Dataset Information

Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank.

ABSTRACT: Background Red blood cell (RBC) transfusion and erythropoiesis-stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome-wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best-fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance-weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05-1.41) with VTE. Sensitivity analyses (mendelian randomization-Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks.

SUBMITTER: Luo S

PROVIDER: S-EPMC7660720 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank.

Luo Shan S Au Yeung Shiu Lun SL Zuber Verena V Burgess Stephen S Schooling Catherine Mary CM

Journal of the American Heart Association 20200708 14

Background Red blood cell (RBC) transfusion and erythropoiesis-stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obta ...[more]

PMID: 32635790

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Project description:ObjectiveTo determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction.DesignTwo sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence.SettingReduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study.Participants3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation.Main outcome measuresThromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death.ResultsOf the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.ConclusionsEndogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.

Project description:Background Increasing incidences of both atrial fibrillation (AF) and cancer have been observed in recent years. However, the casual association of both serious conditions has been scarcely evaluated and is considered to be a blank slate in cardio-oncology. Thus, we introduced Mendelian randomization (MR) methods to estimate the effects of AF on cancer risks. Methods We performed univariable and multivariable two-sample MR analyses to evaluate the effects of AF on the risk of 19 site-specific types of cancer. This MR study was conducted based on 111 independent AF-associated genetic instruments from genome-wide association studies and summarized-level data from corresponding cancer consortia. Multiple sensitivity analyses, including the leave-one-out analysis, MR-Egger regression, and MR-PRESSO tests, were further performed to examine the potential directional pleiotropic effects. Functional annotation was performed for common differentially expressed genes of AF and prostate cancer (PCA). Results A total of 6,777,155 European-descent people, including 533,725 cases and 6,243,430 controls, were included in the present MR analysis. Univariable MR analyses demonstrated a causal effect of AF on the incidence of PCA [odds ratio (OR): 0.96; 95% confidence interval (CI) 0.92–0.99, p = 0.01], and the causal effect remained significant (OR: 0.65; 95% CI 0.47–0.90, p = 0.01) after adjusting for potential confounders through the multivariable MR approach. However, no casual associations between AF and the other 18 site-specific cancer risks were observed (all p-values were > 0.05). The consistency of outcomes across complementary sensitivity MR methods further supported the causality. The functional analysis emphasized the essential role of antioxidant and xenobiotic catabolic processes in AF and PCA. Conclusion Contrary to the findings of several previous observational studies, our comprehensive MR analyses did not corroborate a causal role for AF in increasing the risk of various types of cancer. They did, however, demonstrate that AF may decrease the risk of PCA. Studies from larger sample sizes and individuals with different ethnic backgrounds are required to further support our conclusions.

Project description:BackgroundHigh circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerosis and age-associated cardiovascular events. Long-term dyslipidaemia could contribute to the development of frailty in older individuals through its role in determining cardiovascular health and potentially other physiological pathways.MethodsWe conducted Mendelian randomization (MR) analyses using genetic variants to estimate the effects of long-term LDL-C modification on frailty in UK Biobank (n = 378,161). Frailty was derived from health questionnaire and interview responses at baseline when participants were aged 40 to 69 years, and calculated using an accumulation-of-deficits approach, i.e. the frailty index (FI). Several aggregated instrumental variables (IVs) using 50 and 274 genetic variants were constructed from independent single-nucleotide polymorphisms (SNPs) to instrument circulating LDL-C concentrations. Specific sets of variants in or near genes that encode six lipid-lowering drug targets (HMGCR, PCSK9, NPC1L1, APOB, APOC3, and LDLR) were used to index effects of exposure to related drug classes on frailty. SNP-LDL-C effects were available from previously published studies. SNP-FI effects were obtained using adjusted linear regression models. Two-sample MR analyses were performed with the IVs as instruments using inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. To address the stability of the findings, MR analyses were also performed using i) a modified FI excluding the cardiometabolic deficit items and ii) data from comparatively older individuals (aged ≥60 years) only. Several sensitivity analyses were also conducted.FindingsOn average 0.14% to 0.23% and 0.16% to 0.31% decrements in frailty were observed per standard deviation reduction in LDL-C exposure, instrumented by the general IVs consisting of 50 and 274 variants, respectively. Consistent, though less precise, associations were observed in the HMGCR-, APOC3-, NPC1L1-, and LDLR-specific IV analyses. In contrast, results for PCSK9 were in the same direction but more modest, and null for APOB. All sensitivity analyses produced similar findings.InterpretationA genetically-predicted life-long lowering of LDL-C is associated with decreased frailty in midlife and older age, representing supportive evidence for LDL-C's role in multiple health- and age-related pathways. The use of lipid-lowering therapeutics with varying mechanisms of action may differ by the extent to which they provide overall health benefits.

Project description:Background & aimsArachidonic acid (AA) is metabolized by cyclooxygenases and lipoxygenases to pro-inflammatory eicosanoids, which according to experimental research modulate tumor cell proliferation, differentiation, and apoptosis. We employed the Mendelian randomization design to test the hypothesis that higher plasma phospholipid AA concentrations are associated with increased risk of 10 site-specific cancers.MethodsTwo genetic variants associated with plasma phospholipid concentrations of AA (rs174547 in FADS1 [P = 3.0 × 10-971] and rs16966952 in PDXDC1 [P = 2.4 × 10-10]) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium were used as genetic instruments. The associations of those variants with cancer were taken from the UK Biobank (n = 367,643), FinnGen consortium (n = 135,638), International Lung Cancer Consortium (n = 27,209), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254), Breast Cancer Association Consortium (n = 228,951), Ovarian Cancer Association Consortium (n = 66,450), and BioBank Japan (n = 212,453).ResultsHigher genetically predicted plasma phospholipid AA concentrations were associated with increased risk of colorectal and lung cancer. Results were consistent across data sources and variants. The combined odds ratios per standard deviation increase of AA concentrations were 1.08 (95% CI 1.05-1.11; P = 6.3 × 10-8) for colorectal cancer and 1.07 (95%CI 1.05-1.10; P = 3.5 × 10-7) for lung cancer. Genetically predicted AA concentrations had a suggestive positive association with esophageal cancer (odds ratio 1.09; 95% CI 1.02-1.17; P = 0.016) but were not associated with cancers of the stomach, pancreas, bladder, prostate, breast, uterus, or ovary.ConclusionThese results indicate that AA may be implicated in the development of colorectal and lung cancer and possibly esophageal cancer. Treatments with plasma AA-lowering properties should be evaluated for clinical benefit.

Project description:Background: It is not clarified whether the elevation of adiponectin is the results of kidney damage, or the cause of kidney function injury. To explore the causal association of adiponectin on estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), this study was performed. Materials and methods: The genetic association of adiponectin were retrieved from one genome-wide association studies with 39,883 participants. The summary-level statistics regarding the eGFR (133,413 participants) and CKD (12,385 CKD cases and 104,780 controls) were retrieved from the CKDGen consortium in the European ancestry. Single-variable Mendelian randomization (MR), bilateral and multivariable MR analyses were used to verify the causal association between adiponectin, eGFR, and CKD. Results: Genetically predicted adiponectin reduces the risk of CKD (OR = 0.71, 95% CI = 0.57-0.89, p = 0.002) and increases the eGFR (β = 0.014, 95% CI = 0.001-0.026, p = 0.034) by the inverse variance weighting (IVW) estimator. These findings remain consistent in the sensitivity analyses. No heterogeneity and pleiotropy were detected in this study (P for MR-Egger 0.617, P for global test > 0.05, and P for Cochran's Q statistics = 0.617). The bilateral MR identified no causal association of CKD on adiponectin (OR = 1.01, 95% CI = 0.96-1.07, p = 0.658), nor did it support the association of eGFR on adiponectin (OR = 0.86, 95% CI = 0.68-1.09, p = 0.207) by the IVW estimator. All the sensitivity analyses reported similar findings (p > 0.05). Additionally, after adjusting for cigarette consumption, alcohol consumption, body mass index, low density lipoprotein, and total cholesterol, the ORs for CKD are 0.70 (95% CI = 0.55-0.90, p = 0.005), 0.75 (95% CI = 0.58-0.97, p = 0.027), 0.82 (95% CI = 0.68-0.99, p = 0.039), 0.74 (95% CI = 0.59-0.93, p = 0.011), and 0.79 (95% CI = 0.61-0.95, p = 0.018), respectively. Conclusion: Using genetic data, this study provides novel causal evidence that adiponectin can protect the kidney function and further reduce the risk of CKD.

Dataset Information

Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank.

Publications

Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank.

Similar Datasets

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