Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease
Journal of the American Heart Association
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© 2017 The Authors. Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.
AuthorsSong, C; Burgess, S; Eicher, JD; O'Donnell, CJ; Johnson, AD; Huang, J; Sabater-Lleal, M; Asselbergs, FW; Tregouet, D; Shin, SY; Ding, J; Baumert, J; Oudot-Mellakh, T; Folkersen, L; Smith, NL; Williams, SM; Ikram, MA; Kleber, ME; Becker, DM; Truong, V; Mychaleckyj, JC; Tang, W; Yang, Q; Sennblad, B; Moore, JH; Williams, FMK; Dehghan, A; Silbernagel, G; Schrijvers, EMC; Smith, S; Karakas, M; Tofler, GH; Silveira, A; Navis, GJ; Lohman, K; Chen, MH; Peters, A; Goel, A; Hopewell, JC; Chambers, JC; Saleheen, D; Lundmark, P; Psaty, BM; Strawbridge, RJ; Boehm, BO; Carter, AM; Meisinger, C; Peden, JF; Bis, JC; McKnight, B; Öhrvik, J; Taylor, K; Franzosi, MG; Seedorf, U; Collins, R; Franco-Cereceda, A; Syvänen, AC; Goodall, AH; Yanek, LR; Cushman, M; Müller-Nurasyid, M; Folsom, AR; Basu, S; Matijevic, N; van Gilst, WH; Kooner, JS; Danesh, J; Clarke, R; Meigs, JB; Kathiresan, S; Reilly, MP; Klopp, N; Harris, TB; Winkelmann, BR; Grant, PJ; Hillege, HL; Watkins, H; Spector, TD; Becker, LC; Tracy, RP; März, W; Uitterlinden, AG; Eriksson, P; Cambien, F; Morange, PE; Koenig, W; Soranzo, N; van der Harst, P; Liu, Y; Hamsten, A; Ehret, GB; Munroe, PB; Rice, KM; Bochud, M; Chasman, DI; Smith, AV
- Cardiovascular