Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease

Brian A. Ference, John J.P. Kastelein, Kausik K. Ray, Henry N. Ginsberg, M. John Chapman, Chris J. Packard, Ulrich Laufs, Clare Oliver-Williams, Angela M. Wood, Adam S. Butterworth, Emanuele Di Angelantonio, John Danesh, Stephen J. Nicholls, Deepak L. Bhatt, Marc S. Sabatine, Alberico L. Catapano

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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 languageEnglish
Pages (from-to)364-373
Number of pages10
JournalJAMA
Volume321
Issue number4
DOIs
Publication statusPublished - 29 Jan 2019

Cite this

Ference, B. A., Kastelein, J. J. P., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., ... Catapano, A. L. (2019). Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease. JAMA, 321(4), 364-373. https://doi.org/10.1001/jama.2018.20045
Ference, Brian A. ; Kastelein, John J.P. ; Ray, Kausik K. ; Ginsberg, Henry N. ; Chapman, M. John ; Packard, Chris J. ; Laufs, Ulrich ; Oliver-Williams, Clare ; Wood, Angela M. ; Butterworth, Adam S. ; Di Angelantonio, Emanuele ; Danesh, John ; Nicholls, Stephen J. ; Bhatt, Deepak L. ; Sabatine, Marc S. ; Catapano, Alberico L. / Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease. In: JAMA. 2019 ; Vol. 321, No. 4. pp. 364-373.
@article{8e6eecb36f3c4633baa692c0c1763cba,
title = "Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease",
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.",
author = "Ference, {Brian A.} and Kastelein, {John J.P.} and Ray, {Kausik K.} and Ginsberg, {Henry N.} and Chapman, {M. John} and Packard, {Chris J.} and Ulrich Laufs and Clare Oliver-Williams and Wood, {Angela M.} and Butterworth, {Adam S.} and {Di Angelantonio}, Emanuele and John Danesh and Nicholls, {Stephen J.} and Bhatt, {Deepak L.} and Sabatine, {Marc S.} and Catapano, {Alberico L.}",
year = "2019",
month = "1",
day = "29",
doi = "10.1001/jama.2018.20045",
language = "English",
volume = "321",
pages = "364--373",
journal = "JAMA",
issn = "0098-7484",
publisher = "American Medical Association (AMA)",
number = "4",

}

Ference, BA, Kastelein, JJP, Ray, KK, Ginsberg, HN, Chapman, MJ, Packard, CJ, Laufs, U, Oliver-Williams, C, Wood, AM, Butterworth, AS, Di Angelantonio, E, Danesh, J, Nicholls, SJ, Bhatt, DL, Sabatine, MS & Catapano, AL 2019, 'Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease', JAMA, vol. 321, no. 4, pp. 364-373. https://doi.org/10.1001/jama.2018.20045

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.; Ginsberg, Henry N.; Chapman, M. John; Packard, Chris J.; Laufs, Ulrich; Oliver-Williams, Clare; Wood, Angela M.; Butterworth, Adam S.; Di Angelantonio, Emanuele; Danesh, John; Nicholls, Stephen J.; Bhatt, Deepak L.; Sabatine, Marc S.; Catapano, Alberico L.

In: JAMA, Vol. 321, No. 4, 29.01.2019, p. 364-373.

Research output: Contribution to journalArticleResearchpeer-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.

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.

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U2 - 10.1001/jama.2018.20045

DO - 10.1001/jama.2018.20045

M3 - Article

VL - 321

SP - 364

EP - 373

JO - JAMA

JF - JAMA

SN - 0098-7484

IS - 4

ER -

Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ et al. Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants with Risk of Coronary Heart Disease. JAMA. 2019 Jan 29;321(4):364-373. https://doi.org/10.1001/jama.2018.20045