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Polygenic Risk Score Adds to Clinical Risk Score for CVD Prediction
Quick Takes
- Persons 40-79 years old enrolled in general practice(s) in England without CVD identified high risk by the extensive QRISK2 (10-year risk ≥10%) and agreeing to participate in the genetic study were provided standard primary prevention treatment if not already treated, which is consistent with a real-world setting.
- The addition of genetic information (CVD-PRS) to clinical risk assessment significantly improved the identification of individuals who went on to have a major CVD event, especially among younger individuals defined as age 40-59 years.
- The findings were similar when the CVD-PRS was added to the US ACC/AHA ASCVD-PCE and SCORE2 developed in populations across Europe aged 40-69 years.
Study Questions:
Does the addition of a polygenic risk score for cardiovascular disease (CVD-PRS) to clinical risk scores improve the identification of individuals at increased risk in a real-world clinical setting?
Methods:
The Genetics and the Vascular Health Check Study (GENVASC) in England was embedded within the UK National Health Service Health Check (NHSHC) program and enrolled persons 40–74 years of age without known CVD to obtain risk factors for the QRISK2 risk score. Between 2012–2020, 44,141 individuals (55.7% females, 15.8% non-White) who attended NHSHC were recruited and followed. When 195 individuals (cases) had suffered a major CVD event (CVD death, myocardial infarction or acute coronary syndrome, coronary revascularization, stroke), 396 propensity-matched controls with a similar risk profile were identified, and a nested case-control genetic study undertaken to see if the addition of a CVD-PRS to QRISK2 in the form of an integrated risk tool (IRT) combined with QRISK2 would have identified more individuals at the time of their NHSHC as high risk (QRISK2 10-year CVD risk of ≥10%), compared with QRISK2 alone.
Results:
The distribution of the standardized CVD-PRS was significantly different in cases compared with controls (cases mean score, 0.32; controls, −0.18, p = 8.28 × 10−9). QRISK2 identified 61.5% (95% confidence interval [CI], 54.3%–68.4%) of individuals who subsequently developed a major CVD event as being at high risk, while the combination of QRISK2 and IRT identified 68.7% (95% CI, 61.7%–75.2%), a relative increase of 11.7% (p = 1 × 10−4). The odds ratio (OR) of being up-classified was 2.41 (95% CI, 1.03–5.64; p = 0.031) for cases compared with controls. In individuals aged 40–54 years, QRISK2 identified 26.0% (95% CI, 16.5%–37.6%) of those who developed a major CVD event, while the combination of QRISK2 and IRT identified 38.4% (95% CI, 27.2%–50.5%), indicating a stronger relative increase of 47.7% in the younger age group (p = 0.001). The combination of QRISK2 and IRT increased the proportion of additional cases identified similarly in women as in men, and in non-White compared with Whites. The findings were similar when the CVD-PRS was added to the atherosclerotic CVD pooled cohort equation (ASCVD-PCE) or SCORE2.
Conclusions:
In a clinical setting, the addition of genetic information to clinical risk assessment by the commonly used risk scores significantly improved the identification of individuals who went on to have a major CVD event as being at high risk, especially among younger individuals. The findings provide important real-world evidence of the potential value of implementing a CVD-PRS into health systems.
Perspective:
The PRS is the weighted sum of the total number of risk alleles in an individual that can be used to identify the genetic risk for CVD in large prospective cohorts. The cost of a PRS is about $250. Surprisingly, the PRS in this study added value that was similar in persons aged 40-79 years using the ASCVD-PCE and QRISK2. In the former, CVD risk factors are limited to age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive treatment, diabetes, and smoking, while the QRISK2 in persons aged 40-79 years includes age, gender, ethnicity, hypertension, cholesterol, body mass index, smoking, alcohol intake, diabetes, rheumatoid arthritis, and chronic kidney disease. QRISK2 includes people aged 30-95 years, which were not included in this study. The new American Heart Association (AHA) PREVENT risk calculator has the added benefit of estimating the 10- and 30-year CVD risk and heart failure in people aged 30-79 years by adding CV, kidney, and metabolic risk factors. Whether the PRS would be additive is an important query.
Clinical Topics: Prevention
Keywords: Atherosclerosis, Heart Disease Risk Factors, Risk Assessment
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