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Genetic Association of Arterial Stiffness Index with Blood Pressure and Coronary Artery Disease

By Seyedeh Maryam Zekavat, Mary Haas, Krishna G. Aragam, Connor Emdin, Amit V. Khera, Derek M. Klarin, Hongyu Zhao, Pradeep Natarajan

Posted 26 Oct 2018
bioRxiv DOI: 10.1101/453878 (published DOI: 10.1161/ATVBAHA.119.312626)

Background: Arterial stiffness index (ASI) has been proposed as an independent mediator of blood pressure phenotypes and coronary artery disease (CAD) risk given epidemiologic associations. However, it is unknown whether these associations represent causal relationships. Here, we leverage human genetics to query whether genetic predisposition to increased ASI (m/s), acquired from finger photoplethysmography (PPG), is associated with elevated blood pressure and CAD risk. Methods: Genome-wide association analysis (GWAS) of ASI was performed in 131,686 participants from the UK Biobank. Across 223,061 separate UK Biobank participants not in the ASI GWAS, an ASI polygenic risk score consisting of the top 6 independent variants (P<5x10-7, LD r2<0.25) was applied. Mendelian randomization analyses of ASI were performed with systolic blood pressure (SBP, N=208,897), diastolic blood pressure (DBP, N=208,894), and incident CAD (7,534 cases) over 10 years follow-up in UK Biobank. The lack of association observed with respect to CAD was replicated among 184,305 participants (60,810 cases) from the Coronary Artery Disease Genetics Consortium (CARDIOGRAMplusC4D). Results: Among the 131,686 individuals with ASI phenotype, median age was 59 (IQR 51-63) years, 70,847 (54%) were female. We replicated previous reports of the epidemiologic association of ASI with SBP (Beta 0.55mmHg, [95% CI, 0.45-0.65], P=5.77x10-24), DBP (Beta 1.05mmHg, [95% CI, 0.99-1.11], P=7.27x10-272), and incident CAD (HR 1.09 [95% CI, 1.05-1.12], P=1.5x10-6) in multivariable models. Genome-wide association analysis of ASI yielded two significant loci (P<5x10-8) at TEX41-ZEB2 and FOXO1, and three suggestive loci (P<5x10-7) at COL4A2-COL4A1, RNF126, and TCF20. While each SD increase in genetic predisposition to elevated ASI was highly associated with SBP (Beta 4.63 mmHg [95% CI, 2.1-7.2]; P=3.37x10-4), and DBP (Beta 2.61 mmHg [95% CI, 1.2-4.0]; P=2.85x10-4), no association was observed with incident CAD in UK Biobank (HR 1.12 [95% CI, 0.55-2.3]; P=0.75), or with prevalent CAD in CARDIOGRAMplusC4D (OR 0.56 [95% CI, 0.26-1.24]; P=0.15). Conclusions: A genetic predisposition to higher ASI was associated with elevated systolic and diastolic blood pressures, but not associated with increased risk of developing CAD.

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