Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain

Morten Krogh Christiansen; Simon Winther; Louise Nissen; Bjarni Jóhann Vilhjálmsson; Lars Frost; Jane Kirk Johansen; Peter Loof Møller; Samuel Emil Schmidt; Jelmer Sybren Westra; Niels Ramsing Holm; Henrik Kjærulf Jensen; Evald Høj Christiansen; Daníel Fannar Guðbjartsson; Hilma Hólm; Kári Stefansson; Hans Erik Bøtker; Morten Bøttcher; Mette Nyegaard

doi:10.1161/CIRCGEN.120.003298

Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain

Morten Krogh Christiansen^*, Simon Winther, Louise Nissen, Bjarni Jóhann Vilhjálmsson, Lars Frost, Jane Kirk Johansen, Peter Loof Møller, Samuel Emil Schmidt, Jelmer Sybren Westra, Niels Ramsing Holm, Henrik Kjærulf Jensen, Evald Høj Christiansen, Daníel Fannar Guðbjartsson, Hilma Hólm, Kári Stefansson, Hans Erik Bøtker, Morten Bøttcher, Mette Nyegaard

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

9 Citations (Scopus)

Abstract

Background - Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography (CTA) on a suspicion of obstructive CAD. Methods - In this prespecified diagnostic substudy of the Dan-NICAD trial we included 1617 consecutive patients with stable chest symptoms and no prior history of CAD referred for coronary CTA. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped and their PRSs were calculated. All patients underwent coronary CTA. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). A combined endpoint of obstructive CAD was defined as a visual ICA stenosis >90%, FFR <0.80, or a quantitative coronary analysis stenosis >50% if FFR measurements were not feasible. Results - The PRS was associated with obstructive CAD independent of CRFs (adjusted OR 1.8 [95%CI 1.5-2.2] per SD). The PRS had an area under the curve (AUC) of 0.63 (0.59-0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with AUC of 0.75 (0.71-0.79), which was 0.04 more than the CRF model (P=0.0029). By using pre-test probability (PTP) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% (P=3.1e-4) was obtained, with a down-classification of risk in 24% of patients (211/862) in whom the PTP was 5%-15% based on CRFs alone. Conclusions - Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting.

Original language	English
Article number	003298
Journal	Circulation: Genomic and Precision Medicine
Volume	14
Issue	3
Pages (from-to)	323-330
Number of pages	8
ISSN	2574-8300
DOIs	https://doi.org/10.1161/CIRCGEN.120.003298
Publication status	Published - 1 Jun 2021

Keywords

angina, stable
coronary disease
genetic testing
human genetics
polymorphism, genetic

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10.1161/CIRCGEN.120.003298

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Christiansen, M. K., Winther, S., Nissen, L., Vilhjálmsson, B. J., Frost, L., Johansen, J. K., Loof Møller, P., Schmidt, S. E., Westra, J. S., Holm, N. R., Jensen, H. K., Christiansen, E. H., Guðbjartsson, D. F., Hólm, H., Stefansson, K., Bøtker, H. E., Bøttcher, M., & Nyegaard, M. (2021). Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain. Circulation: Genomic and Precision Medicine, 14(3), 323-330. Article 003298. https://doi.org/10.1161/CIRCGEN.120.003298

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title = "Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain",

abstract = "Background - Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography (CTA) on a suspicion of obstructive CAD. Methods - In this prespecified diagnostic substudy of the Dan-NICAD trial we included 1617 consecutive patients with stable chest symptoms and no prior history of CAD referred for coronary CTA. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped and their PRSs were calculated. All patients underwent coronary CTA. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). A combined endpoint of obstructive CAD was defined as a visual ICA stenosis >90%, FFR <0.80, or a quantitative coronary analysis stenosis >50% if FFR measurements were not feasible. Results - The PRS was associated with obstructive CAD independent of CRFs (adjusted OR 1.8 [95%CI 1.5-2.2] per SD). The PRS had an area under the curve (AUC) of 0.63 (0.59-0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with AUC of 0.75 (0.71-0.79), which was 0.04 more than the CRF model (P=0.0029). By using pre-test probability (PTP) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% (P=3.1e-4) was obtained, with a down-classification of risk in 24% of patients (211/862) in whom the PTP was 5%-15% based on CRFs alone. Conclusions - Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting.",

keywords = "angina, stable, coronary disease, genetic testing, human genetics, polymorphism, genetic",

author = "Christiansen, {Morten Krogh} and Simon Winther and Louise Nissen and Vilhj{\'a}lmsson, {Bjarni J{\'o}hann} and Lars Frost and Johansen, {Jane Kirk} and {Loof M{\o}ller}, Peter and Schmidt, {Samuel Emil} and Westra, {Jelmer Sybren} and Holm, {Niels Ramsing} and Jensen, {Henrik Kj{\ae}rulf} and Christiansen, {Evald H{\o}j} and Gu{\dh}bjartsson, {Dan{\'i}el Fannar} and Hilma H{\'o}lm and K{\'a}ri Stefansson and B{\o}tker, {Hans Erik} and Morten B{\o}ttcher and Mette Nyegaard",

year = "2021",

month = jun,

day = "1",

doi = "10.1161/CIRCGEN.120.003298",

language = "English",

volume = "14",

pages = "323--330",

journal = "Circulation: Genomic and Precision Medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins",

number = "3",

}

Christiansen, MK , Winther, S, Nissen, L, Vilhjálmsson, BJ, Frost, L, Johansen, JK, Loof Møller, P, Schmidt, SE, Westra, JS , Holm, NR , Jensen, HK , Christiansen, EH, Guðbjartsson, DF, Hólm, H, Stefansson, K, Bøtker, HE , Bøttcher, M & Nyegaard, M 2021, 'Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain', Circulation: Genomic and Precision Medicine, vol. 14, no. 3, 003298, pp. 323-330. https://doi.org/10.1161/CIRCGEN.120.003298

Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain. / Christiansen, Morten Krogh ; Winther, Simon; Nissen, Louise et al.
In: Circulation: Genomic and Precision Medicine, Vol. 14, No. 3, 003298, 01.06.2021, p. 323-330.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain

AU - Christiansen, Morten Krogh

AU - Winther, Simon

AU - Nissen, Louise

AU - Vilhjálmsson, Bjarni Jóhann

AU - Frost, Lars

AU - Johansen, Jane Kirk

AU - Loof Møller, Peter

AU - Schmidt, Samuel Emil

AU - Westra, Jelmer Sybren

AU - Holm, Niels Ramsing

AU - Jensen, Henrik Kjærulf

AU - Christiansen, Evald Høj

AU - Guðbjartsson, Daníel Fannar

AU - Hólm, Hilma

AU - Stefansson, Kári

AU - Bøtker, Hans Erik

AU - Bøttcher, Morten

AU - Nyegaard, Mette

PY - 2021/6/1

Y1 - 2021/6/1

N2 - Background - Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography (CTA) on a suspicion of obstructive CAD. Methods - In this prespecified diagnostic substudy of the Dan-NICAD trial we included 1617 consecutive patients with stable chest symptoms and no prior history of CAD referred for coronary CTA. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped and their PRSs were calculated. All patients underwent coronary CTA. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). A combined endpoint of obstructive CAD was defined as a visual ICA stenosis >90%, FFR <0.80, or a quantitative coronary analysis stenosis >50% if FFR measurements were not feasible. Results - The PRS was associated with obstructive CAD independent of CRFs (adjusted OR 1.8 [95%CI 1.5-2.2] per SD). The PRS had an area under the curve (AUC) of 0.63 (0.59-0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with AUC of 0.75 (0.71-0.79), which was 0.04 more than the CRF model (P=0.0029). By using pre-test probability (PTP) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% (P=3.1e-4) was obtained, with a down-classification of risk in 24% of patients (211/862) in whom the PTP was 5%-15% based on CRFs alone. Conclusions - Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting.

AB - Background - Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography (CTA) on a suspicion of obstructive CAD. Methods - In this prespecified diagnostic substudy of the Dan-NICAD trial we included 1617 consecutive patients with stable chest symptoms and no prior history of CAD referred for coronary CTA. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped and their PRSs were calculated. All patients underwent coronary CTA. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). A combined endpoint of obstructive CAD was defined as a visual ICA stenosis >90%, FFR <0.80, or a quantitative coronary analysis stenosis >50% if FFR measurements were not feasible. Results - The PRS was associated with obstructive CAD independent of CRFs (adjusted OR 1.8 [95%CI 1.5-2.2] per SD). The PRS had an area under the curve (AUC) of 0.63 (0.59-0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with AUC of 0.75 (0.71-0.79), which was 0.04 more than the CRF model (P=0.0029). By using pre-test probability (PTP) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% (P=3.1e-4) was obtained, with a down-classification of risk in 24% of patients (211/862) in whom the PTP was 5%-15% based on CRFs alone. Conclusions - Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting.

KW - angina, stable

KW - coronary disease

KW - genetic testing

KW - human genetics

KW - polymorphism, genetic

UR - http://www.scopus.com/inward/record.url?scp=85108168347&partnerID=8YFLogxK

U2 - 10.1161/CIRCGEN.120.003298

DO - 10.1161/CIRCGEN.120.003298

M3 - Journal article

C2 - 34032468

SN - 2574-8300

VL - 14

SP - 323

EP - 330

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

IS - 3

M1 - 003298

ER -

Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain

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