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

Burgess, S. et al. (2018) Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies. JAMA Cardiology, 3(7), pp. 619-627. (doi: 10.1001/jamacardio.2018.1470) (PMID:29926099)

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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 analysis was 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 100 mg/dL may 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 38.67 mg/dL (ie, 1 mmol/L).

Item Type:Articles
Additional Information:The study’s coordinating centre has been underpinned by grants G0800270 and MR/L003120/1 from the UK Medical Research Council, grants SP/09/002, RG/08/014, and RG13/ 13/30194 from the British Heart Foundation, grants from the National Institute for Health Research through the Cambridge Biomedical Research Centre, grant HEALTH-F2-2012-279233 from the European Commission Framework 7 through the EPIC-CVD award, and grants from the European Research Council through an Advanced Investigator Award 268834 to Dr Danesh. Dr Burgess is supported by a Sir Henry Dale Fellowship jointly funded by theWellcome Trust and the Royal Society (grant number 204623/Z/16/Z). Dr Danesh holds a BHF Professorship and NIHR Senior Investigator Award. Aspects of the analysis were supported by the Cambridge Substantive Site of Health Data Research UK.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ford, Professor Ian and Young, Dr Robin and Packard, Professor Chris and Sattar, Professor Naveed
Authors: Burgess, S., Ference, B. A., Staley, J. R., Freitag, D. F., Mason, A. M., Nielsen, S. F., Willeit, P., Young, R., Surendran, P., Karthikeyan, S., Bolton, T. R., Peters, J. E., Kamstrup, P. R., Tybjærg-Hansen, A., Benn, M., Langsted, A., Schnohr, P., Vedel-Krogh, S., Kobylecki, C. J., Ford, I., Packard, C., Trompet, S., Jukema, J. W., Sattar, N., Di Angelantonio, E., Saleheen, D., Howson, J. M. M., Nordestgaard, B. G., Butterworth, A. S., and Danesh, J.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:JAMA Cardiology
Publisher:American Medical Association
ISSN:2380-6583
ISSN (Online):2380-6591
Published Online:20 June 2018
Copyright Holders:Copyright © 2018 Burgess S et al.
First Published:First published in JAMA Cardiology 3(7):619-627
Publisher Policy:Reproduced under a Creative Commons License

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