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Association ofLPAVariants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies
- Source :
- JAMA Cardiology, 3(7), 619. American Medical Association, 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, 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, Danesh, J, European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium & Overvad, K 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, JAMA Cardiology, 3(7), 619-627, 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, Danesh, J 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
- Publication Year :
- 2018
- Publisher :
- American Medical Association (AMA), 2018.
-
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).
- Subjects :
- Male
medicine.medical_specialty
Population
Coronary Disease
Coronary Artery Disease
030204 cardiovascular system & hematology
Polymorphism, Single Nucleotide
Article
law.invention
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Randomized controlled trial
Ezetimibe
Risk Factors
law
Internal medicine
medicine
Humans
Prospective Studies
030212 general & internal medicine
Precision Medicine
Prospective cohort study
education
Hypolipidemic Agents
education.field_of_study
biology
Cholesterol
business.industry
Genetic Variation
Mendelian Randomization Analysis
Cholesterol, LDL
Lipoprotein(a)
Odds ratio
Middle Aged
Prognosis
Phenotype
chemistry
biology.protein
Female
Cardiology and Cardiovascular Medicine
business
Biomarkers
Follow-Up Studies
medicine.drug
Subjects
Details
- ISSN :
- 23806583
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- JAMA Cardiology
- Accession number :
- edsair.doi.dedup.....2d0351ef9f388bfc345e4bfe424eb98a