Measured Blood Pressure, Genetically Predicted Blood Pressure, and Cardiovascular Disease Risk in the UK Biobank

Abstract

ImportanceHypertension remains the major cardiovascular disease risk factor globally, but variability in measured blood pressure may result in suboptimal management. Whether genetic contributors to elevated blood pressure may complementarily inform cardiovascular disease risk assessment is unknown.ObjectiveTo examine incident cardiovascular disease by blood pressure polygenic risk score independent of measured blood pressures and antihypertensive medication prescriptions.Design, Setting, and ParticipantsThe cohort study (UK Biobank) recruited UK residents aged 40 to 69 years between March 2006 and August 2010. Participants without a prior physician diagnosis of cardiovascular disease, including myocardial infarction, stroke, or heart failure, were included. Excluded were individuals with mismatch between self-reported and genotypically inferred sex, sex aneuploidy, missing genotype rates of 1% or greater, and excess genotypic heterozygosity. Data analyses were performed from September 25, 2021, to July 21, 2022.ExposuresMeasured blood pressure and externally derived blood pressure polygenic risk score stratified by hypertension diagnosis and management, which included normal blood pressure (<130/80 mm Hg without antihypertensives), untreated hypertension (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg without antihypertensives), and treated hypertension (current antihypertensives prescriptions).Main Outcomes and MeasuresComposite of first incident myocardial infarction, stroke, heart failure, or cardiovascular-related death.ResultsOf the 331 078 study participants included (mean [SD] age at enrollment, 56.9 [8.1] years; 178 824 female [54.0%]), 83 094 (25.1%) had normal blood pressure, 197 597 (59.7%) had untreated hypertension, and 50 387 (15.2%) had treated hypertension. Over a median (IQR) follow-up of 11.1 (10.4-11.8) years, the primary outcome occurred in 15 293 participants. Among those with normal blood pressure, untreated hypertension, and treated hypertension, each SD increase in measured systolic blood pressure was associated with hazard ratios of 1.08 (95% CI, 0.93-1.25), 1.20 (95% CI, 1.16-1.23), and 1.16 (95% CI, 1.11-1.20), respectively, for the primary outcome. Among these same categories, each SD increase in genetically predicted systolic blood pressure was associated with increased hazard ratios of 1.13 (95% CI, 1.05-1.20), 1.04 (95% CI, 1.01-1.07), and 1.06 (95% CI, 1.02-1.10), respectively, for the primary outcome independent of measured blood pressures and other covariates. Findings were similar for measured and genetically predicted diastolic blood pressure.Conclusions and RelevanceBlood pressure polygenic risk score may augment identification of individuals at heightened cardiovascular risk, including those with both normal blood pressure and hypertension. Whether it may also guide antihypertensive initiation or intensification requires further study.

Combining pharmacogenetics and patient characteristic polygenic scores to improve outcome prediction for Calcium Channel Blocker treatment

“…Also, a UK Biobank study that included patients who reported antihypertensive use at baseline found SBP polygenic score was associated with uncontrolled BP (Odds ratio: 1.70; 95% CI: 1.6-1.8) 27 , top vs. bottom quintile. Another UK Biobank study testing cardiovascular associations with SBP polygenic score at baseline found high SBP increased the cardiovascular outcomes in untreated hypertension with 1.04-fold and in treated hypertension with 1.06-fold 44 . In our study, high SBP and DBP polygenic scores are associated with decrease the risk for discontinuation in patients with high polygenic score (HR SBP : 0.93, 0.88-0.99 and HR DBP : 0.93, 0.87-0.99, top vs. bottom quintile), and high polygenic scores of DBP decrease the risk of heart failure and coronary heart disease in people treated with dCCB (HR HF : 0.86, 0.74-0.99 and HR CHD : 0.91, 0.84-0.99, top vs. bottom quintile) suggesting that those with the most severely increased blood pressures are more likely to continue treatment compared to those with more moderately increased pressures (although we lack data to test this directly).…”

Systolic Blood Pressure and Cardiovascular Risk: Straightening the Evidence

“…For younger individuals, polygenic risk scores may be helpful in identifying high-risk individuals meriting antihypertensives earlier. 11 This study by Clarke and colleagues also provides important insights regarding the influence of sex on the EDITORIAL cardiovascular risk associated with SBP. Observational studies have yielded conflicting results as to whether men and women have the same cardiovascular risk for a given SBP range with uncertainty over residual confounding.…”

“…For younger individuals, polygenic risk scores may be helpful in identifying high-risk individuals meriting antihypertensives earlier. 11…”

Improved prediction of blood biomarkers using deep learning

“…PGSs combine the effect of many genetic variants on a phenotype, which can either be qualitative (e.g., disease status) or quantitative (e.g., blood biomarker level). While ethical and societal implications need careful consideration before widespread deployment 17,18 , PGSs are increasingly being considered for their clinical utility, e.g., in the context of precision medicine 17,[19][20][21][22][23] . Numerous methods exist for computing trait and disease PGSs on individual-level data [24][25][26][27][28] and summary statistics [29][30][31][32][33][34] , but they generally only model additive relationships between genotype and target.…”