Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations

Charlotte Andersson; Maria Lukács Krogager; Regitze Kuhr Skals; Emil Vincent Rosenbaum Appel; Christian Theil Have; Niels Grarup; Oluf Pedersen; Jørgen L Jeppesen; Ole Dyg Pedersen; Helena Dominguez; Ulrik Dixen; Thomas Engstrøm; Niels Tønder; Dan M Roden; Steen Stender; Gunnar H Gislason; Henrik Enghusen-Poulsen; Torben Hansen; Lars Køber; Christian Torp-Pedersen; Peter E Weeke

doi:10.1371/journal.pone.0211690

Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations

Charlotte Andersson^*, Maria Lukács Krogager, Regitze Kuhr Skals, Emil Vincent Rosenbaum Appel, Christian Theil Have, Niels Grarup, Oluf Pedersen, Jørgen L Jeppesen, Ole Dyg Pedersen, Helena Dominguez, Ulrik Dixen, Thomas Engstrøm, Niels Tønder, Dan M Roden, Steen Stender, Gunnar H Gislason, Henrik Enghusen-Poulsen, Torben Hansen, Lars Køber, Christian Torp-PedersenPeter E Weeke

^*Corresponding author for this work

Abstract

Background: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography.

Methods: 1599 individuals (mean age 64 years [min-max 29–96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010–2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies.

Results: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively.

Conclusions: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a “missing heritability” in early-onset CAD warrants more research.

Original language	English
Article number	e0211690
Journal	P L o S One
Volume	14
Issue number	2
Number of pages	12
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0211690
Publication status	Published - 2019

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Andersson, C., Krogager, M. L., Skals, R. K., Appel, E. V. R., Have, C. T., Grarup, N., Pedersen, O., Jeppesen, J. L., Pedersen, O. D., Dominguez, H., Dixen, U., Engstrøm, T., Tønder, N., Roden, D. M., Stender, S., Gislason, G. H., Enghusen-Poulsen, H., Hansen, T., Køber, L., ... Weeke, P. E. (2019). Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations. P L o S One, 14(2), [e0211690]. https://doi.org/10.1371/journal.pone.0211690

Andersson, C, Krogager, ML, Skals, RK, Appel, EVR, Have, CT, Grarup, N , Pedersen, O, Jeppesen, JL, Pedersen, OD, Dominguez, H , Dixen, U , Engstrøm, T, Tønder, N, Roden, DM, Stender, S , Gislason, GH , Enghusen-Poulsen, H , Hansen, T , Køber, L, Torp-Pedersen, C & Weeke, PE 2019, 'Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations', P L o S One, vol. 14, no. 2, e0211690. https://doi.org/10.1371/journal.pone.0211690

@article{39a51ac94a6c4144b5094788acf37fcf,

title = "Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations",

abstract = "Background: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. Methods: 1599 individuals (mean age 64 years [min-max 29–96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010–2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. Results: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. Conclusions: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a “missing heritability” in early-onset CAD warrants more research.",

author = "Charlotte Andersson and Krogager, {Maria Luk{\'a}cs} and Skals, {Regitze Kuhr} and Appel, {Emil Vincent Rosenbaum} and Have, {Christian Theil} and Niels Grarup and Oluf Pedersen and Jeppesen, {J{\o}rgen L} and Pedersen, {Ole Dyg} and Helena Dominguez and Ulrik Dixen and Thomas Engstr{\o}m and Niels T{\o}nder and Roden, {Dan M} and Steen Stender and Gislason, {Gunnar H} and Henrik Enghusen-Poulsen and Torben Hansen and Lars K{\o}ber and Christian Torp-Pedersen and Weeke, {Peter E}",

year = "2019",

doi = "10.1371/journal.pone.0211690",

language = "English",

volume = "14",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "2",

}

TY - JOUR

T1 - Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations

AU - Andersson, Charlotte

AU - Krogager, Maria Lukács

AU - Skals, Regitze Kuhr

AU - Appel, Emil Vincent Rosenbaum

AU - Have, Christian Theil

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Jeppesen, Jørgen L

AU - Pedersen, Ole Dyg

AU - Dominguez, Helena

AU - Dixen, Ulrik

AU - Engstrøm, Thomas

AU - Tønder, Niels

AU - Roden, Dan M

AU - Stender, Steen

AU - Gislason, Gunnar H

AU - Enghusen-Poulsen, Henrik

AU - Hansen, Torben

AU - Køber, Lars

AU - Torp-Pedersen, Christian

AU - Weeke, Peter E

PY - 2019

Y1 - 2019

N2 - Background: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. Methods: 1599 individuals (mean age 64 years [min-max 29–96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010–2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. Results: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. Conclusions: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a “missing heritability” in early-onset CAD warrants more research.

AB - Background: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. Methods: 1599 individuals (mean age 64 years [min-max 29–96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010–2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. Results: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. Conclusions: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a “missing heritability” in early-onset CAD warrants more research.

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U2 - 10.1371/journal.pone.0211690

DO - 10.1371/journal.pone.0211690

M3 - Journal article

C2 - 30726294

AN - SCOPUS:85061158930

SN - 1932-6203

VL - 14

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 2

M1 - e0211690

ER -

Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations

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