Polygenic Determinants of Arterial Stiffness: Implications for Hypertension

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ABSTRACT Background Components of arterial stiffness (structural stiffness from aging and load-dependent stiffness from high blood pressure) are markers for cardiovascular disease risk. We evaluated relationships between polygenic risk scores (PRS) for blood pressure (BP) and arterial stiffness. Methods Participants (n=5942) are from the Multi-Ethnic Study of Atherosclerosis with measures of carotid ultrasound and genomic DNA. Pulse wave velocity (PWV) was calculated from carotid ultrasound representing total stiffness. Structural stiffness was calculated by adjusting PWV to a 120/80 mmHg blood pressure with participant-specific models. Load-dependent stiffness was the difference of total and structural stiffness. Blood pressure PRSs were previously derived from a genome-wide association study. Associations between BP PRSs and components of carotid arterial stiffness were assessed with multivariable-adjusted regression models. Mendelian Randomization (MR) was performed with two-stage least squares to 1) confirm that BP PRSs strongly predict MAP and 2) estimate the effect of MAP on arterial stiffness. Results Participants (n=5,942) were mean (standard deviation) age of 62.8 (10.3) years (52% female; 39% White, 25% African-American, 13% Asian, 23% Hispanic). Systolic BP (SBP) was 133.5 (20.5) mmHg, diastolic BP (DBP) was 74.27 (10.28) mmHg and pulse pressure (PP) was 59.22 (16.17) mmHg. Total carotid stiffness was associated with the SBP PRS ( β =0.10 +/-0.02, p=5.25E-08) and the DBP PRS ( β : 0.08 +/-0.02, p=7.26E-07) but not PP PRS ( β =0.04 +/-0.02, P=0.05). Load dependent carotid stiffness was associated with the SBP PRS β =0.09 +/-0.01, p=7.93*10 -30 ) the DBP PRS ( β =0.09 +/-0.01, p= 4.92*10 -34 ) and the PP PRS ( β =0.03 +/-0.01, p= 8.18* 10-5 ). Structural carotid stiffness was not associated with any BP PRSs. MR showed that SBP and DPB PRS strongly predict MAP (p<0.001) and each 1-mmHg increase in MAP raised load dependent stiffness by 0.0494 m/s (p<0.001). Conclusion There are key differences in the genetic underpinnings of the mechanistic components of arterial stiffness.

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