‘Genetics is not destiny’: Lifetime CVD risk prediction varies by exposure to elevated LDL, BP
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Regardless of polygenic risk score for CAD, lifetime risk for CVD varies greatly depending on exposure to elevated LDL and systolic BP, according to research presented at the virtual American College of Cardiology Scientific Session.
Thus, “a polygenic score should be combined with information about lifetime exposure to LDL and blood pressure to more accurately estimate lifetime risk of cardiovascular disease, more accurately identify persons who may benefit from early interventions to reduce risk and to better estimate the potential clinical benefit from early interventions,” Brian A. Ference, MD, MPhil, MSc, FACC, FESC, director of research (professor) in translational therapeutics and executive director of the Center for Naturally Randomized Trials at the University of Cambridge, U.K., said during a presentation.
The researchers examined a cohort of 445,566 participants from the U.K. Biobank (mean age, 57 years; 54% women). Ference and colleagues constructed a polygenic CAD risk score and stratified participants into quintiles to analyze changes in CV risk by lifetime LDL and systolic BP levels.
The primary outcome of fatal or nonfatal MI or coronary revascularization occurred in 5.2% of participants during the study period, which impacted the trajectories of CV risk calculated between ages 40 and 80, Ference said.
In a time-to-event analysis, compared with the lowest quintile, each successive quintile had greater risk for the primary outcome (HR for quintile 2 = 1.31; 95% CI, 1.25-1.38; HR for quintile 3 = 1.63; 95% CI, 1.56-1.71; HR for quintile 4 = 1.85; 95% CI, 1.76-1.93; HR for quintile 5 = 2.77; 95% CI, 2.65-2.89).
Trajectories changed
However, Ference said, trajectories of CV risk by polygenic score changed based on lifetime exposure to elevated LDL and systolic BP. Among participants in the middle quintile, those with 10 mg/dL higher-than-average LDL and 2 mm Hg higher-than-average systolic BP had a similar trajectory to participants in the highest quintile, while those with 10 mg/dL lower-than-average LDL and 2 mm Hg lower-than-average systolic BP had a similar trajectory to participants in the lowest quintile.
In a Mendelian randomization analysis, lifetime risk for major coronary events up to age 75 years varied greatly within each quintile according to lifetime exposure to elevated LDL and systolic BP, according to Ference. He noted that those in the lowest quintile of polygenic risk score who had high LDL and systolic BP had greater risk for major coronary events than those in the highest quintile of polygenic risk score who had low LDL and systolic BP (P < .001); the same was true in an observational cohort analysis of short-term risk.
The expected clinical benefit of lowering LDL by 30% was highest in those with the highest levels of LDL and systolic BP across all polygenic risk quintiles, he said.
“Participants with the highest polygenic score were not necessarily the ones expected to benefit most from treatments to lower LDL,” Ference said during the presentation. “Instead, participants with the highest LDL and blood pressure levels had the highest expected clinical benefit from lowering LDL across a range of polygenic score quintiles. The clinical benefit of lowering LDL is determined by both the absolute risk of disease, which in turn depends on polygenic scores as well as LDL and blood pressure, and the absolute reduction in LDL or blood pressure due to treatment.”
The results did not vary by sex, by method of construction of the polygenic risk score and by number of variants in the polygenic risk score, according to the researchers.
“This finding implies that the trajectory of cardiovascular disease predicted by a polygenic score can be reduced by lowering LDL and blood pressure,” Ference said during the presentation. “Indeed, participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of polygenic score for coronary disease. This implies that LDL and systolic blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition. Therefore, maintaining low levels of LDL and systolic blood pressure throughout life should be the primary focus to reduce the lifetime risk of cardiovascular disease for all persons at all levels of the polygenic score for coronary disease.”
‘Genetics is not destiny’
“The take-home message ... is that the polygenic score can stratify the population into different risk groups, and at the same time, lifetime exposure to LDL cholesterol and blood pressure significantly modifies this risk, suggesting that genetics is not destiny and that we may be able to intervene,” Cardiology Today Editorial Board Member Vera A. Bittner, MD, MSPH, professor of medicine and section head of general cardiology, prevention and imaging at University of Alabama at Birmingham, said during a discussion. – by Erik Swain
Reference:
Ference BA, et al. Featured Clinical Research I. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Disclosures: Ference reports he received research grants from Amgen, Esperion Therapeutics, Ionis Pharmaceuticals, Merck and Novartis and consultant fees, advisory board fees or honoraria from Amgen, Celera, CiVi Pharma, Daiichi Sankyo, dalCOR, Eli Lilly, Ionis Pharmaceuticals, KrKa Phamaceuticals, Medtronic Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Silence Therapeutics and The Medicines Company. Bittner reports she received institutional research grants from Amgen, AstraZeneca, DalCor, Sanofi and The Medicines Company.