Background: Previous studies have identified several genetic variants associated with arterial stiffness. The aim of this study was to investigate whether expression profiles of these genes associate with measures of aortic stiffness and diameter.

Method and Results: In a cross-sectional study of 2092 women aged 21–84 years from the TwinsUK cohort, measures of aortic stiffness (carotid-femoral pulse wave velocity [PWV], carotid distensibility), carotid diameter and heritability were made. In a subsample (n=470), gene expression levels of 62 genes previously associated with PWV were measured in leukocytes with Affymetrix microarrays. PWV and carotid diameter increased by 75% and 18%, respectively, from the second to seventh decade. Carotid distensibility decreased by 73%. Pleiotropic genetic effects accounted for 53% of the phenotypic correlation between carotid distensibility and diameter. Leukocyte-derived transcript ENPP1 significantly correlated with PWV. In 121 women that had repeat vascular measures over a follow-up period of 4.3±1.4 years, leukocyte-derived ENPP1 expression and COL4A1 strongly related to PWV progression in multivariable regression (beta=0.19, p<0.01 and beta=0.32, p<0.0001; respectively). For carotid distensibility, leukocyte-derived transcript for angiotensin converting enzyme (ACE) most strongly associated with a reduction in carotid distensibility (beta=−0.20, p<0.001). Expression levels of ACE gene also associated with progression in carotid diameter (beta=0.21, p<0.05).

Conclusion: This study demonstrates that expression levels of ENPP1, which associated with arterial calcification, and COL4A1, associated with collagen formation, relate to progression in PWV. In addition, our findings suggest that ACE gene expression may exert pleiotropic effects on reduced carotid distensibility and dilation.