Casual Associations Research Articles

Examining Casual Associations Between Sedentary Time And Heart Failure: A Two-sample Mendelian Randomization Analysis

Examining Casual Associations Between Sedentary Time And Heart Failure: A Two-sample Mendelian Randomization Analysis

Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization

BackgroundsA growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs.ObjectivesThis study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs.MethodsGenetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets.ResultsThere was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10− 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10− 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10− 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10− 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042).ConclusionsOur study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.

Casual associations between brain structure and sarcopenia: A large-scale genetic correlation and mendelian randomization study.

Sarcopenia presenting a critical challenge in population-aging healthcare. The elucidation of the interplay between brain structure and sarcopenia necessitates further research. The aim of this study is to explore the casual association between brain structure and sarcopenia. Linkage disequilibrium score regression (LDSC) was conducted to estimate the genetic correlations; MR was then performed to explore the causal relationship between Brain imaging-derived phenotypes (BIDPs) and three sarcopenia-related traits: handgrip strength, walking pace, and appendicular lean mass (ALM). The main analyses were conducted using the inverse-variance weighted method. Moreover, weighted median and MR-Egger were conducted as sensitivity analyses. Genetic association between 6.41% of BIDPs and ALM was observed, and 4.68% of BIDPs exhibited causal MR association with handgrip strength, 2.11% of BIDPs were causally associated with walking pace, and 2.04% of BIDPs showed causal association with ALM. Volume of ventromedial hypothalamus was associated with increased odds of handgrip strength (OR: 1.18, 95% CI: 1.02 to 1.37) and ALM (OR: 1.05, 95% CI: 1.01 to 1.09). Mean thickness of G-pariet-inf-Angular was associated with decreased odds of handgrip strength (OR: 0.83, 95% CI: 0.70 to 0.97) and walking pace (OR: 0.97, 95% CI: 0.93 to 0.99). As part of the brain structure forward causally influences sarcopenia, which may provide new perspectives for the prevention of sarcopenia and offer valuable insights for further research on the brain-muscle axis.

Casual associations between blood metabolites and colon cancer.

Limited knowledge exists regarding the casual associations linking blood metabolites and the risk of developing colorectal cancer. To investigate causal associations between blood metabolites and colon cancer. The study utilized a two-sample Mendelian randomization (MR) analysis to investigate the causal impact of 486 blood metabolites on colorectal cancer. The primary method of analysis used was the inverse variance weighted model. To further validate the results several sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, and MR robust adjusted profile score. These additional analyses were conducted to ensure the reliability and robustness of the findings. After rigorous selection for genetic variation, 486 blood metabolites were included in the MR analysis. We found Mannose [odds ratio (OR) = 2.09 (1.10-3.97), P = 0.024], N-acetylglycine [OR = 3.14 (1.78-5.53), P = 7.54 × 10-8], X-11593-O-methylascorbate [OR = 1.68 (1.04-2.72), P = 0.034], 1-arachidonoylglycerophosphocholine [OR = 4.23 (2.51-7.12), P = 6.35 × 10-8] and 1-arachidonoylglycerophosphoethanolamine 4 [OR = 3.99 (1.17-13.54), P = 0.027] were positively causally associated with colorectal cancer, and we also found a negative causal relationship between Tyrosine [OR = 0.08 (0.01-0.63), P = 0.014], Urate [OR = 0.25 (0.10-0.62), P = 0.003], N-acetylglycine [0.73 (0.54-0.98), P = 0.033], X-12092 [OR = 0.89 (0.81-0.99), P = 0.028], Succinylcarnitine [OR = 0.48 (0.27-0.84), P = 0.09] with colorectal cancer. A series of sensitivity analyses were performed to confirm the rigidity of the results. This study showed a causal relationship between 10 blood metabolites and colorectal cancer, of which 5 blood metabolites were found to be causal for the development of colorectal cancer and were confirmed as risk factors. The other five blood metabolites are protective factors.

Abstract 1009: Elevated Lipoprotein (a) Is Associated With Increased Risk Of Abdominal Aortic Aneurysm.

Introduction: Lipoprotein(a) (Lp(a)) is an apolipoprotein B (ApoB) containing particle that is causally associated with atherosclerotic vascular disease and the target of emerging therapeutics. Recent work has highlighted the role of circulating lipoproteins in abdominal aortic aneurysm (AAA). We sought to triangulate human observational and genetic evidence to evaluate the role of Lp(a) in AAA. Methods: We tested the association between levels of Lp(a) and clinically diagnosed aortic aneurysms while controlling for traditional AAA risk factors and levels of ApoB using logistic regression among 798 individuals with and 384,499 individuals without AAA in the UK biobank (UKB). Multivariable Mendelian randomization (MVMR) was used to test for putatively casual associations between Lp(a) and AAA controlling for ApoB. Genetic instruments for Lp(a) and ApoB were created from genome-wide association studies (GWAS) of Lp(a) and ApoB comprising 335,796 and 418,505 UKB participants, respectively. The instruments were tested against AAA using data from a GWAS of 39,221 individuals with and 1,086,107 without AAA. Results: Elevated Lp(a) levels were associated with an increased risk of AAA (OR 1.04 per 10 nmol/L Lp(a); 95%CI 1.02-1.05; P<0.01). Clinically elevated Lp(a) levels (>150nmol/L) were likewise associated with an increased risk of AAA (OR 1.50; 95%CI 1.17-1.91; P<0.01) when compared to individuals with Lp(a) levels <150nmol/L. MVMR confirmed a significant association between genetically proxied increased Lp(a) and increased genetic liability to AAA (OR 1.13 per SD increased in Lp(a); 95%CI 1.02-1.24; P<0.02). Conclusion: Both observational and genetic casual inference analyses support an association between increased Lp(a) and AAA risk that is independent of ApoB. Mendelian randomization analyses posit a causal relationship. These findings suggest that Lp(a) may be a therapeutic target for AAA and drive the inclusion of AAA as an outcome in clinical trials of Lp(a) antagonists.

Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis.

To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved. Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations. Our research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL. Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

예이츠의 슬라이고와 엘리엇의 이스트 코우커

Starting with a general assumption that poets and regions are closely connected, this study discusses the significance of specific locales in the works of Yeats and Eliot, who are at the center of “international” modernism beyond regional boundaries. This paper focuses on Yeats’s Sligo and Eliot’s East Coker, the places that they chose as their burial grounds, with the locales’ close proximity to their origins in mind. While examining their biographical details and letters related to Sligo and East Coker, and exploring how these regions are reproduced in Yeats’s poems and Eliot’s “East Coker,” we will find interesting points of comparison between the two poets. Yeats’s experience in Sligo County provides explicit settings and materials such as Sligo place names and mythic figures, and in his poems about Sligo, the literal and the mythical are mingled. In “East Coker,” however, Eliot explores more symbolic and metaphysical meanings evoked by the small village of East Coker, even with its casual or distinct associations with him and his ancestors. In addition, this study concludes with how the present ambience of Sligo and East Coker may function for the 21st century readers of Yeats and Eliot.

Casual associations of thyroid function with inflammatory bowel disease and the mediating role of cytokines.

Previous observational epidemiological studies have suggested a potential association between thyroid function and inflammatory bowel disease (IBD). However, the findings remain inconclusive, and whether this association is causal remains uncertain. The objective of this study is to investigate the causal association between thyroid function and IBD. Genome-wide association studies (GWAS) involving seven indicators of thyroid function, IBD, and 41 cytokines were analyzed. Bidirectional two-sample Mendelian randomization (MR) and multivariable MR were conducted to examine the causal relationship between thyroid function and IBD and to explore the potential mechanisms underlying the associations. Genetically determined hypothyroidism significantly reduced the risk of CD (odds ratio [OR] = 0.761, 95% CI: 0.655-0.882, p < 0.001). Genetically determined reference-range TSH was found to have a suggestive causal effect on IBD (OR = 0.931, 95% CI: 0.888-0.976, p = 0.003), (Crohn disease) CD (OR = 0.915, 95% CI: 0.857-0.977, p = 0.008), and ulcerative colitis (UC) (OR =0.910, 95% CI: 0.830-0.997, p = 0.043). In reverse MR analysis, both IBD and CD appeared to have a suggestive causal effect on the fT3/fT4 ratio (OR = 1.002, p = 0.013 and OR = 1.001, p = 0.015, respectively). Among 41 cytokines, hypothyroidism had a significant impact on interferon-inducible protein-10 (IP-10) (OR = 1.465, 95% CI: 1.094-1.962, p = 0.010). The results of multivariable MR showed that IP-10 may mediate the causal effects of hypothyroidism with CD. Our results suggest that an elevated TSH level reduces the risk of CD, with IP-10 potentially mediating this association. This highlights the pituitary-thyroid axis could serve as a potential therapeutic strategy for CD.

Identifying the plasma metabolome responsible for mediating immune cell action in severe COVID-19: a Mendelian randomization investigation.

The immune response regulates the severity of COVID-19 (sCOVID-19). This study examined the cause-and-effect relationship between immune cell traits (ICTs) and the risk of severe COVID-19. Additionally, we discovered the potential role of plasma metabolome in modulating this risk. Employing data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian randomization (MR) assessment of 731 genetic ICTs and sCOVID-19 (5,101 cases, 1,383,241 controls) incidence. The MR analysis was utilized to further quantitate the degree of plasma metabolome-mediated regulation of immune traits in sCOVID-19. The inverse variance weighted method recognized 2 plasma metabolites (PMs) responsible for casual associations between immune cells and sCOVID-19 risk. These included Tridecenedioate (C13:1-DC) which regulated the association between CD27 on IgD- CD38br (OR 0.804, 95% CI 0.699-0.925, p = 0.002) and sCOVID-19 risk (mediated proportion: 18.7%); arginine to citrulline ratio which controlled the relationship of CD39 on monocyte (OR 1.053, 95% CI 1.013-1.094, p = 0.009) with sCOVID-19 risk (mediated proportion: -7.11%). No strong evidence that genetically predicted sCOVID-19 influenced the aforementioned immune traits. In this study, we have successfully identified a cause-and-effect relationship between certain ICTs, PMs, and the likelihood of contracting severe COVID-19. Our findings can potentially improve the accuracy of COVID-19 prognostic evaluation and provide valuable insights into the underlying mechanisms of the disease.

Does green finance reduce environmental degradation? The role of green innovation, environmental tax, and geopolitical risk in China

In the last few decades, China has faced the pressing effects of climate change due to its rapid progress in industrialization and economic expansion. China has taken the lead in developing aggressive plans to reduce environmental degradation. Considering this, several studies conclude that green finance, green innovation, and environmental taxation stand out as the most efficacious strategies for reducing environmental degradation. Also, geopolitical concerns can make it difficult to implement plans, particularly when there is political unrest, hostilities, or hostility between countries. Therefore, this work explores the influence of green finance, green innovation, environmental tax, and geopolitical risk to mitigate environmental degradation in China. This research employed a novel dynamic ARDL simulation model for long-run association, KRLS for robustness check, and frequency domain causality for checking casual relationships from 1990 to 2020. The findings indicated that green finance, green innovation, and environmental tax mitigate the consumption and production-based carbon emissions, while geopolitical risk has adverse implications for environmental sustainability. The frequency domain causality test findings suggested that green finance, green innovation, environmental tax, and geopolitical risk have long-term casual associations in both models. These findings provide specific policy suggestions to assist China in reducing environmental deterioration and achieving the SDGs.

Circulating inflammatory cytokines and risk of idiopathic pulmonary fibrosis: a Mendelian randomization study

BackgroundThe previous epidemiological and experimental evidence has implied the linkage between chronic inflammation to idiopathic pulmonary fibrosis (IPF). However, it was still unclear whether there were casual associations between circulating inflammatory cytokines and IPF development. The objective of present study was to examine whether altered genetically predicted concentration of circulating cytokines were associated with IPF development using a two-sample Mendelian randomization (MR) analysis.Materials and methodsThe causal effects of 23 circulating inflammatory cytokines were evaluated on IPF using MR analysis. The primary approach of MR analysis was the inverse variance-weighted (IVW) method. The sensitivity analyses were conducted by simple median, weighted median, penalized weighted median and MR-Egger regression methods.ResultsThe present MR study found suggestive evidence that a higher circulating IL-14 level was associated with an increased risk of IPF (random effects IVW method: odds ratio: 1.001, 95% confidence interval: 1.000-1.001, P = 0.026). The sensitivity analysis yielded directionally similar results for IL-14. There was no significant association found between other circulating inflammatory cytokines and IPF.ConclusionThe high level of IL14 predicted by genes had a casual relationship with the increased risk of IPF. This finding provided epidemiological evidence for drug therapy targeting inflammatory factors in the prevention and treatment of IPF. It’s warranted further exploration to validate the clinical significance of IL14 associated with developmental risk of IPF.

Assessing the Casual Association between Sex Hormone Levels and Fracture Risk: A Two-Sample Mendelian Randomization Study.

Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone-binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome-wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two-sample MR approach. For the main analysis, the inverse-variance-weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR-Egger method were utilized. To evaluate potential pleiotropy, MR-Egger regression was conducted. Additionally, a leave-one-SNP-out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52-3.85; p = 1.93 × 10-4 ]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10-4 ), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10-6 ). Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two-sample Mendelian randomization study.

Observational studies have indicated that the incidence of primary biliary cholangitis (PBC) is higher in inflammatory bowel disease (IBD) patients than that in healthy people. However, whether the correlation is causal remains unclear. The genetic associations with IBD were obtained from publicly available genome-wide association studies (GWAS) of European ancestry with 31 665 cases and 33 977 controls, consisting of 17 897 Crohn's disease (CD) and 13 768 ulcerative colitis (UC) cases. The genetic associations with PBC were obtained from a European GWAS with 2764 cases and 10 475 controls. A bidirectional two-sample Mendelian randomization (MR) design was implemented to determine the causal relationship between IBD and PBC. In the forward MR, the IBD was treated as the exposure while the PBC was the exposure in the reverse MR. The inverse-variance-weighted (IVW) method was utilized as the main statistic method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. A total of 99 valid instrumental variables (IVs) were selected for IBD and the number of IVs for PBC was 18. The forward MR analysis indicated that genetically predicted IBD (UC and CD) was significantly associated with an increased risk of PBC (IVW OR = 1.343; 95% CI: 1.220-1.466). Similar casual associations were observed in UC (IVW OR = 1.244; 95% CI: 1.057-1.430) and CD (IVW OR = 1.269; 95% CI: 1.159-1.379). Such results were still consistent in multiple MR methods. The reverse MR analysis implicated that genetic susceptibility to PBC might not alter the risk of IBD (IVW OR = 1.070; 95% CI: 0.984-1.164). Our study found that genetically predicted IBD can increase the risk of PBC while not vice versa in the European population, which may enlighten the aetiology of PBC, together with the IBD patient management.

Use of the human reference genome 38 enhances integration of the multi‐tissue proteomics with genetics and disease

AbstractBackgroundMost existing protein quantitative trait locus (pQTL) studies focus on a single tissue and use the reference Genome Reference Consortium Human Build 37 (GRCh37/hg19) published in 2009. GRCh38/hg38 was updated in 2013 with correcting thousands of sequencing artifacts that cause false SNPs and updating non‐nuclear genomic sequence. Many papers strongly recommend switching to GRCh38/hg38. The goal of this study is to use multiple tissues (brain, CSF and plasma) to explore the genetic architecture of protein levels in neurologically relevant tissues and to update the human reference genome as hg38 to compare the findings.MethodIn this study, 805 CSF samples and 869 proteins, 529 plasma samples and 953 proteins and 378 brain samples and 1,300 proteins passed quality control process. We performed genome‐wide association analyses of over 8 million autosomal variants (MAF ≥ 0.01) imputed using the most updated hg38 TOPMed imputation panel to identify cis/trans pQTLs. We performed conditional analysis to identify independent pQTLs. After removing pleiotropic loci and including Alzheimer’s disease (AD) variants, Mendelian randomization (MR) was applied to detect the casual associations between proteins and AD risk. To decrease unmeasured pleiotropy effect, we used co‐localization analysis to get more supporting information among multiple traits. Finally, we replicated our findings in much larger studies.ResultIn brain tissue, we identified 4269 pQTLs in hg38 compared to 2418 pQTLs in hg19 with a threshold of 5 × 10−8 for cis‐pQTLs and 5 × 10−8/(number of independent proteins) for trans‐pQTLs. We found the independent SNPs and highlight the complexity of regions with multiple independent local pQTLs. Analysis for CSF and plasma is underway.ConclusionThis study is to apply the hg38 as the human reference genome to detect much more pQTLs and correct possible false findings in the previous hg19 study. With the following analysis, we could get more valuable and confirmed information about the additional GWAS loci and identify the function of certain proteins on the disease risk. The multiple tissue samples and multiple traits could help us detect the complex genetic architecture of protein levels in neurologically relevant tissues.

Unprocessed Red Meat and Processed Meat Consumption, Plasma Metabolome, and Risk of Ischemic Heart Disease: AProspective Cohort Study of UK Biobank.

Background The evidence is equivocal on the association between meat consumption and ischemic heart disease (IHD) risk. To what extent the variation of individuals' metabolic responses to the same diet may account for this association is not fully understood. We aim to identify metabolomic signatures characterizing consumption of unprocessed red meat and processed meat and whether such signatures are associated with IHD risk. Methods and Results We conducted a cohort study of 92 246 individuals (mean age, 56.1 years; 55.1% women) using the UK Biobank. During the median follow-up of 8.74 years, 3059 incident IHD events were documented. Unprocessed red meat and processed meat consumption was assessed using a touchscreen dietary questionnaire. Plasma metabolome was profiled by high-throughput nuclear magnetic resonance spectroscopy. Cox proportional hazards regression model was used to test the association of meat consumption with IHD. Genome-wide association analysis and 1-sample Mendelian randomization were performed for metabolomic signatures and causal association of signatures with IHD. Using elastic net regularized regressions, we constructed metabolomic signatures consisting of 157 and 142 metabolites for unprocessed red meat (Spearman correlation coefficient [r]=0.223) and processed meat (r=0.329), respectively. These signatures showed positive associations with incident IHD (red meat related signature: hazard ratio [HR] per SD increment=1.11 [95% CI, 1.06-1.16], P<0.001; processed meat related signature: HR, 1.16 [95% CI, 1.11-1.21], P<0.001). Genome-wide association studies identified 45 and 4 loci, involved in lipid and lipoprotein metabolism, for red and processed meat related signatures. Mendelian randomization showed that there were casual associations of signatures with risk of incident IHD. Conclusions We identify metabolomic signatures that reflect consumption of unprocessed red meat and processed meat, and these signatures are associated with an increased risk of IHD.

Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types.

Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences. Summary statistics from 18 common cancers (2107-491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000-31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers. We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66; 95% CI, 0.49-0.83; P=9.77×10-7), NSUN4 expression level with both breast cancer risk (OR per SD, 1.05; 95% CI, 1.03-1.07; P=5.24×10-6) and prostate cancer risk (OR per SD, 1.06; 95% CI, 1.03-1.09; P=1.01×10-5), NSUN4 methylation level with both breast and prostate cancer risk, and VARS2 methylation level with lung cancer risk. This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention. This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).

Exploring the causality and pathogenesis of systemic lupus erythematosus in breast cancer based on Mendelian randomization and transcriptome data analyses.

There has been a cumulative interest in relationships between systemic lupus erythematosus (SLE) and cancer risk. Breast cancer is the most common cancer among women worldwide. However, the casual association and pathogenesis between SLE and breast cancer remains incompletely unknown. Mendelian randomization (MR) analysis was first conducted to investigate the potential causality between SLE and breast cancer. Sensitivity analyses were applied to validate the reliability of MR results. Transcriptomic data analyses based on the Cancer Genome Atlas and Gene Expression Omnibus databases were then performed to identify and construct a SLE-related gene signature (SLEscore). The MR analysis demonstrated that genetic predisposition to SLE was casually associated with the decreased risk of breast cancer in the East Asian cohort (odds ratios: 0.95, 95% confidence interval: 0.92-0.98, p=0.006). However, no casual associations were observed in the European population. Furthermore, sensitivity analyses proved the robustness of the present MR results. A prognostic SLEscore consisting of five SLE-related genes (RACGAP1, HMMR, TTK, TOP2A, and KIF15) could distribute patients with breast cancer into the high- and low-risk groups according to survival rates with good predictive ability (p < 0.05). Our MR study provided evidence that genetic changes in SLE were significantly associated with the decreased risk of breast cancer in the East Asian population, while no causality was found in the European cohorts. Transcriptome data analyses indicated that the SLEscore could serve as a novel biomarker for predicting prognosis when breast cancer and SLE coexisted in patients.

Impact of genetically predicted atrial fibrillation on cancer risks: A large cardio-oncology Mendelian randomization study using UK biobank.

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. 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). 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. 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.

Dietary energy density, metabolic parameters, and blood pressure in a sample of adults with obesity

BackgroundSeveral previous studies revealed the role of dietary energy density (DED) in developing obesity and related disorders. However, the possible role of DED in triggering cardiometabolic risk factors of individuals with obesity has not been studied yet. This study aimed to evaluate the association between DED and anthropometric parameters, blood pressure, and components of metabolic syndrome (MetS) (such as glycemic markers, lipid profile, and blood pressure) among individuals with obesity.MethodsIn this cross-sectional study, we included 335 adults with obesity (BMI ≥ 30 kg/m2) aged 20–50 years in Tabriz and Tehran, Iran. Dietary intake was assessed by a validated semi-quantitative Food Frequency Questionnaire (FFQ), including 168 food items; then, DED was calculated. MetS was defined based on the guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III). Enzymatic methods were used to assess serum lipids, glucose, and insulin concentrations. Blood pressure was measured by sphygmomanometer and body composition by bioelectrical impedance analysis (BIA).ResultsParticipants in the higher tertiles of DED had more intake of carbohydrate, dietary fat, saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), and meat, fish, poultry (MFP). Increasing the DED in both methods had no association with systolic blood pressure (SBP), fasting blood sugar (FBS), low-density lipoprotein cholesterol (LDL-C), insulin, triglyceride (TG), and homeostatic model assessment of insulin resistance (HOMA-IR) even after adjustment for confounders. However, diastolic blood pressure (DBP) decreased in second tertile of DED I (β = 0.921, P = 0.004). The quantitative insulin-sensitivity check index (QUICKI) in second tertile of both DED methods had significant positive association with DED. In the second tertile of DED II, while total cholesterol (TC) significantly decreased (P crude = 0.036, P adjusted = 0.024), high-density lipoprotein cholesterol (HDL-C) increased (β = 1.096, p = 0.03). There was no significant changes in biochemical parameters in third tertile of DED I and II even after adjustment for covariates. Also, higher tertiles of DED was associated with reduced prevalence of MetS.ConclusionHigh DED was associated with lower levels of blood pressure and TC but elevated levels of HDL and QUICKI independent of such confounders as age, BMI, sex, and physical activity. Further longitudinal studies are warranted to better elucidate casual associations.

The Effect of Consumer price index, Foreign Exchange Reserve and Labour Force on economic growth of Nepal

One of the main objectives for any country is to attain higher economic growth. Even though there are many factors that affect the economic growth of the country, this paper tries to examine the casual associations between the major economic indicator (GDP) with other factors such as consumer price index (CPI), foreign exechange reserve (FOREX), Labour force, so as to confirm the short run and long run relationship between GDP and these factors. This study uses the data from 1990 to 2021. Johansen approach to cointegration and vector error correction model has been implemented and the result have confirmed that a percentage increase in consumer price index will decrease GDP by 0.98 percentage, a percentage increase in foreign exechange reserve increase GDP by 0.017 percentage, where as a percentage increase in labour force will decrease GDP by 0.25 percentage.