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Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: A mendelian randomization analysis

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European Prospective Investigation Into Cancer and Nutritioon-Cardiovascular Disease (EPIC-CVD) Consortium 2018, 'Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: A mendelian randomization analysis' JAMA Cardiology, vol. 3, no. 7, pp. 619-627. https://doi.org/10.1001/jamacardio.2018.1470

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European Prospective Investigation Into Cancer and Nutritioon-Cardiovascular Disease (EPIC-CVD) Consortium. / Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies : A mendelian randomization analysis. In: JAMA Cardiology. 2018 ; Vol. 3, No. 7. pp. 619-627.

Bibtex

@article{c019023bd20c493c82357596aba42e2e,
title = "Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: A mendelian randomization analysis",
abstract = "IMPORTANCE Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25{\%}to 35{\%}have not provided any evidence that lowering Lp(a) level reduces CHD risk. OBJECTIVE To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. DESIGN, SETTING, AND PARTICIPANTS A mendelian randomization analysiswas conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. EXPOSURES Genetic LPA score and plasma Lp(a) mass concentration. MAIN OUTCOMES AND MEASURES Coronary heart disease. RESULTS Of the included study participants, 53{\%}were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8{\%} lower CHD risk (odds ratio [OR], 0.942; 95{\%}CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5{\%}lower CHD risk (OR, 0.855; 95{\%}CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95{\%}CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. CONCLUSIONS AND RELEVANCE The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100mg/dLmay be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67mg/dL (ie, 1 mmol/L).",
author = "Stephen Burgess and Ference, {Brian A.} and Staley, {James R.} and Freitag, {Daniel F.} and Mason, {Amy M.} and Nielsen, {Sune F.} and Peter Willeit and Robin Young and Praveen Surendran and Savita Karthikeyan and Bolton, {Thomas R.} and Peters, {James E.} and Pia Kamstrup and Anne Tybj{\ae}rg-Hansen and Marianne Benn and Anne Langsted and Peter Schnohr and Signe Vedel-Krogh and Kobylecki, {Camilla J.} and Ian Ford and Chris Packard and Stella Trompet and Jukema, {J. Wouter} and Naveed Sattar and {Di Angelantonio}, Emanuele and Danish Saleheen and Howson, {Joanna M.M.} and Nordestgaard, {B{\o}rge G.} and Butterworth, {Adam S.} and John Danesh and {European Prospective Investigation Into Cancer and Nutritioon-Cardiovascular Disease (EPIC-CVD) Consortium}",
year = "2018",
month = "7",
day = "1",
doi = "10.1001/jamacardio.2018.1470",
language = "English",
volume = "3",
pages = "619--627",
journal = "JAMA Cardiology",
issn = "2380-6583",
publisher = "American Medical Association",
number = "7",

}

RIS

TY - JOUR

T1 - Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies

T2 - A mendelian randomization analysis

AU - Burgess, Stephen

AU - Ference, Brian A.

AU - Staley, James R.

AU - Freitag, Daniel F.

AU - Mason, Amy M.

AU - Nielsen, Sune F.

AU - Willeit, Peter

AU - Young, Robin

AU - Surendran, Praveen

AU - Karthikeyan, Savita

AU - Bolton, Thomas R.

AU - Peters, James E.

AU - Kamstrup, Pia

AU - Tybjærg-Hansen, Anne

AU - Benn, Marianne

AU - Langsted, Anne

AU - Schnohr, Peter

AU - Vedel-Krogh, Signe

AU - Kobylecki, Camilla J.

AU - Ford, Ian

AU - Packard, Chris

AU - Trompet, Stella

AU - Jukema, J. Wouter

AU - Sattar, Naveed

AU - Di Angelantonio, Emanuele

AU - Saleheen, Danish

AU - Howson, Joanna M.M.

AU - Nordestgaard, Børge G.

AU - Butterworth, Adam S.

AU - Danesh, John

AU - European Prospective Investigation Into Cancer and Nutritioon-Cardiovascular Disease (EPIC-CVD) Consortium

PY - 2018/7/1

Y1 - 2018/7/1

N2 - IMPORTANCE Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25%to 35%have not provided any evidence that lowering Lp(a) level reduces CHD risk. OBJECTIVE To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. DESIGN, SETTING, AND PARTICIPANTS A mendelian randomization analysiswas conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. EXPOSURES Genetic LPA score and plasma Lp(a) mass concentration. MAIN OUTCOMES AND MEASURES Coronary heart disease. RESULTS Of the included study participants, 53%were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95%CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5%lower CHD risk (OR, 0.855; 95%CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95%CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. CONCLUSIONS AND RELEVANCE The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100mg/dLmay be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67mg/dL (ie, 1 mmol/L).

AB - IMPORTANCE Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25%to 35%have not provided any evidence that lowering Lp(a) level reduces CHD risk. OBJECTIVE To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. DESIGN, SETTING, AND PARTICIPANTS A mendelian randomization analysiswas conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. EXPOSURES Genetic LPA score and plasma Lp(a) mass concentration. MAIN OUTCOMES AND MEASURES Coronary heart disease. RESULTS Of the included study participants, 53%were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95%CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5%lower CHD risk (OR, 0.855; 95%CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95%CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. CONCLUSIONS AND RELEVANCE The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100mg/dLmay be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67mg/dL (ie, 1 mmol/L).

UR - http://www.scopus.com/inward/record.url?scp=85051796935&partnerID=8YFLogxK

U2 - 10.1001/jamacardio.2018.1470

DO - 10.1001/jamacardio.2018.1470

M3 - Journal article

VL - 3

SP - 619

EP - 627

JO - JAMA Cardiology

JF - JAMA Cardiology

SN - 2380-6583

IS - 7

ER -

ID: 55677939