Polygenic Determinants of Arterial Stiffness: Implications for Hypertension.

<h4>Background</h4>Components of arterial stiffness (structural stiffness from aging and load-dependent stiffness from high blood pressure [BP]) are markers for cardiovascular disease risk. We evaluated relationships between polygenic risk scores (PRSs) for BP and arterial stiffness.<h4>Methods</h4>Participants (n=5804) are from MESA (Multi-Ethnic Study of Atherosclerosis) with measures of carotid ultrasound and genomic DNA. Carotid pulse wave velocity (PWV) was calculated from carotid ultrasound. Structural stiffness was calculated by adjusting carotid PWV to a 120/80 mm Hg BP with participant-specific models. Load-dependent stiffness was the difference of total and structural stiffness. BP PRSs were derived from genome-wide associations. Associations were assessed with multivariable-adjusted regression models. Mendelian randomization was performed with 2-stage least squares.<h4>Results</h4>Participants were aged 62.8±10.3 years. Systolic BP (SBP) was 133.5±20.5 mm Hg, diastolic BP (DBP) was 74.27±10.28 mm Hg, and pulse pressure was 59.22±16.17 mm Hg. Total carotid PWV was associated with the SBP PRS (β=0.10±0.02, <i>P</i>=5.25E-08) and the DBP PRS (β: 0.08±0.02, <i>P</i>=7.26E-07) but not pulse pressure PRS (<i>P</i>=0.05). Load-dependent carotid PWV was associated with the SBP PRS (β=0.09±0.01, <i>P</i>=7.93×10^-30), the DBP PRS (β=0.09±0.01, <i>P</i>=4.92×10^-34) and the pulse pressure PRS (β=0.03±0.01, <i>P</i>=8.18×10^-5). Structural carotid PWV was not associated with any BP PRSs. With Mendelian randomization, SBP and DBP showed significant independent positive effects on load-dependent stiffness (<i>P</i><0.001); only SBP was significant for total carotid PWV after accounting for DBP.<h4>Conclusions</h4>There are key differences in the genetic underpinnings of the mechanistic components of arterial stiffness.