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Multicenter Study
. 2018 Jul 1;3(7):619-627.
doi: 10.1001/jamacardio.2018.1470.

Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis

Stephen Burgess  1   2 , Brian A Ference  2   3   4 , James R Staley  2   5 , Daniel F Freitag  2 , Amy M Mason  2 , Sune F Nielsen  6   7   8 , Peter Willeit  2   9 , Robin Young  2   10 , Praveen Surendran  2 , Savita Karthikeyan  2 , Thomas R Bolton  2 , James E Peters  2 , Pia R Kamstrup  6   7 , Anne Tybjærg-Hansen  7   8   11   12 , Marianne Benn  7   8   11 , Anne Langsted  6   7 , Peter Schnohr  12 , Signe Vedel-Krogh  6   7   8 , Camilla J Kobylecki  6   7   8 , Ian Ford  10 , Chris Packard  13 , Stella Trompet  14   15 , J Wouter Jukema  14   16 , Naveed Sattar  13 , Emanuele Di Angelantonio  2   17 , Danish Saleheen  18   19 , Joanna M M Howson  2 , Børge G Nordestgaard  6   7   8   12 , Adam S Butterworth  2   17 , John Danesh  2   17   20 ; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium
Affiliations
Multicenter Study

Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis

Stephen Burgess et al. JAMA Cardiol. .

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).

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ference has received grants from Merck & Co, Amgen, Esperion Therapeutics, and Novartis as well as personal fees from Merck & Co, Amgen, Ionis Pharmaceuticals, Krka, d. d., Novo mesto, Medicines Company, and Sanofi Regeneron. Dr Freitag has been a full-time employee of Bayer AG since October 2015. Dr Peters has received travel and accommodation expenses to speak at Olink-sponsored academic meetings. Dr Packard has received grants from Merck Sharp & Dohme as well as personal fees from Pfizer, Amgen, Sanofi Regeneron, and Daiichi Sankyo. Dr Sattar has received personal fees from Amgen and Sanofi. Dr Nordestgaard has received personal fees for consultation or speaking from AstraZeneca, Sanofi Regeneron, Ionis Pharmaceuticals, Aegerion Pharmaceuticals, Dezima Pharma, and Amgen. Dr Butterworth has received grants from Pfizer, Novartis, Merck, Biogen, and AstraZeneca as well as personal fees from Novartis. Dr Danesh has received grants from the UK Medical Research Council, the British Heart Foundation, the UK National Institute of Health Research, and the European Commission during the conduct of the study; grants from the European Research Council, Merck & Co, NHS Blood and Transplant, Novartis, Pfizer, Wellcome Trust, and AstraZeneca; personal fees and nonfinancial support from Merck Sharp & Dohme UK Atherosclerosis; and has served on the Novartis cardiovascular and metabolic advisory board and the Pfizer population research advisory panel. No other disclosures were reported.

Figures

Figure 1
Figure 1. Association of LPA Variants With Lipoprotein(a) (Lp[a]) Concentration and Coronary Heart Disease (CHD) Risk
Marginal genetic associations with Lp(a) and CHD risk (error bars indicate 95% confidence intervals) obtained in the CHD Exome+ consortium for 43 variants included in the LPA genetic score. Associations are orientated to the minor allele.
Figure 2
Figure 2. Shape of Association Between Genetically Predicted Lipoprotein(a) (Lp[a]) and Coronary Heart Disease (CHD) Risk
A, Arithmetic mean of Lp(a) in each decile (untransformed, linear scale). B, Geometric mean of Lp(a) in each decile (log-transformed, log-scale). Points on the curve indicate mendelian randomization estimates in each decile of genetically predicted Lp(a) (error bars indicate 95% confidence intervals; first decile is reference group). The solid line indicates the best-fitting fractional polynomial (left, linear term only; right, square root and cubic terms) to model the dose-dependent relationship; the dotted lines indicate the 95% confidence intervals for the relationship.
Figure 3
Figure 3. Estimates of Coronary Heart Disease (CHD) Risk Reduction With Lowering of Low-Density Lipoprotein Cholesterol (LDL-C) Level and Lipoprotein(a) (Lp[a]) Concentration
Genetic estimates of lifelong lowering from mendelian randomization (brown line), observational estimates from prospective cohort studies (blue line), and (A) trial estimate from short-term statin trials (for LDL-C) or (B) predicted trial estimate (for Lp[a]) (orange line). The vertical line is at 38.67 mg/dL (ie, 1 mmol/L) for LDL-C level and at 101.5 mg/dL for Lp(a) concentration, the estimated equivalent lowering in Lp(a) for the same reduction in CHD risk. To convert LDL-C to millimoles per liter, multiply by 0.0259.
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