Association of a Multiancestry Genome-Wide Blood Pressure Polygenic Risk Score With Adverse Cardiovascular Events

Abstract

Background - Traditional cardiovascular (CV) risk factors and the underlying genetic risk of elevated blood pressure (BP) determine an individual's composite risk of developing adverse CV events. We sought to evaluate the relative contributions of the traditional CV risk factors to the development of adverse CV events in the context of varying BP genetic risk profiles. Methods - Genome-wide polygenic risk score (PRS) was computed using multi-ancestry genome-wide association estimates among US adults who underwent whole-genome sequencing in the Trans-Omics for Precision program. Individuals were stratified into high, intermediate, and low genetic risk groups (>80th, 20-80th, <20th centiles of systolic BP [SBP] PRS). Based on the ACC/AHA Pooled Cohort Equations (PCE), participants were stratified into low and high (10y-ASCVD risk: <10% or ≥10%) CV risk factor profile groups. The primary study outcome was incident CV event (composite of incident heart failure, incident stroke, and incident coronary heart disease). Results - Among 21,897 US adults (median age:56 years; 56.0% women; 35.8% non-White race/ethnicity), 1 SD increase in the SBP PRS, computed using 1.08 million variants, was associated with systolic BP (β:4.39 [95%CI:4.13-4.65]) and HTN (OR:1.50 [95%CI:1.46-1.55]), respectively. This association was robustly seen across racial/ethnic groups. Each SD increase in SBP PRS was associated with a higher risk of the incident CVD (HR adj :1.07 [95%CI:1.04-1.10]) after controlling for ACC/AHA PCE risk scores. Among individuals with a high SBP PRS, low ASCVD risk was associated with a 58% lower hazard for incident CVD (HR adj :0.42 [95%CI:0.36-0.50]) compared to those with high ASCVD risk. A similar pattern was noted in intermediate and low genetic risk groups. Conclusions - In a multi-ancestry cohort of >21,000 US adults, genome-wide SBP PRS was associated with BP traits and adverse CV events. Adequate control of modifiable CV risk factors may reduce the predisposition to adverse CV events among those with a high SBP PRS.

Sex Differences in the Association of Multiethnic Genome-Wide Blood Pressure Polygenic Risk Score With Population-Level Systolic Blood Pressure Trajectories

“…ypertension, a highly heritable trait and the primary modifiable risk factor for cardiovascular disease, affects nearly half of the US population. 1,2 Although the prevalence of hypertension is higher in men, the ageassociated increase in systolic blood pressure (SBP) is more rapid in women. 3 Genetic determinants of BP may partly explain the observed sex-associated differences in the SBP trajectory.…”

“…4 SBP was corrected by adding 15 mm Hg for individuals on antihypertensive medications. 1 The nonlinear relationship of SBP with age was modeled using restricted cubic splines with 3 knots. The regression models were adjusted for first 10 principal components of genetic ancestry, diabetes, smoking, total cholesterol, and body mass index.…”

Sex Differences in the Association of Genome-Wide Systolic Blood Pressure Polygenic Risk Score With Hypertension

“…Hypertension is the primary modifiable risk factor for cardiovascular disease, which is the leading cause of death in the United States. 1,2 Hypertension is highly heritable and affects about half the US population. 1 The prevalence of hypertension varies by sex with an observed male predominance.…”

“…The Trans-Omics for Precision Medicine panel was used to impute single nucleotide polymorphisms. Scalable and Accurate Implementation of Generalized mixed models adjusted for age, age 2 , genotyping array, and the first 10 principal components of genetic ancestry were used for GWAS. METASOFT was used to meta-analyze the GWASs across the ancestry groups to generate a multiancestry GWAS for each sex.…”

“…The average of 3 blood measurements recorded in rested and seated participants was used in this study. 2 Hypertension was defined as a blood pressure of ≥130/80 mm Hg or the use of antihypertensive medications. Interaction was tested by using a multiplicative term of SBP-PRS and sex (SBP-PRS×sex) in logistic regression models.…”