Coagulation factors and the incidence of COVID-19 severity: Mendelian randomization analyses and supporting evidence.
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ABSTRACT:
SUBMITTER: Zhou Y
PROVIDER: S-EPMC8181534 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Coagulation factors and the incidence of COVID-19 severity: Mendelian randomization analyses and supporting evidence.
Zhou Yao Y Qian Xinyi X Liu Zipeng Z Yang Hongxi H Liu Tong T Chen Kexin K Wang Yaogang Y Sham Pak Chung PC Yu Ying Y Li Mulin Jun MJ
Signal transduction and targeted therapy 20210607 1
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Project description:BackgroundEpidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses.Methods and findingsWe selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10-8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10-5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10-5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null.ConclusionsIn this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.
| S-EPMC7971850 | biostudies-literature
Project description:BackgroundEndometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6-10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis.MethodsTo investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF, ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran's Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis.ResultsOur two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of ADAMTS13 and vWF on different sub-phenotypes of endometrioses.ConclusionsOur MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.
| S-EPMC10210381 | biostudies-literature
Project description:Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown. Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses. Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19-0.74, P: 4.77E-03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses. Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.
| S-EPMC8656944 | biostudies-literature
Project description:BackgroundThe severe acute respiratory syndrome coronavirus in 2019 (COVID-19) is still spreading and causing deaths worldwide, which further increased the burden of chronic diseases. Dyslipidemia is a common metabolic syndrome, which is a major risk factor for cardiovascular disease. However, studies on whether there is a direct causal relationship between COVID-19 and the exacerbation of hyperlipidemia are still scarce.MethodsTwo-sample Mendelian randomization was conducted using publicly available summary statistics from independent cohorts of European ancestry. For COVID-19 and hyperlipidemia, we used data from the ieu open GWAS project database. Inverse variance-weighted, mendelian randomization Egger, weighted median, simple mode, and weighted mode mendelian randomization analyses were performed, together with a range of sensitivity analyses.ResultsThere is no direct causal relationship between COVID-19 and dyslipidemia, regardless of COVID-19 severity or either dyslipidemic outcome. In combination with previous studies, the reason for the clinical outcome that COVID-19 increased the burden of dyslipidemia may be due to the exacerbation of pre-existing disease caused by COVID-19.ConclusionsCOVID-19 has no direct causal relationship with dyslipidemia.
| S-EPMC10560011 | biostudies-literature
Project description:The objective of this study was to investigate the potential causal relationship between coagulation factors and autoimmune diseases (ADs). We employed Mendelian randomization to investigate the associations between selected 7 coagulation factors and 10 ADs, leveraging genetic variants as instrumental variables to assess causal relationships between exposures of interest and outcomes. Within the scope of this investigation, coagulation factors were designated as the exposure source, while ADs were observed to manifest as the consequent outcome. Our analysis using the inverse-variance weighted (IVW) method revealed that Factor VIII (FVIII) (P = .0067) exhibited significant causal associations with a reduced risk of multiple sclerosis. In contrast, fibrinogen (P = .0004) was associated with an increased risk of multiple sclerosis. The analysis also indicated that activated partial thromboplastin time (P = .0047) was implicated in elevating the risk of urticaria. The results also showed that protein C (P = .0188) was inversely associated with the risk of systemic lupus erythematosus. The results unveiled a significant positive correlation between fibrinogen (P = .0318) and the risk of rheumatoid arthritis. Similarly, Factor VII (P = .0119), FVIII (P = .0141), and von Willebrand Factor (P = .0494) were also found to be positively associated with the risk of inflammatory bowel disease. The IVW analysis demonstrated a causal relationship between von Willebrand Factor (P = .0316) and FVIII (P = .0408) and a decreased risk of primary sclerosing cholangitis. IVW results confirmed that protein C (P = .0409) had a protective effect on vitiligo. No significant associations were found between psoriatic arthritis, rosacea, and the 7 coagulation factors in this study. This is of significant importance for advancing the prevention, diagnosis, and treatment of ADs.
| S-EPMC11688059 | biostudies-literature
Project description: Not available
| S-EPMC5992499 | biostudies-literature
Project description:Background We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases. Methods and Results Genetic instruments proxying coagulation factor inhibition were identified from genome-wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age- and sex-adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (P≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large-artery stroke risk (P=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (P<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage. Conclusions This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.
| S-EPMC8174173 | biostudies-literature
Project description:BackgroundThe causal relationship between homocysteine (Hcy) levels and chronic kidney disease (CKD) remains unclear. This study was performed to estimate the potential causal effects of Hcy on the estimated glomerular filtration rate (eGFR) and CKD.Materials and methodsThe single nucleotide polymorphisms (SNPs) associated with one standard deviation (SD) Hcy increase were identified using the genome-wide association study (GWAS). The summary statistics of the eGFR and CKD were from the CKDGen project in the European ancestry and the Population Architecture using Genomics and Epidemiology (PAGE) project in the non-European ancestry. Two-sample Mendelian randomization (MR) analyses were used in this study to verify the causal effects among Hcy, eGFR, and CKD.ResultsThe results showed that 1-SD Hcy increase was causally associated with eGFR decline in the CKDGen project (β = -0.027 log ml.min-1/1.73 m2, p < 0.01 for the overall cohort; β = -0.028 log ml.min-1/1.73 m2, p < 0.01 after excluding the patients with diabetes). In addition, 1-SD Hcy increase was associated with a 1.32-fold risk of CKD in the PAGE project (95% CI = 1.06-1.64, p < 0.05). The association was directionally similar in the CKDGen project [odds ratio (OR) = 1.08, 95% CI = 0.97-1.44, p = 0.098]. The pooled OR of CKD was 1.24 (95% CI = 1.07-1.44, p < 0.05) per 1-SD Hcy increase.ConclusionUsing genetic data, Hcy increase is causally associated with renal function injury and further CKD.
| S-EPMC9048023 | biostudies-literature
Project description:The protection of physical activity (PA) against COVID-19 is a rising research interest. However, the role of physical activity intensity on this topic is yet unclear. To bridge the gap, we performed a Mendelian randomization (MR) study to verify the causal influence of light and moderate-to-vigorous PA on COVID-19 susceptibility, hospitalization, and severity. The Genome-Wide Association Study (GWAS) dataset of PA (n = 88,411) was obtained from the UK biobank and the datasets of COVID-19 susceptibility (n = 1,683,768), hospitalization (n = 1,887,658), and severity (n = 1,161,073) were extracted from the COVID-19 Host Genetics Initiative. A random-effect inverse variance weighted (IVW) model was carried out to estimate the potential causal effects. A Bonferroni correction was used for counteracting. The problem of multiple comparisons. MR-Egger test, MR-PRESSO test, Cochran's Q statistic, and Leave-One-Out (LOO) were used as sensitive analysis tools. Eventually, we found that light PA significantly reduced the risk of COVID-19 infection (OR = 0.644, 95% CI: 0.480-0.864, p = 0.003). Suggestive evidence indicated that light PA reduced the risks of COVID-19 hospitalization (OR = 0.446, 95% CI: 0.227 to 0.879, p = 0.020) and severe complications (OR = 0.406, 95% CI: 0.167-0.446, p = 0.046). By comparison, the effects of moderate-to-vigorous PA on the three COVID-19 outcomes were all non-significant. Generally, our findings may offer evidence for prescribing personalized prevention and treatment programs. Limited by the available datasets and the quality of evidence, further research is warranted to re-examine the effects of light PA on COVID-19 when new GWAS datasets emerge.
| S-EPMC10030504 | biostudies-literature
Project description:Emerging evidence supports a link between environmental factors-including air pollution and chemical exposures, climate, and the built environment-and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and coronavirus disease 2019 (COVID-19) susceptibility and severity. Climate, air pollution, and the built environment have long been recognized to influence viral respiratory infections, and studies have established similar associations with COVID-19 outcomes. More limited evidence links chemical exposures to COVID-19. Environmental factors were found to influence COVID-19 through four major interlinking mechanisms: increased risk of preexisting conditions associated with disease severity; immune system impairment; viral survival and transport; and behaviors that increase viral exposure. Both data and methodologic issues complicate the investigation of these relationships, including reliance on coarse COVID-19 surveillance data; gaps in mechanistic studies; and the predominance of ecological designs. We evaluate the strength of evidence for environment-COVID-19 relationships and discuss environmental actions that might simultaneously address the COVID-19 pandemic, environmental determinants of health, and health disparities.
| S-EPMC10044492 | biostudies-literature