Risk prediction for coronary heart disease by a genetic risk score - results from the Heinz Nixdorf Recall study

Abstract

Background A Genetic risk score for coronary artery disease (CAD) improves the ability of predicting coronary heart disease (CHD). It is unclear whether i) the use of a CAD genetic risk score is superior to the measurement of coronary artery calcification (CAC) for CHD risk assessment and ii) the CHD risk assessment using a CAD genetic risk score differs between men and women. Methods We included 4041 participants (age-range: 45–76 years, 1919 men) of the Heinz Nixdorf Recall study without CHD or stroke at baseline. A standardized weighted CAD genetic risk score was constructed using 70 known genetic variants. The risk score was divided into quintiles (Q1-Q5). We specified low (Q1), intermediate (Q2-Q4) and high (Q5) genetic risk groups. Incident CHD was defined as fatal and non-fatal myocardial infarction, stroke and coronary death. The association between the genetic risk score and genetic risk groups with incident CHD was assessed using Cox models to estimate hazard ratios (HR) and 95%-confidence intervals (CI). The models were adjusted by age and sex (Model1), as well as by established CHD risk factors (RF) and CAC (Model2). The analyses were further stratified by sex and controlled for multiple testing. Results During a median follow-up time of 11.6 ± 3.7 years, 343 participants experienced CHD events (219 men). Per-standard deviation (SD) increase in the genetic risk score was associated with 18% increased risk for incident CHD (Model1: p = 0.002) which did not change after full adjustment (Model2: HR = 1.18 per-SD (p = 0.003)). In Model2 we observed a 60% increased CHD risk in the high (p = 0.009) compared to the low genetic risk group. Stratifying by sex, only men showed statistically significantly higher risk for CHD (Model2: HR = 1.23 per-SD (p = 0.004); intermediate: HR = 1.52 (p = 0.04) and high: HR = 1.88 (p = 0.008)) with no statistically significant risk observed in women. Conclusion Our results suggest that the CAD genetic risk score could be useful for CHD risk prediction, at least in men belonging to the higher genetic risk group, but it does not outbalance the value of CT-based quantification of CAC which works independently on both men and women and allows better risk stratification in both the genders.

Etiologic Puzzle of Coronary Artery Disease: How Important Is Genetic Component?

“…Coronary atherosclerosis is the main pathogenic mechanism in CAD, regardless of its clinical form, that ranges from subclinical atherosclerosis to chronic and acute coronary sindroms and SCD [ 6 , 14 ]. Some data indicate that about 50% of SCD are due to MI, and about a third of MI cases are silent [ 6 , 13 ]. The average age at which the first MI occurs varies between the two sexes, being 64.9 years for men and 72.3 years for women [ 1 ].…”

“…Numerous epidemiological studies have been conducted in recent years in an attempt to determine which are the risk factors for CAD, in order to develop models that would allow the development of risk scores (CAD risk prediction models) [ 4 , 12 , 13 ].…”

“…The Framingham Heart Study (FHS, 1948) was the first study to attempt to elucidate cardiovascular disease risk factors (CRF), followed by the FINRISK study (Finland, 1972) and other cohort studies conducted at Uppsala University in Sweden (ULSAM, PIVUS, POEM, EpiHealth and SCAPIS), INTERHEART study (a case–control study of acute myocardial infarction in 52 countries) and another study in New Zealand (PREDICT Cardiovascular Disease Cohort). In these studies, CAD risk factors are classified into two categories: modifiable risk factors (hypercholesterolemia, smoking, diabetes mellitus, systolic hypertension, sedentary lifestyle) and non-modifiable risk factors (age, sex, family history for CAD) ( Figure 1 ) [ 4 , 5 , 6 , 7 , 8 , 12 , 13 , 14 , 15 ].…”

“…Currently, the Multi Ethnic Study Group of Atherosclerosis (MESA) is considering the inclusion of coronary artery calcification (CAC) in the category of risk factors for CAD [ 13 ]. The European Association for Cardiovascular Prevention and Rehabilitation (EACRP) and the American College of Cardiology/American Heart Association (ACC/AHA) have developed practical guidelines, based on CAD risk prediction models, to reduce the risk of acute coronary syndromes (ACS) [ 13 ].…”

“…Geneticists point to the need to achieve polygenic risk scores (PRS) that could play an important role in identifying people at high risk for CAD. In their case, the early implementation of prophylactic measures would help to improve the prognosis and life expectancy [ 6 , 13 ].…”