A genetic risk score of 45 coronary artery disease risk variants associates with increased risk of myocardial infarction in 6041 Danish individuals

2015 ◽  
Vol 240 (2) ◽  
pp. 305-310 ◽  
Author(s):  
N.T. Krarup ◽  
A. Borglykke ◽  
K.H. Allin ◽  
C.H. Sandholt ◽  
J.M. Justesen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genetic Risk ◽  
Disease Risk ◽  
Genetic Risk Score ◽  
Coronary Artery Disease Risk ◽  
Risk Variants ◽  
Increased Risk ◽  
Artery Disease

scholarly journals Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort

2018 ◽  
Vol 5 ◽  
Author(s):  
Wangjing Ke ◽  
Kristin A. Rand ◽  
David V. Conti ◽  
Veronica W. Setiawan ◽  
Daniel O. Stram ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Disease Risk ◽  
Coronary Artery Disease Risk ◽  
Risk Variants ◽  
Multiethnic Cohort ◽  
Artery Disease

scholarly journals Functional Characterization of LIPA (Lysosomal Acid Lipase) Variants Associated With Coronary Artery Disease

2019 ◽  
Vol 39 (12) ◽  
pp. 2480-2491 ◽  
Author(s):  
Trent D. Evans ◽  
Xiangyu Zhang ◽  
Reece E. Clark ◽  
Arturo Alisio ◽  
Eric Song ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Signal Peptide ◽  
Disease Risk ◽  
Coronary Artery Disease Risk ◽  
Acid Lipase ◽  
Risk Variants ◽  
Artery Disease ◽  
Intronic Variants

Objective: LIPA (lysosomal acid lipase) mediates cholesteryl ester hydrolysis, and patients with rare loss-of-function mutations develop hypercholesterolemia and severe disease. Genome-wide association studies of coronary artery disease have identified several tightly linked, common intronic risk variants in LIPA which unexpectedly associate with increased mRNA expression. However, an exonic variant (rs1051338 resulting in T16P) in linkage with intronic variants lies in the signal peptide region and putatively disrupts trafficking. We sought to functionally investigate the net impact of this locus on LIPA and whether rs1051338 could disrupt LIPA processing and function to explain coronary artery disease risk. Approach and Results: In monocytes isolated from a large cohort of healthy individuals, we demonstrate both exonic and intronic risk variants are associated with increased LIPA enzyme activity coincident with the increased transcript levels. To functionally isolate the impact of rs1051338, we studied several in vitro overexpression systems and consistently observed no differences in LIPA expression, processing, activity, or secretion. Further, we characterized a second common exonic coding variant (rs1051339), which is predicted to alter LIPA signal peptide cleavage similarly to rs1051338, yet is not linked to intronic variants. rs1051339 also does not impact LIPA function in vitro and confers no coronary artery disease risk. Conclusions: Our findings show that common LIPA exonic variants in the signal peptide are of minimal functional significance and suggest coronary artery disease risk is instead associated with increased LIPA function linked to intronic variants. Understanding the mechanisms and cell-specific contexts of LIPA function in the plaque is necessary to understand its association with cardiovascular risk.

scholarly journals Physical activity, sedentary behavior and risk of coronary artery disease, myocardial infarction and ischemic stroke: a two-sample Mendelian randomization study

2021 ◽  
Author(s):  
Martin Bahls ◽  
Michael F. Leitzmann ◽  
André Karch ◽  
Alexander Teumer ◽  
Marcus Dörr ◽  
...  
Keyword(s):  
Physical Activity ◽  
Myocardial Infarction ◽  
Coronary Artery Disease ◽  
Ischemic Stroke ◽  
Coronary Artery ◽  
Sedentary Behavior ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Artery Disease

Abstract Aims Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke. Methods and results We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease (99,121 controls), 27,509 cases of myocardial infarction (99,121 controls), and 34,217 cases of ischemic stroke (404,630 controls). We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke. Conclusions These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased. Graphic abstract

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