Axel Muendlein1, Andreas Leiherer2, Christoph H Saely3, Philipp Rein4, Daniela Zanolin1, Elena Kinz1, Eva-Maria Brandtner5, Peter Fraunberger6, Heinz Drexel7. 1. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein. 2. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Medical Central Laboratories, Feldkirch, Austria. 3. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria. 4. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria. 5. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria. 6. Medical Central Laboratories, Feldkirch, Austria. 7. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; Drexel University College of Medicine, Philadelphia, PA, USA. Electronic address: vivit@lkhf.at.
Abstract
BACKGROUND: Niemann-Pick C1-like 1 (NPC1L1) is involved in dietary cholesterol absorption and is the direct molecular target of the LDL-lowering drug ezetimibe. Recently, genetic variants in NPC1L1 have been associated with the incidence of cardiovascular events, but it remains unclear if the impact of NPC1L1 on cardiovascular risk is dependent on its role in cholesterol absorption. Furthermore, no direct association of genetic variants in NPC1L1 with coronary atherosclerosis has been established. METHODS: To further address these issues, we determined the impact of 34 single nucleotide polymorphisms (SNPs) at the NPC1L1 gene locus on the presence of coronary atherosclerosis and prospectively on future cardiovascular events in a cohort of 984 angiographied Caucasian patients. RESULTS: Out of investigated SNPs, 24 variants were significantly associated with future cardiovascular events. The highest impact was observed for rs55837134 (sex-and age adjusted additive HR = 1.67 [1.28-2.18]; p = 1.3 e-4). Regression analysis conditioned on rs55837134 showed that significant associations between remaining SNPs at the NPC1L1 locus and vascular events did not persist suggesting their dependence on rs55837134. Its significant association remained almost unchanged after further adjustment for total cholesterol, LDL cholesterol, and other cardiovascular risk factors (additive HR = 1.67 [1.28-2.18]; p = 1.7 e-4). In addition, no significant association of investigated NPC1L1 variants with coronary atherosclerosis could be observed, at least after false discovery rate correction. CONCLUSIONS: Genetic variants of NPC1L1, particularly rs55837134, show a predictive impact on cardiovascular events. Further studies to determine the molecular consequences of common genetic variants in NPC1L1 are needed.
BACKGROUND:Niemann-Pick C1-like 1 (NPC1L1) is involved in dietary cholesterol absorption and is the direct molecular target of the LDL-lowering drug ezetimibe. Recently, genetic variants in NPC1L1 have been associated with the incidence of cardiovascular events, but it remains unclear if the impact of NPC1L1 on cardiovascular risk is dependent on its role in cholesterol absorption. Furthermore, no direct association of genetic variants in NPC1L1 with coronary atherosclerosis has been established. METHODS: To further address these issues, we determined the impact of 34 single nucleotide polymorphisms (SNPs) at the NPC1L1 gene locus on the presence of coronary atherosclerosis and prospectively on future cardiovascular events in a cohort of 984 angiographied Caucasian patients. RESULTS: Out of investigated SNPs, 24 variants were significantly associated with future cardiovascular events. The highest impact was observed for rs55837134 (sex-and age adjusted additive HR = 1.67 [1.28-2.18]; p = 1.3 e-4). Regression analysis conditioned on rs55837134 showed that significant associations between remaining SNPs at the NPC1L1 locus and vascular events did not persist suggesting their dependence on rs55837134. Its significant association remained almost unchanged after further adjustment for total cholesterol, LDL cholesterol, and other cardiovascular risk factors (additive HR = 1.67 [1.28-2.18]; p = 1.7 e-4). In addition, no significant association of investigated NPC1L1 variants with coronary atherosclerosis could be observed, at least after false discovery rate correction. CONCLUSIONS: Genetic variants of NPC1L1, particularly rs55837134, show a predictive impact on cardiovascular events. Further studies to determine the molecular consequences of common genetic variants in NPC1L1 are needed.
Authors: Heinz Drexel; Andreas Leiherer; Christoph H Saely; Eva Maria Brandtner; Kathrin Geiger; Alexander Vonbank; Peter Fraunberger; Axel Muendlein Journal: Biosci Rep Date: 2019-08-07 Impact factor: 3.840