Increased ischemic stroke, acute coronary artery disease and mortality in patients with granulomatosis with polyangiitis and microscopic polyangiitis

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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Association between the PPP1R3B polymorphisms and serum lipid traits, the risk of coronary artery disease and ischemic stroke in a southern Chinese Han population

Nutrition & Metabolism ◽

10.1186/s12986-018-0266-y ◽

2018 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Wei-Jun Li ◽

Rui-Xing Yin ◽

Jian-Hua Huang ◽

Yuan Bin ◽

Wu-Xian Chen ◽

...

Keyword(s):

Coronary Artery Disease ◽

Ischemic Stroke ◽

Coronary Artery ◽

Serum Lipid ◽

Chinese Han Population ◽

Chinese Han ◽

Han Population ◽

Southern Chinese ◽

Artery Disease

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How does kinesiophobia change over time in patients with acute coronary artery disease?

Physiotherapy ◽

10.1016/j.physio.2015.03.232 ◽

2015 ◽

Vol 101 ◽

pp. e98

Author(s):

M. Bäck ◽

M. Lundberg ◽

Å. Cider ◽

J. Herlitz ◽

B. Jansson

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Change Over Time ◽

Artery Disease ◽

Acute Coronary Artery Disease ◽

Over Time

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Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1810568115 ◽

2018 ◽

Vol 115 (48) ◽

pp. E11349-E11358 ◽

Cited By ~ 15

Author(s):

Matthew D. Krause ◽

Ru-Ting Huang ◽

David Wu ◽

Tzu-Pin Shentu ◽

Devin L. Harrison ◽

...

Keyword(s):

Coronary Artery Disease ◽

Ischemic Stroke ◽

Coronary Artery ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Enhancer Activity ◽

Protective Allele ◽

Unidirectional Flow ◽

Artery Disease

Biomechanical cues dynamically control major cellular processes, but whether genetic variants actively participate in mechanosensing mechanisms remains unexplored. Vascular homeostasis is tightly regulated by hemodynamics. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constitutive activation of vascular endothelium contributing to atherosclerosis, the major cause of coronary artery disease (CAD) and ischemic stroke (IS). Conversely, unidirectional flow promotes quiescent endothelium. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as strongly associated with CAD/IS; however, the causal mechanism related to this locus remains unknown. Using statistical analyses, assay of transposase accessible chromatin with whole-genome sequencing (ATAC-seq), H3K27ac/H3K4me2 ChIP with whole-genome sequencing (ChIP-seq), and CRISPR interference in human aortic endothelial cells (HAECs), our results demonstrate that rs17114036, a common noncoding polymorphism at 1p32.2, is located in an endothelial enhancer dynamically regulated by hemodynamics. CRISPR-Cas9–based genome editing shows that rs17114036-containing region promotes endothelial quiescence under unidirectional shear stress by regulating phospholipid phosphatase 3 (PLPP3). Chromatin accessibility quantitative trait locus (caQTL) mapping using HAECs from 56 donors, allelic imbalance assay from 7 donors, and luciferase assays demonstrate that CAD/IS-protective allele at rs17114036 in PLPP3 intron 5 confers increased endothelial enhancer activity. ChIP-PCR and luciferase assays show that CAD/IS-protective allele at rs17114036 creates a binding site for transcription factor Krüppel-like factor 2 (KLF2), which increases the enhancer activity under unidirectional flow. These results demonstrate that a human SNP contributes to critical endothelial mechanotransduction mechanisms and suggest that human haplotypes and related cis-regulatory elements provide a previously unappreciated layer of regulatory control in cellular mechanosensing mechanisms.

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