The most common reason for coronary angiogram in the Corogene Study during the study
period was ACS (2 090, 39%). Almost one-fourth of the patients (1 207, 23%) had no
signs of obstructive CAD in coronary angiography. About half of all patients (2 854, 54%)
were finally revascularized.
Of the ACS patients, 263 (12.6%) had recurrent ACS, 455 (21.8%) died during the
follow-up, and 259 (12.4%) had a CAD-related cause of death. The GRS47 was found
associated with recurrent ACS, independent of clinical factors. When added to a risk-
10