Genetically Predicted Pulse Pressure and Risk of Abdominal Aortic Aneurysm: A Mendelian Randomization Analysis.
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ABSTRACT:
SUBMITTER: Burgess S
PROVIDER: S-EPMC9213080 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Genetically Predicted Pulse Pressure and Risk of Abdominal Aortic Aneurysm: A Mendelian Randomization Analysis.
Burgess Stephen S Chirinos Julio A JA Damrauer Scott M SM Gill Dipender D
Circulation. Genomic and precision medicine 20220506 3
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Project description:Background Elevated blood pressure is a major cause of cardiovascular morbidity and mortality. However, it is not known whether midlife blood pressure affects later life cardiovascular risk independent of later life blood pressure. Methods and Results Using genetic association estimates from the UK Biobank and CARDIoGRAMplusC4D consortium, univariable mendelian randomization was performed to investigate the total effect of genetically predicted mean arterial pressure (MAP) at age ≤55 years on coronary artery disease (CAD) risk, and multivariable mendelian randomization was performed to investigate the effect of genetically predicted MAP on CAD risk after adjusting for genetically predicted MAP at age >55 years. In both univariable and multivariable mendelian randomization analyses, there was consistent evidence of higher genetically predicted MAP at age ≤55 years increasing CAD risk. This association persisted after adjusting for genetically predicted MAP at age >55 years, when considering nonoverlapping populations for the derivation of MAP and CAD risk genetic association estimates, when investigating only incident CAD events after age >55 years, and when restricting the analysis to variants with most heterogeneity in their associations with MAP ≤55 and >55 years. For a 10-mm Hg increase in genetically predicted MAP at age ≤55 years, the odds ratio of later life CAD was 1.43 (95% CI, 1.16-1.77; P=0.001) after adjusting for genetically predicted MAP at age >55 years. Conclusions These mendelian randomization findings support a cumulative lifetime effect of elevated blood pressure on increasing CAD risk. Clinical and public health efforts toward cardiovascular disease reduction should optimize blood pressure control throughout life.
| S-EPMC7660704 | biostudies-literature
Project description: Not available
| S-EPMC6213834 | biostudies-literature
Project description:Studies have reported that higher circulating levels of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and lower of high-density lipoprotein (HDL) cholesterol may be associated with increased risk of abdominal aortic aneurysm (AAA). Whether dyslipidemia causes AAA is still unclear and is potentially testable using a Mendelian randomization (MR) approach. We investigated the associations between blood lipids and AAA using two-sample MR analysis with SNP-lipids association estimates from a published genome-wide association study of blood lipids (n = 188,577) and SNP-AAA association estimates from European Americans (EAs) of the Atherosclerosis Risk in Communities (ARIC) study (n = 8,793). We used inverse variance weighted (IVW) MR as the primary method and MR-Egger regression and weighted median MR estimation as sensitivity analyses. Over a median of 22.7 years of follow-up, 338 of 8,793 ARIC participants experienced incident clinical AAA. Using the IVW method, we observed positive associations of plasma LDL cholesterol and TC with the risk of AAA (odds ratio (OR) = 1.55, P = 0.02 for LDL cholesterol and OR = 1.61, P = 0.01 for TC per 1 standard deviation of lipid increment). Using the MR-Egger regression and weighted median methods, we were able to validate the association of AAA risk with TC, although the associations were less consistent for LDL cholesterol due to wider confidence intervals. Triglycerides and HDL cholesterol were not associated with AAA in any of the MR methods. Assuming instrumental variable assumptions are satisfied, our finding suggests that higher plasma TC and LDL cholesterol are causally associated with the increased risk of AAA in EAs.
| S-EPMC5896990 | biostudies-literature
Project description:BackgroundBasal metabolic rate (BMR) is the minimum amount of energy needed by the body to carry out essential physiological functions. The goal of this study was to evaluate whether BMR causally influences venous thromboembolism (VTE) and its subtypes in European individuals.MethodsA two-sample Mendelian randomization (MR) was performed. Within a genome-wide association study (GWAS) involving 454,874 people, genetic variants were chosen as instrumental variables based on their significant associations (p < 5 × 10-8) with BMR and their limited linkage disequilibrium (r2 < 0.001). The FinnGen project served as sources for summary statistics of VTE, encompassing different subtypes.ResultsUsing the multiplicative random-effect inverse variance weighted method, our investigation revealed that one standard deviation higher BMR was associated with VTE (odds ratio [OR] = 1.684, 95% confidence interval [CI]: 1.465-1.936, p = 2.339 × 10-13), PE (OR = 1.824, 95% CI: 1.512-2.200, p = 3.399 × 10-10), and DVT of lower extremities (OR = 1.887, 95% CI: 1.562-2.280, p = 4.778 × 10-11). The consistency of these associations was observed in sensitivity analyses using various MR techniques like Mendelian randomization pleiotropy residual sum and outlier, MR-Egger, weighted median, and contamination mixture method. In addition, multivariable MR revealed direct effects of BMR on VTE and its subtypes when taking body mass index and current tobacco smoking into account.ConclusionHigher BMR may increase the risk of VTE and its subtypes including PE and DVT of lower extremities.
| S-EPMC10768029 | biostudies-literature
Project description:ImportanceInsomnia has been associated with altered inflammatory response as well as increased risk of infections and sepsis in observational studies. However, these studies are prone to bias, such as residual confounding. To further understand the potential causal association between insomnia and sepsis risk, a 2-sample Mendelian randomization (MR) approach should be explored.ObjectiveTo evaluate whether genetically predicted insomnia is associated with risk of sepsis.Design, setting, and participantsTwo-sample MR was performed to estimate the association between genetically predicted insomnia and sepsis risk. Data were obtained from a genome-wide association study identifying 555 independent genetic variants (R2 < 0.01) strongly associated with insomnia (P < 5 × 10-8). Sensitivity analyses were conducted to address bias due to pleiotropy and sample overlap, along with mediation analyses and sex-stratified analyses. The insomnia data set included 2.4 million individuals of European ancestry from the UK Biobank and 23andMe. For sepsis, 462 918 individuals of European ancestry from the UK Biobank were included. Data were extracted between February and December 2022 and analyzed between March 2022 and March 2023.ExposureGenetically predicted insomnia.Main outcome and measureSepsis.ResultsThere were 593 724 individuals with insomnia and 10 154 cases of sepsis. A doubling in the population prevalence of genetically predicted insomnia was associated with an odds ratio of 1.37 (95% CI, 1.19-1.57; P = 7.6 × 10-6) for sepsis. Sensitivity analyses supported this observation. One-third of the association between genetically predicted insomnia and risk of sepsis was mediated through a combination of cardiometabolic risk factors for sepsis (body mass index, type 2 diabetes, smoking, or cardiovascular disease; overall proportion, 35.2%; 95% CI, 5.1-76.9). The association between insomnia and sepsis was more pronounced among women compared with men (women: odds ratio, 1.44; 95% CI, 1.24-1.68; men: OR, 1.10; 95% CI, 0.86-1.40).Conclusions and relevanceThe concordance between these findings and previous observational studies supports that insomnia is potentially causally associated with the risk of sepsis. Thus, insomnia is a potential preventable risk factor of sepsis that should be further investigated, also in non-European populations.
| S-EPMC10413214 | biostudies-literature
Project description:BackgroundThe causal relationship between vitamins supplementation and the risk of skin cancers remains unclear. We conducted a Mendelian randomization study to assess the associations between vitamins supplementation and skin cancers in the general population.ObjectiveWe aimed to investigate the causal relationship of vitamins (A-E) supplementation with skin cancers using and utilizing the linkage disequilibrium score regression (LDSC) Mendelian randomization (MR).Materials and methodsWe selected genome-wide significant single-nucleotide polymorphisms (SNPs) linked to vitamin supplements (A-E). Summary-level data for melanoma, basal cell carcinoma, and squamous cell carcinoma were obtained from large-scale genome-wide association studies. We applied the inverse-variance weighted (IVW) method within a random effects model, alongside weighted median, MR-Egger, simple median, sensitivity analyses, and MRlap methods to ensure robustness. A meta-analysis was conducted to assess the causal relationship between vitamins supplementation and melanoma. The STROBE-MR checklist was followed throughout.ResultsFolate supplementation was associated with a reduced melanoma risk (IVW OR = 0.88; 95% CI 0.80-0.96; P = 0.006). The MR analysis indicated a significant inverse causal relationship. Heterogeneity and sensitivity analyses confirmed minimal impact from individual SNPs. MRlap corrected for potential estimation bias due to sample overlap, which was not significant, reinforcing the IVW findings. The meta-analysis ensured robust and stable results. LDSC regression analysis suggests a weak causal relationship between folate supplementation and melanoma. Yet no association was found between genetically predicted vitamins A, B6, B12, C, D, E, and skin cancers.ConclusionBoth observational meta-analysis and MR analysis based on genetic variation provide robust evidence indicat that folate supplementation decreases the risk of melanoma, suggesting that interventions targeting folate supplementation may contribute to the primary prevention of melanoma. Further studies are needed to explore the potential association between other vitamins supplementation and the risk of skin cancers.
| S-EPMC11839550 | biostudies-literature
Project description:Background: This study aimed to clarify the relationship between tea consumption and osteoarthritis (OA). Methods: Common single-nucleotide polymorphisms (SNPs) from the Open Genome-wide Association Studies database were obtained. Summary statistics on OA were retrieved from the second dataset that enrolled 50,508 participants (10,083 OA cases) of European ancestry. The causal association between tea intake and OA was tested using two-sample Mendelian randomization (MR) analysis. Results: Tea consumption has adverse effects on OA. (inverse-variance weighted method: OR = 1.19, 95% CI = 1.08-1.30; weighted median method: OR = 1.22, 95% CI = 1.07-1.40). The MR-Egger regression intercept (MR intercept = -0.002; p = 0.73) showed no evidence of directional pleiotropy. Moreover, no evidence of underlying heterogeneity in MR analysis was found according to Cochran's Q test and funnel and forest analyses. Conclusion: A genetically predicted high daily tea intake can increase the risk of OA.
| S-EPMC9576864 | biostudies-literature
Project description:BackgroundTestosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies.MethodsWe leveraged public genome-wide association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance-weighted (IVW), MR-Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane's Q value, and the horizontal pleiotropy test was performed on the data through MR-Egger intercept and MR-PRESSO methods. "mRnd" online analysis tool was used to evaluate the statistical power of MR estimates.ResultsThe results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031).ConclusionOur analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.
| S-EPMC10710168 | biostudies-literature
Project description:BackgroundThis systematic review aimed to investigate the current state of risk prediction for abdominal aortic aneurysm in the literature, identifying and comparing published models and describing their performance and applicability to a population-based targeted screening strategy.MethodsElectronic databases MEDLINE (via Ovid), Embase (via Ovid), MedRxiv, Web of Science, and the Cochrane Library were searched for papers reporting or validating risk prediction models for abdominal aortic aneurysm. Studies were included only if they were developed on a cohort or study group derived from the general population and used multiple variables with at least one modifiable risk factor. Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool. A synthesis and comparison of the identified models was undertaken.ResultsThe search identified 4813 articles. After full-text review, 37 prediction models were identified, of which 4 were unique predictive models that were reported in full. Applicability was poor when considering targeted screening strategies using electronic health record-based populations. Common risk factors used for the predictive models were explored across all 37 models; the most common risk factors in predictive models for abdominal aortic aneurysm were: age, sex, biometrics (such as height, weight, or BMI), smoking, hypertension, hypercholesterolaemia, and history of heart disease. Few models had undergone standardized model development, adequate external validation, or impact evaluation.ConclusionThis study identified four risk models that can be replicated and used to predict abdominal aortic aneurysm with acceptable levels of discrimination. None of the models have been validated externally.
| S-EPMC11406543 | biostudies-literature
Project description:Metabolites' connection to sarcopenia through inflammation and mitochondrial dysfunction is presumed, but their impact remains unclear due to limitations in conventional observational studies caused by confounding bias and reverse causation. We conducted a Mendelian randomization (MR) analysis to elucidate the association of serum metabolites with sarcopenia and its related traits, i.e., appendicular lean mass and grip strength. Genetic instruments to proxy the serum metabolites were extracted from the most comprehensive genome-wide association study on the topic published so far. The corresponding summary statistics for the associations of genetic instruments with outcomes were calculated from the UK Biobank (n = 324,976 participants). The primary analyses were assessed by an inverse-variance weighted (IVW) method. The weighted median and MR-PRESSO methods were used as sensitive analyses. Fourteen genetically predicted serum metabolites were associated with the risk of sarcopenia (PIVW < 0.05). Two metabolites showed the overlapped association with sarcopenia and its related traits, which were isovalerylcarnitine (sarcopenia: odds ratio [OR] = 4.00, 95% confidence interval [CI] = 1.11~14.52, PIVW = 0.034; appendicular lean mass: β = -0.45 kg, 95% CI = -0.81~-0.09, PIVW = 0.015; grip strength: β = -1.51 kg, 95% CI = -2.31~-0.71, PIVW = 2.19 × 10-4) and docosapentaenoate (sarcopenia: OR = 0.16, 95% CI = 0.03~0.83, PIVW = 0.029; appendicular lean mass: β = -0.45 kg, 95% CI = 0.08~0.81, PIVW = 0.016). Twenty-seven metabolites were suggestive associated with appendicular lean mass or grip strength. This MR study provided evidence for the potential effects of metabolites on sarcopenia.
| S-EPMC10536442 | biostudies-literature