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

Research output: Contribution to journalArticle

  • Brian Ference
  • Deepak Bhatt
  • Alberico L. Catapano
  • Chris J Packard
  • Ian Graham
  • Stephen Kaptoge
  • Thatcher B Ference
  • Qi Guo
  • Ulrich Laufs
  • Christian T Ruff
  • Arjen Capuido
  • G Kees Hovingh
  • John Danesh
  • Michael V. Holmes
  • George Davey Smith
  • Kausik K Ray
  • Stephen J Nicholls
  • Marc S Sabatine
Original languageEnglish
Pages (from-to)E1-E11
Number of pages11
JournalJAMA Network Open
DateAccepted/In press - 16 Aug 2019
DatePublished (current) - 2 Sep 2019


The association of combined exposure to both lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified. 
OBJECTIVETo 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 PARTICIPANTSAmong 438,952 participants enrolled in the UK Biobank between 2006 to 2010 and followed through 2018, genetic LDL-C and SBP scores were used as instruments to randomly 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. 
EXPOSURESDifferences in plasma LDL-C and SBP as compared to participants with both genetic scores below the median. MAIN OUTCOMES AND MEASURESOdds ratio (OR) for major coronary events (MCE) - defined as coronary death, myocardial infarction or coronary revascularization. 
RESULTSThe mean age of participants was 65.2 years [range:40.4-80.0] and 54.1% were females. Compared to the reference group, participants with LDL-C genetic scores above the median had 14.7 mg/dL lower LDL-C and an OR of 0.73 for MCE (95%CI:0.70-0.75,p<0.001); participants with SBP genetic scores above the median had 2.9 mmHg lower SBP and an OR of 0.82 for MCE (95%CI:0.79-0.85,p<0.001); and participants in the group with both genetic scores above the median had 13.9 mg/dL lower LDL-C, 3.1 mmHg lower SBP and an OR of 0.61 for MCE (95%CI:0.59-0.64,p<0.001). In a 4x4 factorial analysis, exposure to increasing combinations of lower LDL-C and SBP was associated with dose-dependent lower risks of MCE. In a meta-regression analysis, combined exposure to 38.67 mg/dl (1 mmol/L) lower LDL-C and 10 mmHg lower SBP was associated with an OR of 0.22 for MCE (95%CI:0.17-0.26,p<0.001), and 0.32 for cardiovascular death (95%CI:0.25-0.40,p<0.001).
CONCLUSIONS AND RELEVANCELifelong genetic exposure to lower SBP and lower levels of LDL-C 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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