Genome-Wide Association Study for Endothelial Growth Factors

Lieb, Wolfgang; Chen, Ming-Huei; Larson, Martin G.; Safa, Radwan; Teumer, Alexander; Baumeister, Sebastian E.; Lin, Honghuang; Smith, Holly; Koch, Manja; Lorbeer, Roberto; Völker, Uwe; Nauck, Matthias; Völzke, Henry; Wallaschofski, Henri; Sawyer, Douglas B.; Vasan, Ramachandran S.

doi:10.1161/circgenetics.114.000597

Cited by 10 publications

(7 citation statements)

References 51 publications

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“…In a literature search, we identified suitable IVs for IL-1ra (rs4251961 and rs6759676) ( 15 ), HGF (rs5745687) ( 16 ), and t -PA (rs9399599, rs3136739, and rs7301826) ( 17 ). In a GWAS for the remaining four biomarkers using the conventional threshold for genome-wide significance ( P < 5 × 10 −8 ), we found a suitable genetic IV for cathepsin D only (rs55861089) ( Supplementary Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts

et al. 2015

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Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid–binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03–1.59) and t-PA (HR 1.30, 1.02–1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02–1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62–0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI −0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.

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Section: Resultsmentioning

confidence: 99%

Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts

et al. 2015

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“…[100][101][102][103][104] With regard to ARDS, ABO variation that determines blood type is strongly associated with plasma levels of multiple endothelial-derived glycoproteins important in ARDS, including VWF, intercellular adhesion molecule 1 (ICAM-1), and Ang-2. [104][105][106][107][108] It is possible that a therapeutic targeting these proteins or the endothelium in general could have a distinct effect in different blood types, a genetic trait that is easily accessible clinically.…”

Section: Genetic and Biomarker-defined Endotypes Of Ardsmentioning

confidence: 99%

Acute Respiratory Distress Syndrome Phenotypes

Reilly

Calfee

Christie

2019

Semin Respir Crit Care Med

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The acute respiratory distress syndrome (ARDS) phenotype was first described over 50 years ago and since that time significant progress has been made in understanding the biologic processes underlying the syndrome. Despite this improved understanding, no pharmacologic therapies aimed at the underlying biology have been proven effective in ARDS. Increasingly, ARDS has been recognized as a heterogeneous syndrome characterized by subphenotypes with distinct clinical, radiographic, and biologic differences, distinct outcomes, and potentially distinct responses to therapy. The Berlin Definition of ARDS specifies three severity classifications: mild, moderate, and severe based on the PaO2 to FiO2 ratio. Two randomized controlled trials have demonstrated a potential benefit to prone positioning and neuromuscular blockade in moderate to severe phenotypes of ARDS only. Precipitating risk factor, direct versus indirect lung injury, and timing of ARDS onset can determine other clinical phenotypes of ARDS after admission. Radiographic phenotypes of ARDS have been described based on a diffuse versus focal pattern of infiltrates on chest imaging. Finally and most promisingly, biologic subphenotypes or endotypes have increasingly been identified using plasma biomarkers, genetics, and unbiased approaches such as latent class analysis. The potential of precision medicine lies in identifying novel therapeutics aimed at ARDS biology and the subpopulation within ARDS most likely to respond. In this review, we discuss the challenges and approaches to subphenotype ARDS into clinical, radiologic, severity, and biologic phenotypes with an eye toward the future of precision medicine in critical care.

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“…We have shown that rs2920656 is an intronic variant in MCPH1 that regulates plasma ANG-2 concentrations. Previous studies have identified genetic variants in MCPH1 [ 37 ] and ANGPT2 [ 38 ] that are associated with ANG-2 concentrations. It is also conceivable that rs2920656 influences MCPH1 expression.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes

et al. 2020

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Background We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes. Methods We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR < 0.05) were tested for cis-biomarker expression and whether genetic risk for AKI-SP2 is mediated through circulating biomarkers. We also completed in vitro studies using human kidney microvascular endothelial cells. Finally, we calculated the renal clearance of plasma biomarkers using 20 different timed urine collections. Results A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31–0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 ( p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant ( p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects. Conclusion Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.

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Genome-Wide Association Study for Endothelial Growth Factors

Cited by 10 publications

References 51 publications

Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts

Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts

Acute Respiratory Distress Syndrome Phenotypes

Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes

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