scholarly journals Prospective Study on Plasma MicroRNA‐4286 and Incident Acute Coronary Syndrome

2021 ◽  
Author(s):  
Miaoyan Shen ◽  
Xuedan Xu ◽  
Xuezhen Liu ◽  
Qiuhong Wang ◽  
Wending Li ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Case Control ◽  
Interquartile Range ◽  
Coronary Syndrome ◽  
Inverse Variance ◽  
Increased Risk ◽  
Outlier Tests ◽  
Plasma Microrna

Background Mounting evidence suggests that circulating microRNAs (miRNAs) are critical indicators of cardiovascular disease. However, prospective studies linking circulating miRNAs to incident acute coronary syndrome (ACS) are limited, and the underlying effect of associated miRNA on incident ACS remains unknown. Methods and Results Based on a 2‐stage prospective nested case–control design within the Dongfeng‐Tongji cohort, we profiled plasma miRNAs from 23 pairs of incident ACS cases and controls by microarray and validated the candidate miRNAs in 572 incident ACS case–control pairs using quantitative real‐time polymerase chain reaction. We observed that plasma miR‐4286 was associated with higher risk of ACS (adjusted odds ratio according to an interquartile range increase, 1.26 [95% CI, 1.07–1.48]). Further association analysis revealed that triglyceride was positively associated with plasma miR‐4286, and an interquartile range increase in triglyceride was associated with an 11.04% (95% CI, 3.77%–18.83%) increase in plasma miR‐4286. In addition, the Mendelian randomization analysis suggested a potential causal effect of triglyceride on plasma miR‐4286 ( β coefficients: 0.27 [95% CI, 0.01–0.53] and 0.27 [95% CI, 0.07–0.47] separately by inverse variance‐weighted and Mendelian randomization‐pleiotropy residual sum and outlier tests). Moreover, the causal mediation analysis indicated that plasma miR‐4286 explained 5.5% (95% CI, 0.7%–17.0%) of the association of triglyceride with incident ACS. Conclusions Higher level of plasma miR‐4286 was associated with an increased risk of ACS. The upregulated miR‐4286 in plasma can be attributed to higher triglyceride level and may mediate the effect of triglyceride on incident ACS.

Abstract 5093: Genetically Elevated Lipoprotein(a) and Risk of Myocardial Infarction - a Positive Mendelian Randomization Study

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Pia Kamstrup ◽  
Anne Tybjærg-Hansen ◽  
Rolf Steffensen ◽  
Børge G Nordestgaard
Keyword(s):  
Myocardial Infarction ◽  
Plasma Levels ◽  
Case Control Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Case Control ◽  
Lipoprotein A ◽  
Increased Risk ◽  
Disease Study ◽  
Control Study

Background: High levels of lipoprotein(a) (Lp(a)) associate with increased risk of myocardial infarction (MI). We tested whether this is a causal effect using a Mendelian randomization design. Methods: We genotyped for the Lp(a) kringle IV type 2 (KIV-2) size polymorphism, which explains 21% of variation in plasma levels of Lp(a). We used a cohort study of the Danish general population, The Copenhagen City Heart Study, including 9867 individuals followed for up to 16 years during which time 599 developed MI, and a case-control study, The Copenhagen Ischemic Heart Disease Study, including 1118 MI patients and 2234 controls. Results: First, increased plasma levels of Lp(a) associated with increased risk of MI (Lp(a) tertiles, trend: p<0.001). Second, number of KIV-2 repeats inversely associated with Lp(a) levels: mean Lp(a) levels were 56, 31, 20, and 15 mg/dL for the 1 st , 2 nd , 3 rd , and 4 th quartile of KIV-2 repeats, respectively (trend, p<0.001, Figure ). Third, multifactorially adjusted hazard ratios for MI were 1.6(95% CI:1.3–.2.0), 1.3(1.0 –1.7), and 1.1(0.9 –1.4) for individuals in the 1 st , 2 nd , and 3 rd quartile, respectively, as compared to individuals in the 4 th quartile of KIV-2 repeats (Figure ). Finally, in the case-control study, multifactorially adjusted odds ratios for MI were 1.5(1.2–1.9), 1.3(1.0 –1.6), and 1.2(1.0 –1.5) for individuals in the 1 st , 2 nd , and 3 rd quartile, respectively, as compared to individuals in the 4 th quartile of KIV-2 repeats. Conclusion: Since Lp(a) levels predict MI, and since Lp(a) KIV-2 genotype predicts both life-long increased Lp(a) levels and MI, increased Lp(a) levels appear to directly cause MI. Figure. Levels of lipoprotein (a) and risk of myocardial infarction by KIV-2

scholarly journals Causal Effect of Obstructive Sleep Apnea on Atrial Fibrillation: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Weiqi Chen ◽  
Xueli Cai ◽  
Hongyi Yan ◽  
Yuesong Pan
Keyword(s):  
Atrial Fibrillation ◽  
Obstructive Sleep Apnea ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Genome Wide ◽  
Inverse Variance ◽  
Obstructive Sleep ◽  
Increased Risk

Background Obstructive sleep apnea (OSA) has shown to be associated with an increased risk of atrial fibrillation in observational studies. Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causal effect of OSA on atrial fibrillation. Methods and Results We used a 2‐sample Mendelian randomization (MR) method to evaluate the causal effect of OSA on atrial fibrillation. Summary data on genetic variant‐OSA association were obtained from a recently published genome‐wide association studies with up to 217 955 individuals and data on variant‐atrial fibrillation association from another genome‐wide association study with up to 1 030 836 individuals. Effect estimates were evaluated using inverse‐variance weighted method. Other MR analyses, including penalized inverse‐variance weighted, penalized robust inverse‐variance weighted, MR‐Egger, simple median, weighted median, weighted mode‐based estimate and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods were performed in sensitivity analyses. The MR analyses in both the fixed‐effect and random‐effect inverse‐variance weighted models showed that genetically predicted OSA was associated with an increased risk of atrial fibrillation (odds ratio [OR], 1.21; 95% CI, 1.12–1.31, P <0.001; OR, 1.21; 95% CI, 1.11–1.32, P <0.001) using 5 single nucleotide polymorphisms as the instruments. MR‐Egger indicated no evidence of genetic pleiotropy (intercept, −0.014; 95% CI, −0.033 to 0.005, P =0.14). Results were robust using other MR methods in sensitivity analyses. Conclusions This MR analysis found that genetically predicted OSA had causal effect on an increased risk of atrial fibrillation.

scholarly journals pIVW: A novel Mendelian Randomization Method Accounting for Weak Instruments and Horizontal Pleiotropy with Applications to the COVID-19 Outcomes

2021 ◽  
Author(s):  
Siqi Xu ◽  
Wing Kam Fung ◽  
Zhonghua Liu
Keyword(s):  
Variance Estimation ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
R Package ◽  
Regularity Conditions ◽  
Strength Increase ◽  
Inverse Variance ◽  
Increased Risk ◽  
Exposure Variable ◽  
Improved Performance

Mendelian randomization (MR) utilizes genetic variants as instrumental variables (IVs) to estimate the causal effect of an exposure variable on an outcome of interest even in the presence of unmeasured confounders. However, many MR methods including the most popular inverse-variance weighted (IVW) estimator could be biased by the weak IVs that are weakly associated with the exposure. In this article, we develop a novel method called penalized inverse-variance weighted (pIVW) estimator, where we adjust the IVW estimator to account for the weak IVs by a proposed penalization method to prevent the denominator of the pIVW estimator from being close to zero. Moreover, we account for the horizontal pleiotropy|a widespread phenomenon in human genome that could bias the inference for the causal effect|by adjusting the variance estimation of the pIVW estimator. The proposed pIVW estimator can reduce to the debiased IVW (dIVW) estimator|another extension of the the IVW estimator|when the number of IVs and the IV strength increase. More generally, we prove that the pIVW estimator can achieve smaller bias and variance than the dIVW estimator under some regularity conditions. We also illustrate the improved performance of the proposed pIVW estimator over competing MR methods through a comprehensive simulation study. Further, we analyze the causal effects of the obesity-related traits and diseases on the Coronavirus disease 2019 (COVID-19). Notably, we find that hypertensive disease is associated with increased risk of hospitalized COVID-19, while peripheral vascular disease and higher body mass index are associated with increased risks of COVID-19 infection, hospitalized COVID-19 and critically ill COVID-19. The R package for the pIVW method is publicly available at https://github.com/siqixu/mr.pivw.

scholarly journals Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Pinpin Long ◽  
Qiuhong Wang ◽  
Yizhi Zhang ◽  
Xiaoyan Zhu ◽  
Kuai Yu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Coronary Syndrome ◽  
Methylation Level ◽  
Meta Analysis ◽  
Regulation Of Gene Expression ◽  
Density Lipoprotein ◽  
Blood Leukocytes ◽  
Coronary Syndrome ◽  
A Genome ◽  
Increased Risk

Abstract Background Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear. Methods We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study. Results We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02–1.48; P = 0.03). Conclusions We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.

scholarly journals Circulating Levels of Dephosphorylated-Uncarboxylated Matrix Gla Protein in Patients with Acute Coronary Syndrome

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1108
Author(s):  
Admira Bilalic ◽  
Tina Ticinovic Kurir ◽  
Marko Kumric ◽  
Josip A. Borovac ◽  
Andrija Matetic ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Coronary Syndrome ◽  
High Risk ◽  
Hospital Mortality ◽  
Vascular Calcification ◽  
Matrix Gla Protein ◽  
St Elevation Myocardial Infarction ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
St Elevation

Vascular calcification contributes to the pathogenesis of coronary artery disease while matrix Gla protein (MGP) was recently identified as a potent inhibitor of vascular calcification. MGP fractions, such as dephosphorylated-uncarboxylated MGP (dp-ucMGP), lack post-translational modifications and are less efficient in vascular calcification inhibition. We sought to compare dp-ucMGP levels between patients with acute coronary syndrome (ACS), stratified by ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) status. Physical examination and clinical data, along with plasma dp-ucMGP levels, were obtained from 90 consecutive ACS patients. We observed that levels of dp-ucMGP were significantly higher in patients with NSTEMI compared to STEMI patients (1063.4 ± 518.6 vs. 742.7 ± 166.6 pmol/L, p < 0.001). NSTEMI status and positive family history of cardiovascular diseases were only independent predictors of the highest tertile of dp-ucMGP levels. Among those with NSTEMI, patients at a high risk of in-hospital mortality (adjudicated by GRACE score) had significantly higher levels of dp-ucMGP compared to non-high-risk patients (1417.8 ± 956.8 vs. 984.6 ± 335.0 pmol/L, p = 0.030). Altogether, our findings suggest that higher dp-ucMGP levels likely reflect higher calcification burden in ACS patients and might aid in the identification of NSTEMI patients at increased risk of in-hospital mortality. Furthermore, observed dp-ucMGP levels might reflect differences in atherosclerotic plaque pathobiology between patients with STEMI and NSTEMI.

scholarly journals Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Susanna C. Larsson
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Increased Risk ◽  
Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

Candidate Genes of the 5-Lipoxygenase Pathway in Acute Coronary Syndrome: A Pilot Study

2008 ◽  
Vol 9 (4) ◽  
pp. 280-292 ◽  
Author(s):  
Shu-Fen Wung ◽  
Bradley E. Aouizerat
Keyword(s):  
Acute Coronary Syndrome ◽  
Pilot Study ◽  
Nucleotide Polymorphisms ◽  
Common Allele ◽  
Lipoxygenase Pathway ◽  
Single Nucleotide ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
Caucasian Patients ◽  
Alox5ap Gene

Purpose. The purpose of this pilot study was to examine arachidonate 5-lipoxygenase (ALOX5) and ALOX5-activating protein (ALOX5AP) gene variations in patients with and without acute coronary syndrome (ACS). Methodology. Four and six single nucleotide polymorphisms spanning the ALOX5 and ALOX5AP genes, respectively, were genotyped in 19 non-Hispanic Caucasian patients with ACS and 27 controls. Results. Presence of the common allele of rs9508835 (ALOX5AP) and the minor allele of rs2029253 (ALOX5) were associated with ACS. After adjustment for age, being a carrier of the rs9508835 common allele was associated with an increased risk of ACS (odds ratio = 2.86). Relevance for nursing practice. Through the inhibition of the ALOX5AP gene by downregulation of the leukotriene pathway, the risk of ACS may be decreased in individuals that carry susceptibility allele(s). Knowledge of the genetic basis of treatments that downregulate the leukotriene pathway may prove essential to the care of individuals with ACS.

Abstract 12644: Growth Differentiation Factor-15 (GDF-15) for Risk Stratification in Patients After an Acute Coronary Syndrome: Insights From the SOLID-TIMI 52 trial

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Eri Toda Kato ◽  
David A Morrow ◽  
Christopher P Cannon ◽  
Mary Ann Lukas ◽  
Andrzej Budaj ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Cardiac Biomarkers ◽  
Individual Element ◽  
Clinical Predictors ◽  
Coronary Syndrome ◽  
Differentiation Factor ◽  
Increased Risk ◽  
Prognostic Utility ◽  
Traditional Risk Factors ◽  
Risk Predictors

Background: Growth differentiation factor (GDF)-15, a stress responsive cytokine, is associated with the risk of CV events after an acute coronary syndrome (ACS). Unlike other established cardiac biomarkers, the level of GDF-15 remains elevated in sub-acute phase after ACS and gradually decreases over time. We evaluated the prognostic utility of GDF-15 in patients after ACS accounting for established markers and risk predictors. Methods: GDF-15 (R&D Systems) and other established cardiac biomarkers (BNP, hsCRP and hsTnI) were measured at baseline in a randomly selected cohort of 4,968 patients enrolled within 30 days of hospitalization with ACS (median=14d) in SOLID-TIMI 52. Previously defined cutpoints were applied for GDF-15 concentration: <1200 (n=3451), 1200-1800 (n=919), and > 1800 ng/L (n=598). Analyses were adjusted for established risk predictors, days from the ACS event and other markers. MACE was defined as CV death, MI or stroke. Median follow-up was 2.5 years. Results: Patients with higher GDF-15 tended to be older, more likely to have diabetes, hypertension, history of revascularization, and CKD at baseline. Higher baseline levels of GDF-15 identified patients with higher rates of MACE as well as each individual element (p-trend <0.001 for all endpoints, Fig). The rate of MI was ∼2-fold higher in those with GDF-15 concentration >1800ng/L compared to patients with GDF-15 concentration <1200 ng/L. After adjustment for clinical predictors and other markers, GDF-15 was independently associated with the risk of MACE (HR 1.4, 95% CI 1.1-1.7; HR 1.8, 95% CI 1.4-2.3 for GDF-15 1200-1800, >1800, respectively). Individuals with GDF-15 >1800 ng/L had an increased risk of MI (adj HR 1.4, 95% CI 1.1-2.0) and stroke (adj HR 2.3, 95% CI 1.3-3.9). Conclusion: In patients after ACS, GDF-15 concentration is associated with the risk of MACE including MI and stroke independent of traditional risk factors and risk markers.

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