scholarly journals The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

2020 ◽  
Author(s):  
Zhuo Wang ◽  
Fangkun Yang ◽  
Menghuai Ma ◽  
Qinyi Bao ◽  
Jinlian Shen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Causal Relationship ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Cardioembolic Stroke ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Increased Risk ◽  
The Impact

Abstract Background: Growth differentiation factor 15(GDF-15) concentration is apparently associated with cardiovascular disease, but whether there is a causal relationship has not been testified. Methods: We utilized Mendelian randomization to assess the function of GDF-15 in incidence of cardiovascular disease. The single-nucleotide polymorphism- GDF-15 association evaluations came from meta-analysis of genome-wide association study (GWAS). Besides inverse-variance weighted, MR-Egger test and weighted median method were applied to examine sensitivity. Results: Base on the instruments, GDF-15 level linked to increased risk of cardioembolic stroke (1.06, OR 1.09 per SD increase, 95% CI 1.01, 1.19) and atrial fibrillation (OR 1.03 per SD increase, 95% CI 1.0, 1.06). However, the significant causal relationship between GDF-15 and the other cardiovascular diseases was not found in our work. Conclusions: The result suggested that GDF-15 is causally associated with the risk of cardioembolic stroke and atrial fibrillation, providing conceivable strategies to alleviate the burden of cardiovascular disease.

scholarly journals The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

2020 ◽  
Author(s):  
Zhuo Wang ◽  
Fangkun Yang ◽  
Menghuai Ma ◽  
Qinyi Bao ◽  
Jinlian Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Cardioembolic Stroke ◽  
Growth Differentiation Factor 15 ◽  
Artery Disease

Abstract Background: Growth differentiation factor 15(GDF-15) concentration is apparently associated with cardiovascular disease, but whether there is a causal relationship has not been testified. Methods: We utilized Mendelian randomization to assess the function of GDF-15 in incidence of cardiovascular disease. The single-nucleotide polymorphism- GDF-15 association evaluations came from meta-analysis of genome-wide association study (GWAS). Besides inverse-variance weighted, MR-Egger test and weighted median method were applied to examine sensitivity. Results: Based on the instruments, GDF-15 level linked to the increasing risk of cardioembolic stroke (OR 1.09 per SD increase, 95% CI 1.01, 1.19) , atrial fibrillation (OR 1.03 per SD increase, 95% CI 1.0, 1.06), coronary artery disease (OR 0.94 per SD increase, 95% CI 0.89, 0.99) and myocardial infarction (OR 0.94 per SD increase, 95% CI 0.90, 0.98). However, the significant causal relationship between GDF-15 and the other cardiovascular diseases was not found in our study. Conclusions: The result suggested that GDF-15 was causally associated with the risk of cardioembolic stroke,atrial fibrillation, coronary artery disease and myocardial infarction, providing us conceivable strategies to alleviate the burden of cardiovascular disease.

scholarly journals The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

2020 ◽  
Author(s):  
Zhuo Wang ◽  
Fangkun Yang ◽  
Menghuai Ma ◽  
Qinyi Bao ◽  
Jinlian Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Cardioembolic Stroke ◽  
Growth Differentiation Factor 15 ◽  
Artery Disease

Abstract Background: Growth differentiation factor 15(GDF-15) concentration is apparently associated with cardiovascular disease, but whether there is a causal relationship has not been testified. Methods: We utilized Mendelian randomization to assess the function of GDF-15 in incidence of cardiovascular disease. The single-nucleotide polymorphism- GDF-15 association evaluations came from meta-analysis of genome-wide association study (GWAS). Besides inverse-variance weighted, MR-Egger test and weighted median method were applied to examine sensitivity. Results: Based on the instruments, GDF-15 level linked to the increasing risk of cardioembolic stroke (1.06, OR 1.09 per SD increase, 95% CI 1.01, 1.19) , atrial fibrillation (OR 1.03 per SD increase, 95% CI 1.0, 1.06), coronary artery disease (OR 0.94 per SD increase, 95% CI 0.89, 0.99) and myocardial infarction (OR 0.94 per SD increase, 95% CI 0.90, 0.98). However, the significant causal relationship between GDF-15 and the other cardiovascular diseases was not found in our study. Conclusions: The result suggested that GDF-15 was causally associated with the risk of cardioembolic stroke,atrial fibrillation, coronary artery disease and myocardial infarction, providing us conceivable strategies to alleviate the burden of cardiovascular disease.

Abstract P009: Growth Differentiation Factor 15 And The Subsequent Risk Of Atrial Fibrillation: The Atherosclerosis Risk In Communities Study

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Mengkun Chen ◽  
Ning Ding ◽  
Lena Mathews ◽  
Ron C Hoogeveen ◽  
Christie M Ballantyne ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Proportional Hazards ◽  
Troponin T ◽  
Cox Proportional Hazards ◽  
Atherosclerosis Risk In Communities ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Cox Proportional Hazards Models ◽  
Increased Risk ◽  
Icd 10

Introduction: Growth differentiation factor 15 (GDF-15) is a marker of oxidative stress and inflammation and has been associated with several cardiovascular disease (CVD) phenotypes. However, conflicting results have been reported regarding the association of GDF-15 with incident atrial fibrillation (AF) in the general population. Hypotheses: Higher GDF-15 level is associated with increased risk of incident AF independent of potential confounders. Methods: In 10,101 White and Black ARIC participants (mean age 60 years and 20.9% Blacks) free of AF at baseline (1993-95), we quantified the association of GDF-15 and incident AF using three Cox proportional hazards models. GDF-15 was measured by SOMA scan assay. AF was defined by hospitalizations with AF diagnosis or death certificates (ICD-9 codes: 427.31-427.32; ICD-10 codes: I48.x) or AF diagnosis by ECG at subsequent ARIC visits. Results: There were 2165 cases of incident AF over a median follow-up of 20.7 years (incidence rate 12.1 cases/1,000 person-years). After adjusting for demographic characteristics and cardiovascular risk factors, log GDF-15 was significantly associated with incident AF (hazard ratio 1.42 (1.25-1.63) for top vs. bottom quartile) (Model 1 in Table ). The result was robust even further adjusting for history of other CVD phenotypes and cardiac markers (Models 2 and 3 in Table ). In Model 3, quartiles of high-sensitive cardiac troponin T (hs-cTnT) did not demonstrate significant associations with incident AF. Conclusions: In community-based population, elevated GDF-15 level was independently and robustly associated with incident AF (even more strongly than troponin). These results suggest the involvement of GDF-15 in the development of AF and the potential of GDF-15 as a risk marker to identify individuals at high risk of AF.

scholarly journals Genetically Predicted Cardiac Troponin I Concentrations and Risk of Stroke and Atrial Fibrillation

2021 ◽  
Author(s):  
Dandan Liu ◽  
Yue Deng ◽  
Jiao Wang ◽  
Yanan Chen ◽  
Jian Yu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Mendelian Randomization ◽  
Cardiac Troponin I ◽  
Cardioembolic Stroke ◽  
Large Artery ◽  
Increased Risk

Abstract Background: Observational studies have shown that elevated circulating cardiac troponin I (cTnI) concentrations were associated with higher risk of stroke and atrial fibrillation, but the causality remains unclear. Therefore, we conducted a two-sample mendelian randomization study to evaluate the causal effects of cTnI concentrations on the risk of stroke subtypes and atrial fibrillation.Methods: The instrumental variables for circulating cTnI concentrations were selected from a genome-wide association study meta-analysis of 48,115 European individuals. Applying a 2-sample mendelian randomization approach, we examined the associations of circulating cTnI concentrations with stroke (40,585 cases and 406,111 controls), ischemic stroke (34,217 cases and 406,111 controls), ischemic stroke subtypes (cardioembolic, large artery, small vessel stroke), intracerebral hemorrhage (1,545 cases and 1,481 controls) and atrial fibrillation (60,620 cases and 970,216 controls). Results: Genetically predicted elevated circulating cTnI concentrations were associated with increased risk of cardioembolic stroke (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.20-2.68; P = 0.004). However, no significant association was observed for cTnI concentrations with large artery stroke, small vessel stroke, total stroke, ischemic stroke and intracerebral hemorrhage. Additionally, we also found that elevated cTnI concentrations were associated with higher risk of atrial fibrillation (OR, 1.30; 95% CI, 1.10-1.53; P = 0.003).Conclusions: This study provides evidence that genetically predicted circulating cTnI concentrations are causally associated with increased risk of cardioembolic stroke and atrial fibrillation.

scholarly journals The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study

2020 ◽  
Author(s):  
Zhuo Wang ◽  
Fangkun Yang ◽  
Menghuai Ma ◽  
Qinyi Bao ◽  
Jinlian Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Mendelian Randomization ◽  
Large Artery ◽  
Nonischemic Cardiomyopathy ◽  
Growth Differentiation Factor 15 ◽  
Increased Risk ◽  
Artery Disease

Abstract Background: Growth differentiation factor 15 (GDF-15), a stress responsive cytokine, belongs to transforming growth factor β (TGF-β) cytokine superfamily. Some evidence support that it’s involved in inflammation, coagulation, oxidative stress, endothelial dysfunction, and hemostasis. However, it’s still controversial whether GDF-15 directly contributes to the morbidity and mortality of patients suffered with cardiovascular disease (CVD). Besides prospective cohort study and randomized controlled trial, Mendelian randomization (MR) is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable to determine the causal relationships between exposures and health outcomes. Herein, we introduced a two-sample MR approach to evaluate the causal relationships of circulating GDF-15 levels with major CVDs incidence.Methods: Genetic instruments and summary statistics for two-sample MR analysis were obtained from 5 independent large genome-wide association studies (GWAS) to investigate the causal correlation between circulating GDF-15 levels and 9 CVDs, respectively. Conventional inverse variance weighted (IVW) method was adopted to evaluate the causality of GDF-15 with different outcomes; weighted median and MR egger were used for sensitivity analyses.Results: Among 9 SNPs identified from 5 GWASs in 2.6 million individuals, 5 SNPs (rs1227731, rs3195944, rs17725099, rs888663, rs749451) coming from chromosome 19 and containing the PGPEP1 and GDF-15 genes were employed. Based on the instruments, circulating GDF-15 levels significantly linked to the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction. However, no significant causal association was observed for circulating GDF-15 levels with the incidence of any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy.Conclusions: The MR study provides with genetic evidence for the causal relationship of circulating GDF-15 levels with the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction, but not any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. It indicates that GDF-15 might be a promising biomarker or potential therapeutic target for some CVDs.

scholarly journals Mendelian randomization study on atrial fibrillation and cardiovascular disease subtypes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Man Ki Kwok ◽  
Catherine Mary Schooling
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Ischemic Stroke ◽  
Mendelian Randomization ◽  
Late Onset ◽  
Cardioembolic Stroke ◽  
Sensitivity Analyses ◽  
Subdural Hemorrhage ◽  
Arterial Thromboembolism

AbstractAtrial fibrillation (AF) has been associated with numerous diseases. However, whether AF is a cause or consequence of these diseases is uncertain. To clarify, we assessed the causal role of AF on ischemic heart disease (IHD), stroke, other cardiovascular disease (CVD) subtypes, type 2 diabetes mellitus (T2DM), and late-onset AD using bi-directional two-sample Mendelian randomization (MR) among people primarily of European descent. Genetically predicted log odds of AF was associated with any stroke (odds ratio (OR) 1.22, 95% CI 1.18 to 1.27), particularly cardioembolic stroke and possibly subdural hemorrhage, with sensitivity analyses showing similar positive findings. Genetically predicted AF was also associated with arterial thromboembolism (1.32, 1.13 to 1.53), and heart failure (1.26, 1.21 to 1.30). No association of genetically predicted AF with IHD, T2DM, cognitive function, or late-onset AD was found. Conversely, genetically predicted IHD, heart failure and possibly ischemic stroke, particularly cardioembolic stroke, were positively associated with AF. Atrial fibrillation plays a role in any stroke, arterial thromboembolism, and heart failure, corroborating current clinical guidelines on the importance of preventing these complications by effective AF management. In addition, patients with IHD, heart failure or possibly ischemic stroke might be predisposed to developing AF, with implications for management.

scholarly journals The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhuo Wang ◽  
Fangkun Yang ◽  
Menghuai Ma ◽  
Qinyi Bao ◽  
Jinlian Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Mendelian Randomization ◽  
Large Artery ◽  
Nonischemic Cardiomyopathy ◽  
Growth Differentiation Factor 15 ◽  
Increased Risk ◽  
Artery Disease

Abstract Background Growth differentiation factor 15 (GDF-15), a stress responsive cytokine, belongs to transforming growth factor β cytokine superfamily. Some evidence support that it’s involved in inflammation, coagulation, oxidative stress, endothelial dysfunction, and hemostasis. However, it’s still controversial whether GDF-15 directly contributes to the morbidity and mortality of patients suffered with cardiovascular disease (CVD). Besides prospective cohort study and randomized controlled trial, Mendelian randomization (MR) is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable to determine the causal relationships between exposures and health outcomes. Herein, we introduced a two-sample MR approach to evaluate the causal relationships of circulating GDF-15 levels with major CVDs incidence. Methods Genetic instruments and summary statistics for two-sample MR analysis were obtained from 5 independent large genome-wide association studies (GWAS) to investigate the causal correlation between circulating GDF-15 levels and 9 CVDs, respectively. Conventional inverse variance weighted method was adopted to evaluate the causality of GDF-15 with different outcomes; weighted median and MR egger were used for sensitivity analyses. Results Among 9 SNPs identified from 5 GWASs in 2.6 million individuals, 5 SNPs (rs1227731, rs3195944, rs17725099, rs888663, rs749451) coming from chromosome 19 and containing the PGPEP1 and GDF-15 genes were employed. Based on the instruments, circulating GDF-15 levels significantly linked to the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction. However, no significant causal association was observed for circulating GDF-15 levels with the incidence of any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. Conclusions The MR study provides with genetic evidence for the causal relationship of circulating GDF-15 levels with the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction, but not any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. It indicates that GDF-15 might be a promising biomarker or potential therapeutic target for some CVDs.

scholarly journals Appraising the Causal Association of Plasma Homocysteine Levels With Atrial Fibrillation Risk: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Songzan Chen ◽  
Fangkun Yang ◽  
Tian Xu ◽  
Yao Wang ◽  
Kaijie Zhang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Plasma Homocysteine ◽  
Fixed Effect ◽  
Sensitivity Analyses ◽  
Causal Association ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

BackgroundAlthough several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk.MethodsA two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10–8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy.ResultsIn total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy.ConclusionsThis two-sample MR analysis found no evidence to support causal association of Hcy with AF.

scholarly journals Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study

2021 ◽  
Author(s):  
Tianyi Wang ◽  
Jun Cheng ◽  
Yanggan Wang
Keyword(s):  
Atrial Fibrillation ◽  
Causal Relationship ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Nucleotide Polymorphisms ◽  
Positive Effects ◽  
A Genome

Background Atrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation. Methods Single nucleotide polymorphisms (SNPs) strongly associated (P< 5.10-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium. Summary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study( including 65,446 atrial fibrillation cases and 522,744 controls) .We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis. Results Genetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation. Conclusion In conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.

scholarly journals Association of Lipoprotein (a) variants with risk of cardiovascular disease: a Mendelian randomization study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Juan Xia ◽  
Chunyue Guo ◽  
Kuo Liu ◽  
Yunyi Xie ◽  
Han Cao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Chinese Population ◽  
Left Ventricular Mass Index ◽  
Mendelian Randomization ◽  
Left Ventricular ◽  
Han Chinese ◽  
Han Chinese Population ◽  
Internal Dimension

Abstract Background There is a well-documented empirical relationship between lipoprotein (a) [Lp(a)] and cardiovascular disease (CVD); however, causal evidence, especially from the Chinese population, is lacking. Therefore, this study aims to estimate the causal association between variants in genes affecting Lp(a) concentrations and CVD in people of Han Chinese ethnicity. Methods Two-sample Mendelian randomization analysis was used to assess the causal effect of Lp(a) concentrations on the risk of CVD. Summary statistics for Lp(a) variants were obtained from 1256 individuals in the Cohort Study on Chronic Disease of Communities Natural Population in Beijing, Tianjin and Hebei. Data on associations between single-nucleotide polymorphisms (SNPs) and CVD were obtained from recently published genome-wide association studies. Results Thirteen SNPs associated with Lp(a) levels in the Han Chinese population were used as instrumental variables. Genetically elevated Lp(a) was inversely associated with the risk of atrial fibrillation [odds ratio (OR), 0.94; 95% confidence interval (95%CI), 0.901–0.987; P = 0.012)], the risk of arrhythmia (OR, 0.96; 95%CI, 0.941–0.990; P = 0.005), the left ventricular mass index (OR, 0.97; 95%CI, 0.949–1.000; P = 0.048), and the left ventricular internal dimension in diastole (OR, 0.97; 95%CI, 0.950–0.997; P = 0.028) according to the inverse-variance weighted method. No significant association was observed for congestive heart failure (OR, 0.99; 95% CI, 0.950–1.038; P = 0.766), ischemic stroke (OR, 1.01; 95%CI, 0.981–1.046; P = 0.422), and left ventricular internal dimension in systole (OR, 0.98; 95%CI, 0.960–1.009; P = 0.214). Conclusions This study provided evidence that genetically elevated Lp(a) was inversely associated with atrial fibrillation, arrhythmia, the left ventricular mass index and the left ventricular internal dimension in diastole, but not with congestive heart failure, ischemic stroke, and the left ventricular internal dimension in systole in the Han Chinese population. Further research is needed to identify the mechanism underlying these results and determine whether genetically elevated Lp(a) increases the risk of coronary heart disease or other CVD subtypes.

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