Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease | Cardiology | JAMA | JAMA Network
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Original Investigation
September 2, 2019

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

Author Affiliations
  • 1Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom
  • 2MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 3Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts
  • 4Department of Pharmacological and Biomolecular Sciences, University of Milan, Multimedica IRCCS, Milano, Italy
  • 5Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
  • 6School of Medicine, Trinity College, Dublin, Ireland
  • 7Department of Cardiology, University of Leipzig, Leipzig, Germany
  • 8Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 9Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 10MRC Population Health Research Unit, Clinical Trial Service Unit, and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 11MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
  • 12School of Public Health, Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London, United Kingdom
  • 13Monash University, Melbourne, Australia
JAMA. 2019;322(14):1381-1391. doi:10.1001/jama.2019.14120
Key Points

Question  What is the association between genetic variants related to lower low-density lipoprotein cholesterol (LDL-C) levels and lower systolic blood pressure (SBP) with lifetime risk of cardiovascular disease?

Findings  In mendelian randomization analyses involving 438 952 participants, genetic variants related to lower LDL-C and lower SBP were significantly associated with independent, additive, and dose-dependent lower risk of cardiovascular disease. For example, participants with genetic variants associated with both 14-mg/dL lower LDL-C and 3-mm Hg lower SBP had an odds ratio of 0.61 for major coronary events (coronary death, myocardial infarction, or coronary revascularization).

Meaning  Lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk.


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.