Benoit J Arsenault1, S Matthijs Boekholdt1, Marie-Pierre Dubé1, Eric Rhéaume1, Nicholas J Wareham1, Kay-Tee Khaw1, Manjinder S Sandhu1, Jean-Claude Tardif2. 1. From the Montreal Heart Institute Research Center, Montreal, Quebec, Canada (B.J.A., M.-P.D., É.R., J.-C.T.); Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada (B.J.A., M.-P.D., É.R., J.-C.T.); Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands (S.M.B.); MRC Epidemiology Unit (N.J.W.) and Department of Public Health and Primary Care (K.-T.K., M.S.S.), University of Cambridge, Cambridge, United Kingdom; and Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Hinxton, United Kingdom (M.S.S.). 2. From the Montreal Heart Institute Research Center, Montreal, Quebec, Canada (B.J.A., M.-P.D., É.R., J.-C.T.); Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada (B.J.A., M.-P.D., É.R., J.-C.T.); Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands (S.M.B.); MRC Epidemiology Unit (N.J.W.) and Department of Public Health and Primary Care (K.-T.K., M.S.S.), University of Cambridge, Cambridge, United Kingdom; and Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Hinxton, United Kingdom (M.S.S.). jean-claude.tardif@icm-mhi.org.
Abstract
BACKGROUND: Although a previous study has suggested that a genetic variant in the LPA region was associated with the presence of aortic valve stenosis (AVS), no prospective study has suggested a role for lipoprotein(a) levels in the pathophysiology of AVS. Our objective was to determine whether lipoprotein(a) levels and a common genetic variant that is strongly associated with lipoprotein(a) levels are associated with an increased risk of developing AVS. METHODS AND RESULTS: Serum lipoprotein(a) levels were measured in 17 553 participants of the European Prospective Investigation into Cancer (EPIC)-Norfolk study. Among these study participants, 118 developed AVS during a mean follow-up of 11.7 years. The rs10455872 genetic variant in LPA was genotyped in 14 735 study participants, who simultaneously had lipoprotein(a) level measurements, and in a replication study of 379 patients with echocardiography-confirmed AVS and 404 controls. In EPIC-Norfolk, compared with participants in the bottom lipoprotein(a) tertile, those in the top lipoprotein(a) tertile had a higher risk of AVS (hazard ratio, 1.57; 95% confidence interval, 1.02-2.42) after adjusting for age, sex, and smoking. Compared with rs10455872 AA homozygotes, carriers of 1 or 2 G alleles were at increased risk of AVS (hazard ratio, 1.78; 95% confidence interval, 1.11-2.87, versus hazard ratio, 4.83; 95% confidence interval, 1.77-13.20, respectively). In the replication study, the genetic variant rs10455872 also showed a positive association with AVS (odds ratio, 1.57; 95% confidence interval, 1.10-2.26). CONCLUSIONS: Patients with high lipoprotein(a) levels are at increased risk for AVS. The rs10455872 variant, which is associated with higher lipoprotein(a) levels, is also associated with increased risk of AVS, suggesting that this association may be causal.
BACKGROUND: Although a previous study has suggested that a genetic variant in the LPA region was associated with the presence of aortic valve stenosis (AVS), no prospective study has suggested a role for lipoprotein(a) levels in the pathophysiology of AVS. Our objective was to determine whether lipoprotein(a) levels and a common genetic variant that is strongly associated with lipoprotein(a) levels are associated with an increased risk of developing AVS. METHODS AND RESULTS: Serum lipoprotein(a) levels were measured in 17 553 participants of the European Prospective Investigation into Cancer (EPIC)-Norfolk study. Among these study participants, 118 developed AVS during a mean follow-up of 11.7 years. The rs10455872 genetic variant in LPA was genotyped in 14 735 study participants, who simultaneously had lipoprotein(a) level measurements, and in a replication study of 379 patients with echocardiography-confirmed AVS and 404 controls. In EPIC-Norfolk, compared with participants in the bottom lipoprotein(a) tertile, those in the top lipoprotein(a) tertile had a higher risk of AVS (hazard ratio, 1.57; 95% confidence interval, 1.02-2.42) after adjusting for age, sex, and smoking. Compared with rs10455872 AA homozygotes, carriers of 1 or 2 G alleles were at increased risk of AVS (hazard ratio, 1.78; 95% confidence interval, 1.11-2.87, versus hazard ratio, 4.83; 95% confidence interval, 1.77-13.20, respectively). In the replication study, the genetic variant rs10455872 also showed a positive association with AVS (odds ratio, 1.57; 95% confidence interval, 1.10-2.26). CONCLUSIONS: Patients with high lipoprotein(a) levels are at increased risk for AVS. The rs10455872 variant, which is associated with higher lipoprotein(a) levels, is also associated with increased risk of AVS, suggesting that this association may be causal.
Authors: Teresa Trenkwalder; Christopher P Nelson; Muntaser D Musameh; Ify R Mordi; Thorsten Kessler; Costanza Pellegrini; Radoslaw Debiec; Tobias Rheude; Viktor Lazovic; Lingyao Zeng; Andreas Martinsson; J Gustav Smith; Jesper R Gådin; Anders Franco-Cereceda; Per Eriksson; Jonas B Nielsen; Sarah E Graham; Cristen J Willer; Kristian Hveem; Adnan Kastrati; Peter S Braund; Colin N A Palmer; Amparo Aracil; Oliver Husser; Wolfgang Koenig; Heribert Schunkert; Chim C Lang; Christian Hengstenberg; Nilesh J Samani Journal: Int J Cardiol Date: 2018-11-17 Impact factor: 4.164
Authors: Brian T Steffen; Daniel Duprez; Alain G Bertoni; Weihua Guan; Michael Y Tsai Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311