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. 2019 Oct 8;322(14):1381-1391.
doi: 10.1001/jama.2019.14120.

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease

Brian A Ference  1   2 , Deepak L Bhatt  3 , Alberico L Catapano  4 , Chris J Packard  5 , Ian Graham  6 , Stephen Kaptoge  2 , Thatcher B Ference  1 , Qi Guo  1   2 , Ulrich Laufs  7 , Christian T Ruff  8 , Arjen Cupido  1   9 , G Kees Hovingh  9 , John Danesh  2 , Michael V Holmes  10 , George Davey Smith  11 , Kausik K Ray  12 , Stephen J Nicholls  13 , Marc S Sabatine  8
Affiliations

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease

Brian A Ference et al. JAMA. .

Abstract

Importance: The relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified.

Objective: To assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease.

Design, setting, and participants: Among 438 952 participants enrolled in the UK Biobank between 2006 and 2010 and followed up through 2018, genetic LDL-C and SBP scores were used as instruments to divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to estimate associations with lifetime risk of cardiovascular disease.

Exposures: Differences in plasma LDL-C and SBP compared with participants with both genetic scores below the median. Genetic risk scores higher than the median were associated with lower LDL-C and lower SBP.

Main outcomes and measures: Odds ratio (OR) for major coronary events, defined as coronary death, nonfatal myocardial infarction, or coronary revascularization.

Results: The mean age of the 438 952 participants was 65.2 years (range, 40.4-80.0 years), 54.1% were women, and 24 980 experienced a first major coronary event. Compared with the reference group, participants with LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels and an OR of 0.73 for major coronary events (95% CI, 0.70-0.75; P < .001). Participants with SBP genetic scores higher than the median had 2.9-mm Hg lower SBP and an OR of 0.82 for major coronary events (95% CI, 0.79-0.85, P < .001). Participants in the group with both genetic scores higher than the median had 13.9-mg/dL lower LDL-C, 3.1-mm Hg lower SBP, and an OR of 0.61 for major coronary events (95% CI, 0.59-0.64; P < .001). In a 4 × 4 factorial analysis, exposure to increasing genetic risk scores and lower LDL-C levels and SBP was associated with dose-dependent lower risks of major coronary events. In a meta-regression analysis, combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP was associated with an OR of 0.22 for major coronary events (95% CI, 0.17-0.26; P < .001), and 0.32 for cardiovascular death (95% CI, 0.25-0.40; P < .001).

Conclusions and relevance: Lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk. However, these findings cannot be assumed to represent the magnitude of benefit achievable from treatment of these risk factors.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr B. Ference reported receiving grants and personal fees from Amgen, Merck & Co, and Regeneron; grants from Novartis and Esperion Therapeutics; and personal fees from Ionis Pharmaceuticals, Medicines Co, Novo Nordisk, Sanofi, Pfizer, Eli Lilly, dalCOR, Silence Therapeutics, Integral Therapeutics, CiVi Pharma, KrKa Pharmaceuticals, Mylan, American College of Cardiology, European Atherosclerosis Society, and European Society of Cardiology, and grants from Afimmune. Dr Bhatt reported receiving grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, The Medicines Company, Roche, Forest Laboratories and AstraZeneca, Ischemix, Pfizer, PhaseBio, Abbott, Regeneron, Idorsia, Synaptic, Amgen, Lilly, Chiesi, Ironwood, and Abbott; other support from FlowCo, PLx Pharma, Takeda, St Jude Medical (now Abbott), American College of Cardiology, Duke Clinical Research Institute, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Clinical Cardiology, Veterans Affairs, Biotronik, Cardax, Boston Scientific, Merck, Svelte, PhaseBio, Merck, Novo Nordisk, Fractyl, and Cereno Scientific; personal fees from Belvoir Publications, Slack Publications, WebMD, Elsevier, Mayo Clinic, Population Health Research Institute, Journal of the American College of Cardiology, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), TobeSoft, Boehringer Ingelheim, Bayer, Cleveland Clinic, Mount Sinai School of Medicine, Medtelligence/ReachMD, CSL Behring, HMP Global, and Ferring Pharmaceuticals; personal fees and nonfinancial support from Society of Cardiovascular Patient Care; and nonfinancial support from the American Heart Association. Dr Catapano reported receiving grants from Pfizer, Merck, Sanofi, Regeneron, Mediolanum, and Amgen; nonfinancial support from SigmaTau, Menarini, Kowa, Recordati, and Eli Lilly; and personal fees from Merck, Sanofi, Regeneron, Pfizer, AstraZeneca, Amgen, Sigma Tau, Recordati, Aegerion, Kowa, Menarini, Eli Lilly, Amaryt, Medco, and Genzyme. Dr Packard reported receiving grants and personal fees from Merck Sharp & Dohme and personal fees from Sanofi, Regeneron, Amgen, Daiichi-Sankyo, and Dalcor. Dr Kaptoge reported receiving grants from the UK Medical Research Council, the British Heart Foundation, and the UK National Institute of Health Research. Dr Laufs reported receiving personal fees from Merck & Co, Amgen, Pfizer, and Sanofi. Dr Ruff reported receiving grants and personal fees from Boehringer Ingelheim, Daiichi Sankyo, MedImmune, and the National Institutes of Health; personal fees from Bayer, Bristol-Myers Squibb, Janssen, Pfizer, Portola, and Anthos and serving as a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital, Abbott, Amgen, Aralez, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc, BRAHMS, GlaxoSmithKline, Intarcia, Novartis Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr Cupido reported receiving grants from Amgen. Dr Hovingh reported receiving grants from ZonMW, national science institute, and VIDI; serving as consultant and speaker for biotech and pharmaceutical companies that develop molecules that influence lipoprotein metabolism, including Regeneron, Pfizer, Merck Sharp & Dohme, Sanofi, and Amgen; having served until April 2019 as principal investigator for clinical trials funded by Amgen, Sanofi, Eli Lilly, Novartis, Kowa, Genzyme, Cerenis, Pfizer, Dezima, AstraZeneca; and being partly employed by Novo Nordisk. Dr Danesh reported receiving grants, personal fees, and nonfinancial support from Merck Sharp & Dohme and Novartis and grants from the British Heart Foundation, the European Research Council, the National Institute for Health Research, National Health Service Blood and Transplant, Pfizer, UK Medical Research Council, Wellcome Trust, and AstraZeneca. Dr Ray reported receiving grants and personal fees from Amgen, Merck Sharp & Dohme, Regeneron, Sanofi, and Pfizer and personal fees from AbbVie, Boehringer Ingelheim, Cerenis, Cipla, Dr Reddy’s Laboratories, Novartis, Kowa, Esperion, The Medicines Company, Novo Nordisk, AstraZeneca, Daiichi Sankyo, Bayer, Algorhythm, Akcea, Zuelliing Pharma, and Takeda. Dr Nicholls reported receiving grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; in addition, Dr Nicholls is a named inventor on a patent focused on PCSK9 inhibitors issued, he receives no funds in respect to this. Dr Sabatine reported receiving grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; grants from Bayer, Eisai, Esperion, GlaxoSmithKline, IFM Therapeutics, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi-Sankyo, DalCor, Dyrnamix, and Ionis; serving as a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from: Abbott, Aralez, Roche, and Zora Biosciences.

Figures

Figure 1.
Figure 1.. Organization of Study Participants by Genetic Score and Clinical Variables
Participants were first divided into 2 groups based on whether their low-density lipoprotein cholesterol (LDL-C) genetic score was equal to or lower than or was higher than the median. Participants in each of these 2 groups were then divided into 2 more groups based on whether their systolic blood pressure (SBP) genetic score was equal to or lower than or was higher than the median. This process produced 4 groups: a reference group, a group with lower SBP, a group with lower LDL-C, and a group with both lower LDL-C and lower SBP. To convert LDL-cholesterol from mg/dL to mmol/L, multiply by 0.0259.
Figure 2.
Figure 2.. Assessment of Independent Associations of Lower LDL-C and Lower SBP With the Risk of Major Coronary Events
A, The top part of the panel presents the observed differences in low-density lipoprotein cholesterol (LDL-C) level and odds ratio for major coronary events for participants with LDL-C genetic scores higher than the median compared with participants with LDL-C scores equal to or lower than the median, both overall and stratified by quartiles of the systolic blood pressure (SBP) genetic score. The bottom part of panel A presents the same comparisons scaled for a 38.67 mg/dL difference in LDL-C. (To convert mg/dL to mmol/L, multiply by 0.0259.) B, The top part of the panel presents the observed differences in SBP and odds ratio for major coronary events for participants with SBP genetic scores higher than the median compared with participants with SBP scores equal to or lower than the median, both overall and stratified by quartiles of the LDL-C genetic score. The bottom part of panel B presents the same comparisons scaled for a 10-mm Hg difference in SBP.
Figure 3.
Figure 3.. Associations of Exposure to Lower LDL-C, Lower SBP, or Both With Risk of Major Coronary Events
The differences in low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) in each group are relative to the reference group. A, Presents the observed odds ratios for major coronary events compared with the reference group. B, Presents the odds ratios scaled for a difference of 38.67-mg/dL lower LDL-C (for the group allocated to lower LDL-C), 10-mm Hg lower SBP (for the group allocated to lower SBP), and the combined difference of both 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP (for the group allocated to both lower LDL-C and lower SBP). To convert mg/dL to mmol/L, multiply by 0.0259.
Figure 4.
Figure 4.. Association of Combined Exposure to Both Lower LDL-C and Lower SBP With Various Cardiovascular Outcomes
A, Presents differences in low-density lipoprotein cholesterol (LDL-C) levels and systolic blood pressure (SBP), and the odds ratio for various cardiovascular events for the group with both LDL-C and SBP genetic scores higher than the median compared with the reference group. B, Presents the same associations scaled for the combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP. To convert mg/dL to mmol/L, multiply by 0.0259.
Figure 5.
Figure 5.. Association of Combined Exposure to Both Lower LDL-C and Lower SBP With Major Coronary Events Within Subgroups
A, Presents differences in low-density lipoprotein cholesterol (LDL-C) levels and SBP, and the odds ratio for major coronary events for the group with both LDL-C and SBP genetic scores higher than the median compared with the reference group for subgroups of participants. B, Presents the same associations scaled for the combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP.
Figure 6.
Figure 6.. Dose-Dependent Associations and Meta-Regression Analysis for Combinations of Increasingly Lower LDL-C and Lower SBP on the Risk of Major Coronary Events
For this analysis, participants were first divided into 4 groups based on quartile value of their low-density lipoprotein cholesterol (LDL-C) genetic score; and then each group was divided into another 4 groups based on the quartile value of their systolic blood pressure (SBP) genetic score. This process produced 16 groups with exposure to increasingly greater genetic risk scores and correspondingly lower LDL-C and lower SBP compared with the reference group (defined as the group with the lowest quartile of both the LDL-C and SBP genetic scores). The risk of major coronary events for each group relative to the reference group is plotted and expressed as a proportional risk reduction (calculated as [1 −odds ratio] × 100). The dashed line is the multivariable meta-regression line. The tabular data for these analyses are presented in the Supplement.
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