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 - Bargess, Stephen
AU - Overvad, Kim
AU - Tjønneland, Anne
AU - Clavel-Chapelon, Francoise
AU - Kaaks, Rudolf
AU - Boeing, Heiner
AU - Trichopoulou, Antonia
AU - Ferrari, Pietro
AU - Palli, Domenico
AU - Krogh, Vittorio
AU - Panico, Salvatore
AU - Tumino, Rosario
AU - Matullo, Giuseppe
AU - Boer, Jolanda
AU - Van Der Schouw, Yvonne
AU - Weiderpass, Elisabete
AU - Quiros, J. Ramon
AU - Sánchez, María José
AU - Navarro, Carmen
AU - Moreno-Iribas, Conchi
AU - Arriola, Larraitz
AU - Melander, Olle
AU - Wennberg, Patrik
AU - Wareham, Nicholas J.
AU - Key, Timothy J.
AU - Riboli, Elio
N1 - Funding Information:
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 the Wellcome 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.
Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
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 - Article
AN - SCOPUS:85051796935
SN - 2380-6583
VL - 3
SP - 619
EP - 627
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 7
ER -