Abstract
Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD) - defined as coronary death, myocardial infarction, or coronary revascularization - per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654783 participants, including 91129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10 -1363 ) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P =.04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10 -465 ) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P =.04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10 -38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10 -46 , respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P =.19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P =.19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10 -20 ). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
| Original language | English |
|---|---|
| Pages (from-to) | 364-373 |
| Number of pages | 10 |
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 321 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published or Issued - 29 Jan 2019 |
ASJC Scopus subject areas
- Medicine(all)
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Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease. / Ference, Brian A.; Kastelein, John J.P.; Ray, Kausik K. et al.
In: JAMA - Journal of the American Medical Association, Vol. 321, No. 4, 29.01.2019, p. 364-373.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease
AU - Ference, Brian A.
AU - Kastelein, John J.P.
AU - Ray, Kausik K.
AU - Ginsberg, Henry N.
AU - Chapman, M. John
AU - Packard, Chris J.
AU - Laufs, Ulrich
AU - Oliver-Williams, Clare
AU - Wood, Angela M.
AU - Butterworth, Adam S.
AU - Di Angelantonio, Emanuele
AU - Danesh, John
AU - Nicholls, Stephen J.
AU - Bhatt, Deepak L.
AU - Sabatine, Marc S.
AU - Catapano, Alberico L.
N1 - Funding Information: 85079, N01 ?HC ?85080, N01 ?HC ?85081, N01 ?HC ?85082, N01 ?HC ?85083, N01 ?HC ? 85084, N01 ?HC ?85085, N01 ?HC ?85086, N01 ?HC ?35129, N01 HC ?15103, N01 HC ? 55222, N01 ?HC ?75150, N01 ?HC ?45133, N01 ?HC ?85239 and HHSN268201200036C; grant numbers U01 HL080295 from the National Heart, Lung, and Blood Institute and R01 AG ?023629 from the National Institute on Aging, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs ? nhlbi.org/pi.htm. This manuscript was not prepared in collaboration with CHS investigators and does not necessarily reflect the opinions or views of CHS, or the NHLBI. Funding Information: DbGaP dataset reference: The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP Study Accession: phs000285.v3.p2 The research reported in this article was supported by contract numbers HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C; all from the National Heart, Lung, and Blood Institute; National Institutes of Health; Bethesda, MD, USA. A full list of principal ARIC investigators and institutions can be found at http://www.cardia.dopm.uab.edu/. This manuscript was not prepared in collaboration with CARDIA investigators and does not necessarily reflect the opinions or views of CARDIA, or the NHLBI. Funding Information: Candidate gene Association Resource (CARe): The MESA CARe data used for the analyses described in this manuscript were obtained through dbGaP (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01 ?HC ?65226. Funding Information: The principal funder of this project was the Wellcome Trust. Case collections were funded by: Arthritis Research Campaign, BDA Research, British Heart Foundation, British Hypertension Society, Diabetes UK, Glaxo ?Smith Kline Research and Development, Juvenile Diabetes Research Foundation, National Association for Colitis and Crohn's disease, SHERT (The Scottish Hospitals Endowment Research Trust), St Bartholomew's and The Royal London Charitable Foundation, UK Medical Research Council, UK NHS R&D and the Wellcome Trust. Funding Information: completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ference reported receiving personal fees from Merck & Co, Amgen, Esperion Therapeutics, Regeneron, Sanofi, Pfizer, dalCOR, The Medicines Company, CiVi BioPharma, KrKA Pharmaceuticals, American College of Cardiology, European Society of Cardiology, and the European Atherosclerosis Society and grants from Merck & Co, Amgen, Novartis, and Esperion Therapeutics. Dr Kastelein reported receiving personal fees from Affiris, Amgen, Corvidia, CSL Behring, CiVi Biopharma, Esperion, Gemphire, Madrigal, The Medicines Company, North Sea Therapeutics, Novartis, Regeneron, Staten Biotech, Merck & Co, Eli Lilly, Roche, Pfizer, and Dezima. Dr Ray reported receiving personal fees from Sanofi, Amgen, Regeneron, Merck Sharp & Dohme, Cipla, Cerenis, Akcea, Eli Lilly, The Medicines Company, AstraZeneca, Pfizer, Kowa, Algorithm, IONIS, Esperion, Novo Nordisk, Takeda, Boehringer Ingelheim, Resverlogix, and Abbvie and grants from Merck & Co, Merck Sharp & Dohme, Sanofi, Regeneron, Pfizer, and Amgen. Dr Ginsberg reported receiving personal fees and grants from Merck & Co, Kowa, Sanofi, Regeneron, Esperion, Akcea, and Amgen. Dr Chapman reported receiving personal fees from Akcea, Alexion, Amarin, Amgen, Daiichi-Sankyo, Kowa, Merck & Co, Pfizer, Sanofi, Regeneron, and Unilever and grants from Amgen, CSL, Kowa, Merck & Co, and Pfizer. Dr Packard reported receiving personal fees from Merck Sharp & Dohme, Merck & Co, Amgen, Pfizer, Sanofi, Regeneron, and Daiichi-Sankyo. Dr Laufs reported receiving personal fees from Merck & Co, Amgen, Pfizer, Esperion, and Sanofi. Dr Oliver-Williams reported receiving prize money from Novartis. Dr Butterworth reported receiving grants from the UK Medical Research Council, British Heart Foundation, European Union Framework Programme 7, and the National Institute for Health during the conduct of the study and grants from Pfizer, AstraZeneca, Merck & Co, Novartis, Biogen, and the European Research Council. Dr Di Angelantonio reported receiving grants from the National Institute for Health Research, Medical Research Council, British Heart Foundation, and NHS Blood and Transplant. Dr Danesh reported receiving personal fees from Merck Sharp & Dohme, Merck & Co, Novartis, Pfizer, and Sanofi; nonfinancial support from diaDexus; and grants from the British Heart Foundation, Bupa Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Center, GlaxoSmithKline, Merck & Co, National Heart, Lung, and Blood Institute, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, NHS Blood and Transplant, Novartis, Pfizer, AstraZeneca, UK Medical Research Council, Wellcome Trust, and the UK Biobank. Dr Nicholls reported receiving personal fees from Eli Lilly, AstraZeneca, Amgen, Anthera, Omthera, Takeda, Novartis, Resverlogix, Sanofi, Regeneron, Esperion, Merck, Boehringer Ingelheim, CSL Behring, and Roche and grants from Eli Lilly, AstraZeneca, Amgen, Anthera, InfraReDx, LipoScience, Novartis, Resverlogix, Sanofi, Regeneron, Cerenis, Esperion, Merck & Co, and The Medicines Company. Dr Bhatt reported receiving grants from Amarin during the conduct of the study; grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Roche, Pfizer, Forest Laboratories/ AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, Ironwood, Abbott, Regeneron, PhaseBio, Idorsia, Synaptic, and The Medicines Company; personal fees or nonfinancial support, including travel and lodging, from FlowCo, PLx Pharma, Takeda, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Clinical Cardiology, VA, St Jude Medical (now Abbott), Biotronik, Cardax, the American College of Cardiology, Boston Scientific, Merck, Svelte, and Novo Nordisk; personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, American College of Cardiology, Belvoir Publications, Slack Publications, WebMD, Elsevier, the Society of Cardiovascular Patient Care, , HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, TobeSoft, Boehringer Ingelheim, and Bayer; and nonfinancial support from the American Heart Association outside the submitted work. Dr Sabatine reported receiving personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Dyrnamix, Intarcia, Merck & Co, Janssen Research Development, MedImmune, Alnylam, CVS Caremark, Ionis, Cubist, Esperion, The Medicines Company, MyoKardia, and Zeus Scientific and grants from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Intarcia, Merck & Co, Roche Diagnostics, Takeda, Novartis, Poxel, Janssen Research and Development, MedImmune, Eisai, Genzyme, and Pfizer. Dr Catapano reported receiving personal fees from AstraZeneca, Amgen, Aegerion, Genzyme, Sanofi, Merck & Co, Menarini, Kowa, and Pfizer and grants from Amgen, Eli Lilly, Genzyme, Mediolanum, Sanofi, Merck & Co, Pfizer, Regeneron, Rottapharm, Recordati, and Sigma tau. No other disclosures were reported. Funding Information: DbGaP dataset reference: The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP Study Accession: phs000007.v23.p8 The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01 ?HC ?25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding Information: Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. Dr Oliver-Williams is supported by Homerton College, University of Cambridge. Dr Butterworth is supported by the European Research Council. Dr Danesh is supported by the Medical Research Council, British Heart Foundation, and the National Institute for Health Research. Funding Information: MESA SNP Health Association Resource (SHARe): Funding for SHARe genotyping was provided by NHLBI Contract N02 ?HL ?64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetric Genome ?Wide Human SNP Array 6.0. Funding Information: PAGE: WHI PAGE is funded through the NHGRI Population Architecture Using Genomics and Epidemiology (PAGE) network (Grant Number U01 HG004790). Assistance with phenotype harmonization, SNP selection, data cleaning, meta ?analyses, data management and dissemination, and general study coordination, was provided by the PAGE Coordinating Center (U01HG004801 ?01). Funding Information: SHARe: Funding for WHI SNP Health Association Resource (SHARe) genotyping was provided by NHLBI Funding Information: Study was provided by the NIH GEI U01HG004438, U01HG04424, and HHSN268200782096C Funding Information: The research reported in this article was supported by contract numbers N01 ?HC ? Funding Information: Support for the Cardiovascular Health Study Whole Genome Study was provided by NHLBI grant HL087652. Additional support for infrastructure was provided by HL105756 and additional genotyping among the African ?American cohort was supported in part by HL085251. DNA handling and genotyping at Cedars ?Sinai Medical Center was supported in part by National Center for Research Resources grant UL1RR033176, now at the National Center for Advancing Translational Technologies CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Publisher Copyright: © 2019 American Medical Association. All Rights Reserved.
PY - 2019/1/29
Y1 - 2019/1/29
N2 - Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD) - defined as coronary death, myocardial infarction, or coronary revascularization - per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654783 participants, including 91129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10 -1363 ) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P =.04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10 -465 ) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P =.04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10 -38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10 -46 , respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P =.19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P =.19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10 -20 ). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
AB - Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD) - defined as coronary death, myocardial infarction, or coronary revascularization - per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654783 participants, including 91129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10 -1363 ) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P =.04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10 -465 ) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P =.04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10 -38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10 -46 , respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P =.19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P =.19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10 -20 ). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
UR - http://www.scopus.com/inward/record.url?scp=85060640239&partnerID=8YFLogxK
U2 - 10.1001/jama.2018.20045
DO - 10.1001/jama.2018.20045
M3 - Article
C2 - 30694319
AN - SCOPUS:85060640239
VL - 321
SP - 364
EP - 373
JO - JAMA : the journal of the American Medical Association
JF - JAMA : the journal of the American Medical Association
SN - 0098-7484
IS - 4
ER -