-
Arthritis Research & Therapy Jul 2023Observational studies have linked hyperuricemia with venous thromboembolism (VTE). We aimed to investigate whether there are causal relationships between uric acid...
BACKGROUND
Observational studies have linked hyperuricemia with venous thromboembolism (VTE). We aimed to investigate whether there are causal relationships between uric acid levels and VTE and its subtypes, including deep venous thrombosis (DVT) of the lower extremities and pulmonary embolism (PE).
METHODS
We utilized Mendelian randomization (MR) analysis to estimate the causal association in European individuals. We extracted two sets of polygenic instruments strongly associated (p < 5 × 10) with uric acid from the CKDGen consortium and UK biobank, respectively. Genetic associations with the risk of VTE, DVT, and PE were obtained from the FinnGen biobank. We used the inverse-variance weighted method as the preliminary estimate. Additionally, we employed MR-Egger, weighted median, and Mendelian randomization pleiotropy residual sum and outlier method as complementary assessments. Sensitivity analyses were performed to test for pleiotropic bias.
RESULTS
The genetically instrumented serum uric acid levels had no causal effects on VTE, DVT, and PE. Two sets of polygenic instruments used for exposure, along with three complementary MR methods, also yielded no significant association.
CONCLUSIONS
Our MR analysis provided no compelling evidence for a causal relationship of serum uric acid with the risk of VTE. This suggests that uric acid-lowering therapies in patients with hyperuricemia may not be effective in reducing the likelihood of developing VTE.
Topics: Humans; Venous Thromboembolism; Hyperuricemia; Mendelian Randomization Analysis; Uric Acid; Lower Extremity; Genome-Wide Association Study
PubMed: 37468959
DOI: 10.1186/s13075-023-03115-6 -
Science Advances Aug 2023This review explains how and why the United States has systemically high poverty. Descriptive evidence shows that U.S. poverty is (i) a huge share of the population,... (Review)
Review
This review explains how and why the United States has systemically high poverty. Descriptive evidence shows that U.S. poverty is (i) a huge share of the population, (ii) a perennial outlier among rich democracies, (iii) staggeringly high for certain groups, (iv) unexpectedly high for those who "play by the rules," and (v) pervasive across various groups and places. This review then discusses and critiques three prevailing approaches focused on the individual poor rather than the systemically high poverty: (i) behavioral explanations "fixing the poor," (ii) emotive compassion "dramatizing the poor," and (iii) cultural explanations both dramatizing and fixing the poor. The essay then reviews political explanations that emphasize the essential role of social policy generosity, political choices to penalize risks, power resources of collective political actors, and institutions. This review demonstrates a long emerging but ascending and warranted shift away from individualistic explanations of the poor toward political explanations of poverty.
Topics: Public Policy; Poverty
PubMed: 37611106
DOI: 10.1126/sciadv.adg1469 -
Scientific Reports Oct 2023Observational studies have reported a correlation between Helicobacter pylori infection and colorectal cancer (CRC); however, the underlying cause has remained unclear....
Observational studies have reported a correlation between Helicobacter pylori infection and colorectal cancer (CRC); however, the underlying cause has remained unclear. This research was aimed at determining whether there is a correlation between H. pylori infection and CRC by measuring the prevalence of H. pylori CagA antibodies and VacA antibodies. Using data from many genome-wide association studies (GWAS), we conducted a Mendelian randomization (MR) study with two sample GWAS. Then, we used bidirectional MR to evaluate the association between H. pylori infection and CRC for identifying causation. The most common method of analysis was the inverse variance-weighted technique. In addition, we performed supplementary analyses using the weighted median technique and MR-Egger regression. Horizontal pleiotropic outliers were identified and corrected using the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) method. Genetically predicted anti-H. pylori IgG seropositivity was not causally associated with CRC [odds ratio (OR): 1.12; 95% confidence interval (CI): 0.98-1.27, P = 0.08] and neither were H. pylori VacA antibody levels (OR = 0.96, 95% CI: 0.90-1.02, P = 0.25) or H. pylori CagA antibody levels (OR = 1.00, 95% CI: 0.93-1.07, P = 0.92). Furthermore, reverse MR analysis did not reveal evidence for a causal effect of CRC on H. pylori infection. The weighted median, the MR-Egger method, and MR-PRESSO yielded identical results. Using genetic data, MR analysis showed there was no evidence for a causal association between seroprevalence of H. pylori infection and CRC. The relationship between H. pylori infection and CRC requires further research.
Topics: Humans; Helicobacter Infections; Genome-Wide Association Study; Helicobacter pylori; Mendelian Randomization Analysis; Seroepidemiologic Studies; Antibodies, Bacterial; Calgranulin A; Colorectal Neoplasms
PubMed: 37899462
DOI: 10.1038/s41598-023-45545-x -
The Journals of Gerontology. Series A,... Jan 2024Benign prostatic hyperplasia (BPH) most often occurs in older men; previous studies and clinical experience suggest a potential link between lifestyle habits such as...
BACKGROUND
Benign prostatic hyperplasia (BPH) most often occurs in older men; previous studies and clinical experience suggest a potential link between lifestyle habits such as sleep habits, sedentary behavior, exercise levels, and BPH, but whether they have a clear causal relationship and the direction of that causality is unclear. We aimed to investigate the causal relationship between lifestyle habits and BPH using 2-sample Mendelian randomization (MR) analysis.
METHODS
Instrumental genetic independent variables strongly associated with the selected exposure factors were filtered from published genome-wide association studies (GWAS) consisting primarily of European ancestry samples. GWAS from BPH was analyzed as an MR outcome with the inverse-variance weighted method, maximum likelihood, weighted median method, MR-Egger regression, and several sensitivity analyses, including Cochran's Q test, intercept of MR-Egger, and MR pleiotropy residual sum and outlier test.
RESULTS
MR analysis showed a significant causal risk relationship between sleep duration and BPH, with an odds ratio of 0.42 (95% confidence interval, 0.25-0.69, p = .001) for BPH when sleep duration was increased by 1 standard deviation, but we did not find a causal relationship between the 2 when we performed a reverse analysis. However, sedentary behavior and different levels of exercise did not significantly affect the risk of BPH.
CONCLUSIONS
This study showed a strong causal relationship between sleep levels and BPH, with adequate sleep duration being a protective factor for BPH.
Topics: Male; Humans; Aged; Prostatic Hyperplasia; Genome-Wide Association Study; Mendelian Randomization Analysis; Life Style; Habits
PubMed: 37526403
DOI: 10.1093/gerona/glad187 -
Cancer Medicine Dec 2023The causal association between osteoarthritis (OA) and bladder cancer remains unclear. This Mendelian randomization (MR) study was carried out to assess the potential...
OBJECTIVE
The causal association between osteoarthritis (OA) and bladder cancer remains unclear. This Mendelian randomization (MR) study was carried out to assess the potential causal effects of any OA, knee OA and hip OA, and bladder cancer.
METHOD
Genome-wide association study (GWAS) summary data for OA and bladder cancer were obtained in GWAS CATALOG, UK Biobank, and FinnGen Consortium. Inverse-variance weighted (IVW) approach was primarily conducted to evaluate the causal relationships between OA and bladder cancer, and MR-Egger intercept and Cochran's Q test were mainly used to estimate heterogeneity and pleiotropy. MR-PRESSO was used to test the presence of horizontal outliers. Leave-one-out analysis was utilized to ensure the reliability of the results.
RESULTS
A higher genetic predisposition to any OA has a causal association with bladder cancer risk, while neither knee OA nor hip OA is causally linked to bladder cancer. MR-Egger intercept analysis exhibited that any OA and knee OA had no pleiotropic effect on the risk of bladder cancer, and Cochran's Q test showed that any OA, knee OA and hip OA had no heterogeneity on bladder cancer risk. Neither MR PRESSO analysis nor leave-one-out analysis revealed any outlier SNPs.
CONCLUSIONS
This MR study exhibited a positive cause-and-effect relationship between any type of OA and bladder cancer risk, but not between site-specific OA, knee OA and hip OA, and bladder cancer. Attention should be paid to the screening and prevention of bladder cancer in OA patients at any site.
PubMed: 38100139
DOI: 10.1002/cam4.6829 -
Frontiers in Microbiology 2023Previous research has reported that the gut microbiota performs an essential role in sleep through the microbiome-gut-brain axis. However, the causal association between...
INTRODUCTION
Previous research has reported that the gut microbiota performs an essential role in sleep through the microbiome-gut-brain axis. However, the causal association between gut microbiota and sleep remains undetermined.
METHODS
We performed a two-sample, bidirectional Mendelian randomization (MR) analysis using genome-wide association study summary data of gut microbiota and self-reported sleep traits from the MiBioGen consortium and UK Biobank to investigate causal relationships between 119 bacterial genera and seven sleep-associated traits. We calculated effect estimates by using the inverse-variance weighted (as the main method), maximum likelihood, simple model, weighted model, weighted median, and MR-Egger methods, whereas heterogeneity and pleiotropy were detected and measured by the MR pleiotropy residual sum and outlier method, Cochran's Q statistics, and MR-Egger regression.
RESULTS
In forward MR analysis, inverse-variance weighted estimates concluded that the genetic forecasts of relative abundance of 42 bacterial genera had causal effects on sleep-associated traits. In the reverse MR analysis, sleep-associated traits had a causal effect on 39 bacterial genera, 13 of which overlapped with the bacterial genera in the forward MR analysis.
DISCUSSION
In conclusion, our research indicates that gut microbiota may be involved in the regulation of sleep, and conversely, changes in sleep-associated traits may also alter the abundance of gut microbiota. These findings suggest an underlying reciprocal causal association between gut microbiota and sleep.
PubMed: 37645227
DOI: 10.3389/fmicb.2023.1236847 -
Cell Reports Nov 2023Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains...
Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53 oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53 esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.
Topics: Humans; Tumor Suppressor Protein p53; Oncogenes; Cell Transformation, Neoplastic; Neoplasms; Carcinogenesis; Gene Amplification
PubMed: 37922313
DOI: 10.1016/j.celrep.2023.113355 -
BMC Medical Genomics Dec 2023This study aimed to investigate the causal associations between several liver traits (liver iron content, percent liver fat, alanine transaminase levels, and liver...
OBJECTIVE
This study aimed to investigate the causal associations between several liver traits (liver iron content, percent liver fat, alanine transaminase levels, and liver volume) and colorectal cancer (CRC) risk using a Mendelian randomization (MR) approach to improve our understanding of the disease and its management.
METHODS
Genetic variants were used as instrumental variables, extracted from genome-wide association studies (GWAS) datasets of liver traits and CRC. The Two-Sample MR package in R was used to conduct inverse variance weighted (IVW), MR Egger, Maximum likelihood, Weighted median, and Inverse variance weighted (multiplicative random effects) MR approaches to generate overall estimates of the effect. MR analysis was conducted with Benjamini-Hochberg method-corrected P values to account for multiple testing (P < 0.013). MR-PRESSO was used to identify and remove outlier genetic variants in Mendelian randomization (MR) analysis. The MR Steiger test was used to assess the validity of the assumption that exposure causes outcomes. Leave-one-out validation, pleiotropy, and heterogeneity testing were also conducted to ensure the reliability of the results. Multivariable MR was utilized for validation of our findings using the IVW method while also adjusting for potential confounding or pleiotropy bias.
RESULTS
The MR analysis suggested a causal effect between liver volume and a reduced risk of CRC (OR 0.60; 95% CI, 0.44-0.82; P = 0.0010) but did not provide evidence for causal effects of liver iron content, percent liver fat, or liver alanine transaminase levels. The MR-PRESSO method did not identify any outliers, and the MR Steiger test confirmed that the causal direction of the analysis results was correct in the Mendelian randomization analysis. MR results were consistent with heterogeneity and pleiotropy analyses, and leave-one-out analysis demonstrated the overall values obtained were consistent with estimates obtained when all available SNPs were included in the analysis. Multivariable MR was utilized for validation of our findings using the IVW method while also adjusting for potential confounding or pleiotropy bias.
CONCLUSION
The study provides tentative evidence for a causal role of liver volume in CRC, while genetically predicted levels of liver iron content, percent liver fat, and liver alanine transaminase levels were not associated with CRC risk. The findings may inform the development of targeted therapeutic interventions for colorectal liver metastasis (CRLM) patients, and the study highlights the importance of MR as a powerful epidemiological tool for investigating causal associations between exposures and outcomes.
Topics: Humans; Alanine Transaminase; Colorectal Neoplasms; Genome-Wide Association Study; Iron; Liver; Mendelian Randomization Analysis; Reproducibility of Results; Adipose Tissue; Organ Size; Risk
PubMed: 38057864
DOI: 10.1186/s12920-023-01755-w -
Frontiers in Microbiology 2023Several observational studies have reported the correlation between gut microbiota and the risk of erectile dysfunction (ED). However, the causal association between...
BACKGROUND
Several observational studies have reported the correlation between gut microbiota and the risk of erectile dysfunction (ED). However, the causal association between them remained unestablished owing to intrinsic limitations, confounding factors, and reverse causality. Therefore, the two-sample Mendelian randomization (MR) study was performed to determine the causal effect of gut microbiota on the risk of ED.
METHODS
The MR analysis utilized the publicly available genome-wide association study (GWAS) summary-level data to explore the causal associations between gut microbiota and ED. The gut microbiota data were extracted from the MiBioGen study ( = 18,340), and the ED data were extracted from the IEU Open GWAS (6,175 ED cases and 217,630 controls). The single nucleotide polymorphisms (SNPs) served as instrumental variables (IVs) by two thresholds of -values, the first -value setting as <1e-05 (locus-wide significance level) and the second -value setting as <5e-08 (genome-wide significance level). The inverse variance weighted approach was used as the primary approach for MR analysis, supplemented with the other methods. In addition, sensitivity analyses were performed to evaluate the robustness of the MR results, including Cochran's Q test for heterogeneity, the MR-Egger intercept test for horizontal pleiotropy, the Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) global test for outliers, and the forest test and leave-one-out test for strong influence SNPs.
RESULTS
Our results presented that the increased abundance of at family level (OR: 1.265, 95% CI: 1.054-1.519), (OR: 1.320, 95% CI: 1.064-1.638), group (OR: 1.197, 95% CI: 1.018-1.407), (OR: 1.138, 95% CI: 1.017-1.273), and (OR: 1.201, 95% CI: 1.035-1.393) at genus level may be risk factors for ED, while the increased abundance of (OR: 0.770, 95% CI: 0.615-0.965) at genus level may have a protective effect on ED. No heterogeneity or pleiotropy was found based on the previously described set of sensitivity analyses.
CONCLUSION
Our MR analysis demonstrated that the gut microbiota had inducing and protective effects on the risk of ED. The results provide clinicians with novel insights into the treatment and prevention of ED in the future. Furthermore, our study also displays novel insights into the pathogenesis of microbiota-mediated ED.
PubMed: 37928685
DOI: 10.3389/fmicb.2023.1257114