| Title: |
LPA variants, risk of coronary disease, and estimated clinical benefit of lipoprotein(a) lowering therapies: A mendelian randomization analysis |
| Authors: |
Ference, BA; Burgess, S; Staley, JR; Freitag, DF; Mason, AM; Nielsen, SF; Willeit, P; Young, R; Surendran, P; Karthikeyan, S; Bolton, TR; Peters, JE; Kamstrup, PR; Tybjærg-Hansen, A; Benn, M; Langsted, A; Schnohr, P; Vedel-Krogh, S; Kobylecki, CJ; Ford, I; Packard, C; Trompet, S; Jukema, JW; Sattar, N; Di Angelantonio, E; Saleheen, D; Consor, JMM Howson for the CHD Exome; Nordestgaard, BG; Consorti, A Butterworth for the EPIC-CVD; Danesh, J |
| Publisher Information: |
Elsevier; //doi.org/10.1016/j.atherosclerosis.2018.06.895 |
| Publication Year: |
2018 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 3201 Cardiovascular Medicine and Haematology; 3202 Clinical Sciences; Heart Disease - Coronary Heart Disease; Heart Disease; Atherosclerosis; Cardiovascular; 2.1 Biological and endogenous factors |
| Description: |
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) by 25-35% have not provided any evidence that lowering Lp(a) reduces CHD risk. Objective: To estimate the magnitude of the change in plasma Lp(a) needed to have the same effect on CHD risk as a 1 mmol/L (38.67 mg/dL) change in LDL-C, a change in LDL-C that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design: Meta-analysis of Mendelian randomization studies conducted using individual participant data from 5 studies; with external validation using summarized data from 48 studies. Setting: Population based prospective cohort and case-control studies. Participants: 20,793 CHD cases and 27,540 controls with individual participant data; 62,240 CHD cases and 127,299 controls with summarized data. Exposure: Genetic Lp(a) score and plasma Lp(a) mass concentration. Main outcomes and measures: Coronary heart disease. Results: The causal effect of Lp(a) on 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 estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (0.855; 0.818–0.893; p=2×10-12). Thus, a 101.5 mg/dL (95% CI: 71.0–137.0) change in Lp(a) had the same effect on CHD risk as a 1 mmol/L change in LDL-C. The effect of Lp(a) on CHD risk appeared to be independent of changes in LDL-C due to genetic variants that mimic the effect of statins, PCSK9 inhibitors and ezetimibe. Conclusions and relevance: Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to a produce clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C by 1 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/278865 |
| DOI: |
10.17863/CAM.26241 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/278865; https://doi.org/10.17863/CAM.26241 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.4FD29C82 |
| Database: |
BASE |