Mendelian Randomization Analysis of Hemostatic Factors and Their Contribution to Peripheral Artery Disease-Brief Report.
Ontology highlight
ABSTRACT: Background and objective
Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. We evaluated the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23-1.62], P=6.0×10-7, VWF: odds ratio, 1.28 [95% CI, 1.07-1.52], P=0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF.Conclusions
Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.
SUBMITTER: Small AM
PROVIDER: S-EPMC7785109 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundMultiple clinical studies have found a significant correlation between elevated galectin-3 (Gal-3) in circulation and the diagnosis and severity of peripheral arterial disease (PAD). The current study used the Mendelian randomization (MR) technique to evaluate the possible causal relationship between Gal-3 and PAD.MethodsGenome-wide association study (GWAS) data of Gal-3 and PAD were obtained through the MR-Base platform. Then, using Gal-3 as the exposure and PAD as the outcome, a two-sample MR analysis was performed utilizing several regression techniques, including MR-Egger regression, inverse variance weighted (IVW), weighted median, and weighted mode.ResultsSix single-nucleotide polymorphisms (SNPs) were identified and designated as instrumental variables (IVs) that exhibited significant correlations with Gal-3 (linkage disequilibrium r2 < 0.001; P < 5 × 10-8). Various statistical methods showed that there was an absence of a significant link between Gal-3 and PAD (IVW: odds ratio (OR) = 0.9869, 95% confidence interval (CI) = 0.8792-1.1078, P = 0.8232). In addition, the presence of genetic pleiotropy did impact the putative causal relationship between PAD and Gal-3 (MR-Egger intercept = 0.0099, P = 0.659).ConclusionsThere is no current evidence to establish a causal relationship between the level of Gal-3 in circulation and PAD.
| S-EPMC10794734 | biostudies-literature
Project description:Background We investigated the causal associations between the genetic liability to cardiovascular and lifestyle risk factors and peripheral artery disease (PAD), using a Mendelian randomization approach. Methods and Results We performed a 2-sample inverse-variance weighted Mendelian randomization analysis, multiple sensitivity analyses to assess pleiotropy and multivariate Mendelian randomization analyses to assess mediating/confounding factors. European-ancestry genomic summary data (P<5×10-8) for type 2 diabetes, lipid-fractions, smoking, alcohol and coffee consumption, physical activity, sleep, and education level were selected. Genetic associations with PAD were extracted from the Million-Veteran-Program genome-wide association studies (cases=31 307, controls=211 753, 72% European-ancestry) and the GoLEAD-SUMMIT genome-wide association studies (11 independent genome-wide association studies, European-ancestry, cases=12 086, controls=449 548). Associations were categorized as robust (Bonferroni-significant (P<0.00294), consistent over PAD-cohorts/sensitivity analyses), suggestive (P value: 0.00294-0.05, associations in 1 PAD-cohort/inconsistent sensitivity analyses) or not present. Robust evidence for genetic liability to type 2 diabetes, smoking, insomnia, and inverse associations for higher education level with PAD were found. Suggestive evidence for the genetic liability to higher low-density lipoprotein cholesterol, triglyceride-levels, alcohol consumption, and inverse associations for high-density lipoprotein cholesterol, and increased sleep duration were found. No associations were found for physical activity and coffee consumption. However, effects fully attenuated for low-density lipoprotein cholesterol and triglycerides after correcting for apoB, and for insomnia after correcting for body mass index and lipid-fractions. Nonsignificant attenuation by potential mediators was observed for education level and type 2 diabetes. Conclusions Detrimental effects of smoking and type 2 diabetes, but not of low-density lipoprotein cholesterol and triglycerides, on PAD were confirmed. Lower education level and insomnia were identified as novel risk factors for PAD; however, complete mediation for insomnia and incomplete mediation for education level by downstream risk factors was observed.
| S-EPMC9496309 | biostudies-literature
Project description:IntroductionThe relationship between gut microbiota and peripheral artery disease (PAD) remains understudied. While traditional risk factors like smoking and hyperlipidemia are well-understood, our study aims to determine the potential causative association of gut microbiota with PAD using Mendelian Randomization.MethodsData from the International MiBioGen Consortium and the FinnGen research project were used to study 211 bacterial taxa. Instrumental variables, comprising 2079 SNPs, were selected based on significance levels and linkage disequilibrium. Analyses were conducted utilizing the inverse-variance weighted (IVW) method and other statistical MR techniques to mitigate biases, processed in R (v4.3.1) with the TwosampleMR package.ResultsThree bacterial taxa, namely genus Coprococcus2, RuminococcaceaeUCG004, and RuminococcaceaeUCG010, emerged as protective factors against PAD. In contrast, family. FamilyXI and the genus Lachnoclostridium and LachnospiraceaeUCG001 were identified as risk factors.ConclusionOur findings hint at a causative association between certain gut microbiota and PAD, introducing new avenues for understanding PAD's etiology and developing effective treatments. The observed associations now warrant further validation in varied populations and detailed exploration at finer taxonomic levels.
| S-EPMC10948605 | biostudies-literature
Project description:Selecting a set of valid genetic variants is critical for Mendelian randomization (MR) to correctly infer risk factors causing a disease. We here developed a method for selecting genetic variants as valid instrumental variables for inferring risk factors causing coronary artery disease (CAD). Using this method, we selected two sets of single-nucleotide-polymorphism (SNP) genetic variants (SNP338 and SNP363) associated with each of the three potential risk factors for CAD including low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and triglycerides (TG) from two independent GWAS datasets. We performed in-depth multivariate MR (MVMR) analyses and the results from both datasets consistently showed that LDL-c was strongly associated with increased risk for CAD (? = 0.396,OR = 1.486 per 1?SD (equivalent to 38?mg/dL), 95CI = (1.38, 1.59) in SNP338; and ? = 0.424, OR = 1.528 per 1?SD, 95%CI = (1.42, 1.65) in SNP363); HDL-c was strongly associated with reduced risk for CAD (? = -0.315, OR = 0.729 per 1?SD (equivalent to 16?mg/dL), 95CI = (0.68, 0.78) in SNP338; and ? = -0.319, OR = 0.726 per 1?SD, 95%CI = (0.66, 0.80), in SNP363). In case of TG, when using the full datasets, an increased risk for CAD (? = 0.184, OR = 1.2 per 1?SD (equivalent to 89?mg/dL), 95%CI = (1.12, 1.28) in SNPP338; and ? = 0.207, OR = 1.222 per 1?SD, 95%CI = (1.10, 1.36) in SNP363) was observed, while using partial datasets that contain shared and unique SNPs showed that TG is not a risk factor for CAD. From these results, it can be inferred that TG itself is not a causal risk factor for CAD, but it's shown as a risk factor due to pleiotropic effects associated with LDL-c and HDL-c SNPs. Large-scale simulation experiments without pleiotropic effects also corroborated these results.
| S-EPMC7280530 | biostudies-literature
Project description:Abstract Aims Sleep duration has been associated with cardiovascular disease, however the effect of sleep on peripheral artery disease (PAD) specifically remains unestablished. We conducted observational and Mendelian randomization (MR) analyses to assess the associations of sleep duration and daytime napping with PAD risk. Methods and results Sleep traits were assessed for associations with incident PAD using cohort analysis among 53 416 Swedish adults. Replicated was sought in a case-control study of 28 123 PAD cases and 128 459 controls from the veterans affairs Million Veteran Program (MVP) and a cohort study of 452 028 individuals from the UK Biobank study (UKB). Two-sample Mendelian randomization (MR) was used for casual inference-based analyses of sleep-related traits and PAD (31 307 PAD cases 211 753 controls). Observational analyses demonstrated a U-shaped association between sleep duration and PAD risk. In Swedish adults, incident PAD risk was higher in those with short sleep [<5 h; hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.31–2.31] or long sleep (≥8 h; HR 1.24; 95% CI 1.08–1.43), compared to individuals with a sleep duration of 7 to <8 h/night. This finding was supported by the analyses in MVP and UKB. Observational analysis also revealed positive associations between daytime napping (HR 1.32, 95% CI 1.18–1.49) with PAD. MR analysis supported an inverse association between sleep duration [odds ratio (OR) per hour increase: 0.79, 95% CI, 0.55, 0.89] and PAD and an association between short sleep and increased PAD (OR 1.20, 95% CI, 1.04–1.38). Conclusion Short sleep duration was associated with an increased risk of PAD. Graphical Abstract Graphical Abstract Graphical summary of the main findings in this study. This figure was created using an image from Servier Medical Art (smart.servier.com). PWV, pulse wave velocity; WMH, white matter hyperintensity.
| S-EPMC10017627 | biostudies-literature
Project description:The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis < 50 years; OR 1.02 diagnosis > 70 years), blood pressure (OR 1.12 < 50 years; OR 1.04 > 70 years), LDL cholesterol (OR 1.16 < 50 years; OR 1.02 > 70 years), and triglyceride levels (OR 1.11 < 50 years; 1.04 > 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age.
| S-EPMC9213623 | biostudies-literature
Project description:ObjectiveTo assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.MethodsTwo-sample Mendelian randomization instrumental analyses leveraging available genome-wide association study (GWAS) summary statistics were applied to hemostatic measures as potentially causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO). Twelve blood-based measures of hemostasis were examined, including plasma level or activity of 8 hemostatic factors and 2 fibrinopeptides together with 2 hemostasis clinical tests.ResultsThere were significant instrumental effects between increased coagulation factor VIII activity (FVIII; odds ratio [95% confidence interval] 1.05 [1.03, 1.08]/SD, p = 6.08 × 10-05), von Willebrand factor level (vWF; 1.05 [1.03, 1.08]/SD, p = 2.25 × 10-06), and phosphorylated fibrinopeptide A level (1.13 [1.07, 1.19]/SD, p = 5.44 × 10-06) with migraine susceptibility. When extended to migraine subtypes, FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76 [0.64, 0.91]/SD, p = 2.32 × 10-03) but not overall migraine. None of the hemostatic factors was linked with MO. In sensitivity analysis, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, whereas independent effects of FVIII and vWF could not be distinguished, and FVIII associations were potentially affected by pleiotropy at the ABO locus. Causal effects from migraine to the hemostatic measures were not supported in reverse Mendelian randomization. However, MA was not included due to lack of instruments.ConclusionsThe findings support potential causality of increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.
| S-EPMC8205479 | biostudies-literature
Project description:Objective- It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results- Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry. PAD cases had a resting/postexercise ankle-brachial index ?0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ?5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO, and ZEB2 to be associated with PAD ( P<4.5×10-5). At the gene level, the strongest associations were for LPL and SH2B3. Conclusions- Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.
| S-EPMC6531315 | biostudies-literature
Project description:Lead is pervasive, although lead exposure has fallen in response to public health efforts. Observationally, lead is positively associated with cardiovascular disease and hypertension. We used separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) based on 13 single nucleotide polymorphisms (SNP), from a genome wide association study, strongly (p-value?<?5?×?10-6) and independently associated with blood lead. These SNPs were applied to a large extensively genotyped coronary artery disease (CAD) study (cases?=?<76014, controls?=?<264785) largely based on CARDIoGRAPMplusC4D 1000 Genomes and the UK Biobank SOFT CAD, to the UK Biobank (n?=?361,194) for blood pressure and to the DIAGRAM 1000 genomes diabetes case (n?=?26,676)-control (n?=?132,532) study. SNP-specific Wald estimates were combined using inverse variance weighting, MR-Egger and MR-PRESSO. Genetically instrumented blood lead was not associated with CAD (odds ratio (OR) 1.01 per effect size of log transformed blood lead, 95% confidence interval (CI) 0.97, 1.05), blood pressure (systolic -0.18?mmHg, 95% CI -0.44 to 0.08 and diastolic -0.03?mmHg, 95% CI -0.09 to 0.15) or diabetes (OR 0.98, 95% CI 0.92 to 1.03) using MR-PRESSO estimates corrected for an outlier SNP (rs550057) from the highly pleiotropic gene ABO. Exogenous lead may have different effects from endogenous lead; nevertheless, this study raises questions about the role of blood lead in CAD.
| S-EPMC6831655 | biostudies-literature
Project description:BackgroundPrevious observational studies have confirmed the relationship between inflammation and acute myocardial infarction (AMI), but genetic evidence is still lacking. The aim of this study was to explore the bidirectional association of multiple peripheral inflammatory factors with this disease at the genetic level.MethodsSummary data for AMI and several peripheral inflammatory factors (such as interleukin-10 and interleukin-18) were collected from published genome-wide correlation studies. Based on the correlation, independence, and exclusivity assumptions, a total of 9 to 110 instrumental variables were selected from these summary data to predict the above traits. Two-sample Mendelian randomization methods, including inverse-variance weighted (IVW), were used to make causal inferences between exposures and outcomes. Sensitivity analyses including Cochran's Q, MR-Egger intercept, leave-one-out, forest plot, and MR-PRESSO were adopted to assess heterogeneity and horizontal pleiotropy.ResultsThe IVW reported that elevated peripheral levels of interleukin-10 and interleukin-18 were nominally associated with a reduced risk of AMI (OR = 0.876, 95% CI = 0.788 ~ 0.974, P = 0.015; OR = 0.934, 95% CI = 0.875 ~ 0.997, P = 0.040). The IVW also reported that the risk of AMI nominally increased the peripheral level of interleukin-10 (OR = 1.062, 95% CI = 1.003 ~ 1.124, P = 0.040). No significant heterogeneity or horizontal pleiotropy were found by sensitivity analyses.ConclusionBoth interleukin-10 and interleukin-18 were peripheral inflammatory factors genetically associated with AMI. In particular, combined with previous knowledge, interleukin-10 may have a protective effect on the onset, progression, and prognosis of the disease.
| S-EPMC10558024 | biostudies-literature