Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. Plasminogen activator inhibitor-1 activity and the 4G/5G polymorphism are prospectively associated with blood pressure and hypertension status Adriaan Jacobs a,b , Aletta E. Schutte b , Cristian Ricci a , and Marlien Pieters a Objectives: Plasminogen activator inhibitor-1 (PAI-1) has consistently shown positive associations with blood pressure (BP). Whether elevations in PAI-1 levels precede or result from raised BP is still under debate and data on prospective studies are limited. Hence, we investigated the prospective associations of PAI-1 and the 4G/5G polymorphism with brachial and central BP and pulse pressure (PP) over a 10-year period. Methods: Black South Africans aged 30 years and older were included. Baseline data collection commenced in 2005 (n ¼ 2010) with follow-up data collection in 2010 (n ¼ 1288) and 2015 (n ¼ 926). Plasma PAI-1 activity (PAI- 1 act ), 4G/5G polymorphism genotyping, waist circumference and BP measurements were performed and analysed using sequential regression and mixed models. Results: In multivariable adjusted analyses, PAI-1 act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension in the total group [1.04 (1.01; 1.08) and 1.82 (1.07; 3.12) respectively]. Furthermore, PAI- 1 act was prospectively associated with brachial SBP (r ¼ 0.0815) and PP (r ¼ 0.0832) in the total group, and with central PP in women (r ¼ 0.1125; all P < 0.05). Addition of waist circumference to the models either decreased or nullified the contribution of PAI-1 act to BP and hypertension development. Conclusion: PAI-1 act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension. Furthermore, PAI-1 act associated prospectively with both brachial and central BP. These associations were mediated in part by central adiposity. The study supports the hypothesis that PAI-1 also contributes to hypertension development rather than solely being a consequence thereof. Keywords: 4G/5G polymorphism, brachial blood pressure, central blood pressure, hypertension, plasminogen activator inhibitor-1 Abbreviations: bDBP, brachial DBP; bPP, brachial pulse pressure; bSBP, brachial SBP; cPP, central pulse pressure; CRP, C-reactive protein; cSBP, central SBP; CVD, cardiovascular disease; DALY, disability-adjusted life year; GGT, g-glutamyl transferase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAI-1, plasminogen activator inhibitor-1; PAI- 1 act , PAI-1 activity; PAI-1 ag , PAI-1 antigen; TC, total cholesterol; VLDL, very low-density lipoprotein INTRODUCTION T he assessment of risk factors for the Global Burden of Disease Study estimated high SBP to be the leading risk factor for risk-attributable global disabil- ity-adjusted life years (DALYs), accounting for 10.4 million deaths and 218 million DALYs globally [1]. Several circulat- ing biomarkers are associated with raised blood pressure, one of these biomarkers being plasminogen activator inhib- itor-1 (PAI-1) [2,3], a known cardiovascular disease (CVD) risk marker [4]. PAI-1 is a serine protease inhibitor (serpin) that plays a classical role in fibrinolysis wherein it regulates fibrin breakdown by inhibition of plasminogen activators [5]. PAI-1’s association with hypertension is presumably due to its suggested alternative roles in endothelial dysfunction [6] and vascular remodelling [7], both processes that are known to be associated with hypertension [8,9]. On a genetic level, associations between blood pressure and the 4G/5G polymorphism in the promoter region of the PAI-1 gene have also been found [10,11]. Numerous cross-sectional studies [12–15] have reported positive associations between PAI-1 and blood pressure or hypertension, but prospective data [3,16,17] are limited. Whether elevated PAI-1 levels precede or result from ele- vated blood pressure is still under debate, as the former [3,16,17] as well as the latter [14,15] have both been sug- gested. Results from experimental studies in mice, how- ever, suggest that PAI-1 may play a causal role in the development of hypertension [18,19]. The aim of this study was to investigate the 10-year prospective associations of PAI-1 and the 4G/5G PAI-1 polymorphism with hyperten- sive status and brachial and central blood pressure mea- sures, with central pressure recently receiving much attention as a stronger predictor of cardiovascular risk [20] than brachial blood pressure. These associations were Journal of Hypertension 2019, 37:2361–2370 a Centre of Excellence for Nutrition (CEN) and b Hypertension in Africa Research Team (HART), Medical Research Council Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa Correspondence to Professor Aletta E. Schutte, Hypertension in Africa Research Team, North-West University, Private Bag X1290, Potchefstroom 2520, South Africa. Tel: +27 (0)18 299 2444; fax: +27 (0)18 285 2432; e-mail: Alta.Schutte@nwu.ac.za Received 1 March 2019 Revised 31 May 2019 Accepted 3 July 2019 J Hypertens 37:2361–2370 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000002204 Journal of Hypertension www.jhypertension.com 2361 Original Article