Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease

ABSTRACTBackgroundCirculating lipid and lipoprotein levels have consistently been identified as risk factors for atherosclerotic cardiovascular disease (ASCVD), largely on the basis of studies focused on coronary artery disease (CAD). The relative contributions of specific lipoproteins to risk of peripheral artery disease (PAD) have not been well-defined. Here, we leveraged large scale genetic association data to identify genetic proxies for circulating lipoprotein-related traits, and employed Mendelian randomization analyses to investigate their effects on PAD risk.MethodsGenome-wide association study summary statistics for PAD (Veterans Affairs Million Veteran Program, 31,307 cases) and CAD (CARDIoGRAMplusC4D, 60,801 cases) were used in the Mendelian Randomization Bayesian model averaging (MR-BMA) framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B lowering on PAD risk using gene regions that proxy potential lipid-lowering drug targets. Transcriptome-wide association studies were performed to identify genes relevant to circulating levels of prioritized lipoprotein subfractions.ResultsApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability 0.86, p = 0.003) and CAD (marginal inclusion probability 0.92, p = 0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (OR 0.87 per 1 standard deviation decrease in ApoB, 95% CI 0.84 to 0.91, p = 9 × 10−10) and CAD (OR 0.66, 95% CI 0.63 to 0.69, p = 4 × 10−73), with a stronger predicted effect of ApoB-lowering on CAD (ratio of ORs 1.33, 95% CI 1.25 to 1.42, p = 9 × 10−19). Among ApoB-containing subfractions, extra-small VLDL particle concentration (XS.VLDL.P) was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability 0.91, p = 2.3 × 10−4), while large LDL particle concentration (L.LDL.P) was the most likely subfraction associated with CAD risk (marginal inclusion probability 0.95, p = 0.011). Genes associated with XS.VLDL.P and L.LDL.P included canonical ApoB-pathway components, although gene-specific effects varied across the lipoprotein subfractions.ConclusionApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, diverse effects of ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions on ASCVD, and distinct subfraction-associated genes suggest possible biologic differences in the role of lipoproteins in the pathogenesis of PAD and CAD.

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Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease

Circulation ◽

10.1161/circulationaha.121.053797 ◽

2021 ◽

Author(s):

Michael G. Levin ◽

Verena Zuber ◽

Venexia M. Walker ◽

Derek Klarin ◽

Julie Lynch ◽

...

Keyword(s):

Risk Factors ◽

Peripheral Artery Disease ◽

Drug Targets ◽

Particle Concentration ◽

Peripheral Artery ◽

Lipoprotein Subfractions ◽

Artery Disease ◽

Lowering Drug ◽

Cad Risk

Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to risk of peripheral artery disease (PAD) have not been well-defined. We leveraged large-scale genetic association data to investigate effects of circulating lipoprotein-related traits on PAD risk. Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the MR Bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. MR was used to estimate the effect of ApoB-lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified using transcriptome-wide association studies. Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability [MIP] 0.86, p = 0.003) and CAD (MIP 0.92, p = 0.005). Genetic proxies for ApoB (apolipoprotein B)-lowering medications were associated with reduced risk of both PAD (OR 0.87 per 1 standard deviation decrease in ApoB, 95% CI 0.84 to 0.91, p = 9 x 10 -10 ) and CAD (OR 0.66, 95% CI 0.63 to 0.69, p = 4 x 10 -73 ), with a stronger predicted effect of ApoB-lowering on CAD (ratio of effects 3.09, 95% CI 2.29 to 4.60, p < 1 × 10 -6 ). Extra-small-VLDL particle concentration (XS.VLDL.P) was identified as the most likely subfraction associated with PAD risk (MIP 0.91, p = 2.3 x 10 -4 ), while large-LDL particle concentration (L.LDL.P) was the most likely subfraction associated with CAD risk (MIP 0.95, p = 0.011). Genes associated with XS.VLDL.P and L.LDL.P included canonical ApoB-pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD, independent of ApoB (OR 1.04, 95% CI 1.03 to 1.04, 95% CI 1.0 x 10 -33 ). Conclusions: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with ASCVD, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.

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Mendelian randomization analyses reveal mediating factors of the causal effect of height on coronary artery disease

10.1101/2021.12.16.21267869 ◽

2021 ◽

Author(s):

Daniel Hui ◽

Christopher S. Thom ◽

Kimberly Lorenz ◽

Scott M. Damrauer ◽

Themistocles L. Assimes ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Lung Function ◽

Mendelian Randomization ◽

Causal Effect ◽

Multivariable Analysis ◽

Inverse Correlation ◽

Artery Disease ◽

Cad Risk

An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested evidence that this association may be causal. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized the largest set of genetic instruments for human stature to date, comprising >2,000 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (~6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 2.1x10-2). We observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest that height does not add meaningful clinical impact on CAD risk prediction beyond established risk factors.

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A Mendelian randomization study of the role of lipoprotein subfractions in coronary artery disease

eLife ◽

10.7554/elife.58361 ◽

2021 ◽

Vol 10 ◽

Author(s):

Qingyuan Zhao ◽

Jingshu Wang ◽

Zhen Miao ◽

Nancy R Zhang ◽

Sean Hennessy ◽

...

Keyword(s):

Coronary Artery Disease ◽

Particle Size ◽

Coronary Artery ◽

Protective Effect ◽

Mendelian Randomization ◽

Causal Effect ◽

Particle Diameter ◽

Lipoprotein Subfractions ◽

Artery Disease

Recent genetic data can offer important insights into the roles of lipoprotein subfractions and particle sizes in preventing coronary artery disease (CAD), as previous observational studies have often reported conflicting results. We used the LD score regression to estimate the genetic correlation of 77 subfraction traits with traditional lipid profile and identified 27 traits that may represent distinct genetic mechanisms. We then used Mendelian randomization (MR) to estimate the causal effect of these traits on the risk of CAD. In univariable MR, the concentration and content of medium high-density lipoprotein (HDL) particles showed a protective effect against CAD. The effect was not attenuated in multivariable analyses. Multivariable MR analyses also found that small HDL particles and smaller mean HDL particle diameter may have a protective effect. We identified four genetic markers for HDL particle size and CAD. Further investigations are needed to fully understand the role of HDL particle size.

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Comparative Study of Risk Factors Among the Male and Female Patients with Acute Myocardial Infarction Admitted in CCU of Sahid Gangalal National Heart Centre

Nepalese Heart Journal ◽

10.3126/njh.v6i1.18446 ◽

2017 ◽

Vol 6 (1) ◽

pp. 4-7

Author(s):

Roshan Raut ◽

Man Bahadur K C ◽

Deewakar Sharma ◽

Sujeeb Rajbhandari ◽

Sajan Gopal Baidhya ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Total Cholesterol ◽

High Total Cholesterol ◽

Male And Female ◽

Low Hdl ◽

Male Patients ◽

Artery Disease ◽

Cad Risk

The role of major cardiovascular risk factors in the development of coronary artery disease (CAD) is well established and is fairly similar in both sexes. However, CAD is markedly more common in male than in female, and this is due to more risk factors, especially smoking and dyslipidemia, in male. In this study, we aim to investigate the five major risk factors as defined by ACC-AHA namely, advancing age, smoking, hypertension, diabetes and dyslipidemia, in the MI patients admitted in CCU, SGNHC from Jan 1 to June 30th 2008 and to compare whether the association of those risk factors with CAD risk is similar in male and female. There were altogether 283 MI patients, Male 208 (73%) and Female 75 (27%). Advancing age was the most common comprising 85.2% followed by smoking 55.5%, Hypertension 48.1%, Dyslipidemia 47% and Diabetes 24.7%. Smoking, dyslipidemia and advancing age were significantly more common in male. Male patients have significantly more risk factors than female. There was trend towards the greater number of high total cholesterol and low HDL in male patients. Advancing age (Male 45 yrs, Female 55 yrs) is the commonest risk factor of CAD. Smoking and dyslipidemia (especially high total cholesterol and low HDL) are significantly more common in male which might have contributed markedly to the excess CAD risk in males.

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The role of lipoprotein subfractions in coronary artery disease: A Mendelian randomization study

10.1101/691089 ◽

2019 ◽

Cited By ~ 2

Author(s):

Qingyuan Zhao ◽

Jingshu Wang ◽

Zhen Miao ◽

Nancy Zhang ◽

Sean Hennessy ◽

...

Keyword(s):

Coronary Artery Disease ◽

Particle Size ◽

Coronary Artery ◽

Mendelian Randomization ◽

Lipoprotein Subfractions ◽

Heterogeneous Effects ◽

Artery Disease ◽

Study Designs ◽

Conventional Study

AbstractLipoprotein subfractions and particle sizes are increasingly used in observational studies to predict the risk of cardiovascular diseases. However, the causal role of the different subfractions remain largely uncertain because the conventional study designs are subject to unmeasured confounding. We used Mendelian randomization and public GWAS summary data to estimate the effect of 82 lipoprotein subfraction and particle size traits on the occurrence of coronary artery disease and myocardial infarction. We found that, unlike LDL and VLDL subfractions, HDL subfraction traits appear to have heterogeneous effects on coronary artery disease according to particle size. The concentration of medium HDL particles may have a protective effect on coronary artery disease that is independent of traditional lipid factors.

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Prevalence, Epidemiological Characteristics, and Pharmacotherapy of Coronary Artery Disease among Patients with Atrial Fibrillation: Data from Jo-Fib Study

Medicina ◽

10.3390/medicina57060605 ◽

2021 ◽

Vol 57 (6) ◽

pp. 605

Author(s):

Hanna K. Al-Makhamreh ◽

Mohammed Q. Al-Sabbagh ◽

Ala’ E. Shaban ◽

Abdelrahman F. Obiedat ◽

Ayman J. Hammoudeh

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Antiplatelet Agents ◽

Retrospective Case ◽

Increased Risk ◽

Artery Disease ◽

Epidemiological Characteristics ◽

Cad Risk

Background and Objectives: Patients with AF are at increased risk for Coronary Artery Disease (CAD) owing to their shared etiologies and risk factors. This study aimed to assess the prevalence, cardiovascular risk factors, and used medications of CAD in AF patients. Materials and Methods: This retrospective, case-control study utilized data from the Jordanian Atrial Fibrillation (Jo-Fib) registry. Investigators collected clinical features, history of co-existing comorbidities, CHA2DS2-VASc, and HAS BLED scores for all AF patients aged >18 visiting 19 hospitals and 30 outpatient cardiology clinics. A multivariable binary logistic regression was used to asses for factors associated with higher odds of having CAD. Results: Out of 2000 patients with AF, 227 (11.35%) had CAD. Compared to the rest of the sample, those with CAD had significantly higher prevalence of hypertension (82.38%; p < 0.01), hypercholesterolemia (66.52%, p < 0.01), diabetes (56.83%, p < 0.01), and smoking (18.06%, p = 0.04). Patients with AF and CAD had higher use of anticoagulants/antiplatelet agents combination (p < 0.01) compared to the rest of the sample. Females had lower CAD risk than males (OR = 0.35, 95% CI: 0.24–0.50). AF Patients with dyslipidemia (OR = 2.5, 95% CI: 1.8–3.4), smoking (OR = 1.7, 95% CI: 1.1–2.6), higher CHA2DS2-VASc score (OR = 1.5, 95% CI: 1.4–1.7), and asymptomatic AF (OR = 1.9, 95% CI: 1.3–2.6) had higher risk for CAD. Conclusions: Owing to the increased prevalence of CAD in patients with AF, better control of cardiac risk factors is recommended for this special group. Future studies should investigate such interesting relationships to stratify CAD risk in AF patients. We believe that this study adds valuable information regarding the prevalence, epidemiological characteristics, and pharmacotherapy of CAD in patients with AF.

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Causal role of L-glutamine in sickle cell disease painful crises: a Mendelian randomization analysis

10.1101/872358 ◽

2019 ◽

Author(s):

Yann Iboudo ◽

Melanie E. Garrett ◽

Pablo Bartolucci ◽

Carlo Brugnara ◽

Clary B. Clish ◽

...

Keyword(s):

Sickle Cell Disease ◽

Small Molecules ◽

Causal Relationship ◽

Sickle Cell ◽

Drug Targets ◽

Mendelian Randomization ◽

Cell Disease ◽

Aseptic Necrosis ◽

Randomization Analysis

ABSTRACTIn a recent clinical trial, the metabolite L-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To confirm this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a causal relationship between L-glutamine levels and painful crises (N=1,278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52 – 0.89], P=0.0048). In two smaller SCD cohorts (N=299 and 406), the protective effect of L-glutamine was observed (OR=0.82 [0.50-1.34]), although the MR result was not significant (P=0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid was associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

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Comparative evaluation of coronary disease burden: bicuspid valve disease is not atheroprotective

Open Heart ◽

10.1136/openhrt-2021-001772 ◽

2021 ◽

Vol 8 (2) ◽

pp. e001772

Author(s):

Onur Baris Dolmaci ◽

Antoine H G Driessen ◽

Robert J M Klautz ◽

Robert Poelmann ◽

Jan H N Lindeman ◽

...

Keyword(s):

Risk Factors ◽

Aortic Valve ◽

General Population ◽

Disease Burden ◽

Atherosclerotic Disease ◽

Disease Spectrum ◽

Age Cohort ◽

Artery Disease ◽

General Populations ◽

Cad Risk

ObjectiveBicuspid aortic valve (BAV) has been associated with less atherosclerosis as compared with tricuspid aortic valve (TAV) patients. It, however, remains unclear whether this reflects the older age of TAV patients and/or accumulation of atherosclerotic risk factors or that the BAV phenotype is atheroprotective. Therefore, we compared the atherosclerotic disease burden of BAV and TAV patients, with that of the general (age-matched) population.MethodsThe prevalence of coronary artery disease (CAD) and CAD risk factors in BAV and TAV patients who underwent aortic valve surgery were compared with the Dutch general practitioners registry data. BAV (n=454) and TAV (n=1101) patients were divided into four groups: BAV with aortic valve stenosis (BAV-AoS), BAV with aortic valve regurgitation (BAV-AR), TAV with AoS (TAV-AoS) and TAV with AR (TAV-AR). The atherosclerotic disease burden of each group was compared with that of the corresponding age cohort for the general population.ResultsCAD risk factors hypertension and hypercholesterolaemia were more prevalent in the surgery groups than the age-matched general population (all p<0.001). All BAVs (BAV-AoS and BAV-AR) and TAV-AR had a similar incidence of CAD history as compared to the age-matched general populations (p=0.689, p=0.325 and p=0.617 respectively), whereas TAV-AoS had a higher incidence (21.6% versus 14.9% in the age-matched general population, p<0.001).ConclusionsStenotic TAV disease is part of the atherosclerotic disease spectrum, while regurgitant TAV and all BAVs are not. Although the prevalence of cardiovascular risk factors is higher in all BAV patients, the prevalence of CAD is similar to the general population.

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APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups

Lipids in Health and Disease ◽

10.1186/s12944-021-01531-8 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Shiwali Goyal ◽

Yosuke Tanigawa ◽

Weihua Zhang ◽

Jin-Fang Chai ◽

Marcio Almeida ◽

...

Keyword(s):

Coronary Artery Disease ◽

Genetic Variation ◽

Coronary Artery ◽

American Indians ◽

Asian Indians ◽

Small Subset ◽

Serum Triglycerides ◽

Artery Disease ◽

Cad Risk

Abstract Background Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. Methods We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. Results One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10− 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). Conclusions Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

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Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes

Wellcome Open Research ◽

10.12688/wellcomeopenres.15334.2 ◽

2019 ◽

Vol 4 ◽

pp. 113 ◽

Cited By ~ 12

Author(s):

Venexia M Walker ◽

Neil M Davies ◽

Gibran Hemani ◽

Jie Zheng ◽

Philip C Haycock ◽

...

Keyword(s):

Risk Factors ◽

Web Application ◽

Drug Targets ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

R Package ◽

Sensitivity Analyses ◽

Link Type ◽

Study Results

Mendelian randomization (MR) estimates the causal effect of exposures on outcomes by exploiting genetic variation to address confounding and reverse causation. This method has a broad range of applications, including investigating risk factors and appraising potential targets for intervention. MR-Base has become established as a freely accessible, online platform, which combines a database of complete genome-wide association study results with an interface for performing Mendelian randomization and sensitivity analyses. This allows the user to explore millions of potentially causal associations. MR-Base is available as a web application or as an R package. The technical aspects of the tool have previously been documented in the literature. The present article is complementary to this as it focuses on the applied aspects. Specifically, we describe how MR-Base can be used in several ways, including to perform novel causal analyses, replicate results and enable transparency, amongst others. We also present three use cases, which demonstrate important applications of Mendelian randomization and highlight the benefits of using MR-Base for these types of analyses.

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