Study Summary

This study explored the association between lifetime exposure to lower LDL-C and lower systolic BP (SBP) with lifetime risk of CVD. Genetic LDL-C and SBP scores were derived from exome variants of 438,953 participants enrolled in the UK Biobank between 2006 and 2010 and followed-up until 2018. The scores were used to divide participants into groups with lifetime exposures to lower LDL-C, lower SBP, or both. Differences between groups were compared with estimate association with lifetime risk of CVD. The main outcome was the OR for MACE. 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 (P < 0.001). Participants with SBP genetic scores above the median had 2.9 mmHg lower SBP and an OR of 0.82 for MACE (P < 0.001). Participants in the group with both genetic scores above the median had an OR of 0.61 for MACE (P < 0.001). Exposure to increasingly low LDL-C and SBP combinations was associated with a dose-dependent reduction in the risk of MACE, and combined exposure lower LDL-C and SBP was associated with a 78% lower lifetime cardiovascular risk (OR 0.22; P < 0.001).

Commentary

Study Strengths: This study extends the results of previous studies by demonstrating that combined exposure to both lower LDL-C and lower SBP is associated with a lower risk of CVD that is additive and dose-dependent. The use of Mendelian randomization using genetic variants is less susceptible to confounding than prospective cohort studies and helps elucidate an important issue that would otherwise require a large, randomized controlled trial spanning several decades.

Study Limitations: The study did not address whether lowering LDL-C or SBP through medications or other interventions would result in the same outcomes associated with the genetic variants of lower LDL-C or SBP.

Next Steps/Clinical Perspective: Lifelong genetic exposure to lower levels of LDL-C and lower SBP was associated with lower cardiovascular risk. Early screening for elevated LDL-C and SBP could provide an opportunity to prevent CVD.

Study Reference

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Ference  BA, Bhatt  DL, Catapano  AL, et al. Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease. JAMA[JAMA and JAMA Network Journals Full Text] doi: 10.1001/jama.2019.14120.