Inhaling a dangerous amount of nanoparticles leads to pulmonary inflammatory and immune disorders, which integrates several kinds of cells. Exosomes are suggested to play a crucial role in intercellular communication via miRNA transmission. To investigate the role of exosomal miRNA in nanoparticle phagocytosis, a total of 54 pneumoconiosis patients along with 100 healthy controls are recruited, exosomes derived from their venous blood are collected, and then exosomal miRNAs are profiled with high-throughput sequencing technology. miRNAs which are differentially expressed are used to predict target genes and conduct functional annotation. Interactions between miRNA hsa-let-7a-5p, hsa-let-7i-5p, and their cotarget gene WASL are found that can affect nanoparticle phagocytosis. The follow-up analysis of gene structure, tissue specificity, and miRNA-target gene regulatory mode supports the findings. Specially, the assumption is further confirmed via a series of cellular experiments, and the fibroblast transdifferentiate rate that is used as an indicator of nanoparticle phagocytosis decreased when elevating miRNA expression level. Thus, data in this study indicate that downregulation of miRNA hsa-let-7a-5p and hsa-let-7i-5p contributes to WASL elevation, promoting WASL and VASP complex formation, which is necessary for initiating Arp2/3 induced phagocytosis.
Observational studies showed an inverse association between birth weight and chronic kidney disease (CKD) in adulthood existed. However, whether such an association is causal remains fully elusive. Moreover, none of prior studies distinguished the direct fetal effect from the indirect maternal effect. Herein, we aimed to investigate the causal relationship between birth weight and CKD and to understand the relative fetal and maternal contributions. Meta-analysis (n = ~22 million) showed that low birth weight led to ~83% (95% confidence interval [CI] 37–146%) higher risk of CKD in late life. With summary statistics from large scale GWASs (n = ~300 000 for birth weight and ~481 000 for CKD), linkage disequilibrium score regression demonstrated birth weight had a negative maternal, but not fetal, genetic correlation with CKD and several other kidney-function related phenotypes. Furthermore, with multiple instruments of birth weight, Mendelian randomization showed there existed a negative fetal casual association (OR = 1.10, 95% CI 1.01–1.16) between birth weight and CKD; a negative but non-significant maternal casual association (OR = 1.09, 95% CI 0.98–1.21) was also identified. Those associations were robust against various sensitivity analyses. However, no maternal/fetal casual effects of birth weight were significant for other kidney-function related phenotypes. Overall, our study confirmed the inverse association between birth weight and CKD observed in prior studies, and further revealed the shared maternal genetic foundation between low birth weight and CKD, and the direct fetal and indirect maternal causal effects of birth weight may commonly drive this negative relationship.
The relationship between birth weight and osteoporosis was inconsistent in previous observational studies. Therefore, we performed a systematic evaluation to determine the inconsistent relationship and further make causal inference based on the UK Biobank datasets ($500,000 individuals) and individual/summary-level genetic datasets. Observational analyses found consistent negative associations either between birth weight and estimated bone mineral density (eBMD) or between genetic risk score (GRS) of birth weight and eBMD in total subjects, and sex-stratified subgroups. Mediation analyses detected significant mediation effects of adult weight and height on associations between birth weight and eBMD. Birth weight was causally associated not only with three BMD phenotypes (eBMD, total body [TB]-BMD, and femoral neck [FN]-BMD) under two effect models (total and fetal effect), but also with the risk of fracture using different Mendelian randomization (MR) methods. Multivariable MR analyses detected the pleiotropic effects of some environmental factors (e.g., gestational duration, head circumference, hip circumference) on the associations between birth weight and BMD/fracture. Three BMD phenotypes (eBMD, TB-BMD, and FN-BMD) have significant mediation effects on the associations between birth weight and fracture by using a novel mediation MR analysis under the multivariable MR framework. This multistage systematic study found consistent causal associations between birth weight and osteoporosis risk, fetal origin of genetic effects underlying the associations, and several mediation factors on the detected associations. The results enhanced our understanding of the effects of fetal original phenotypes on outcomes in late adulthood and provided helpful clues for early prevention research on osteoporosis.
Background: Observational studies have identified gout patients are often comorbid with dyslipidemia, which is characterized by a decrease in high-density lipoprotein cholesterol (HDL) and an increase in triglycerides (TG). However, the relationship between dyslipidemia and gout is still unclear.Methods: We first performed Mendelian randomization (MR) to evaluate the causal effect of four lipid traits on gout and serum urate based on publicly available GWAS summary statistics ( n ~100,000 for lipid, 69,374 for gout and 110,347 for serum urate). We then employed multivariable MR to estimate the independent causal effect for lipid on gout via serum urate with mediation analysis.Results: MR showed each standard deviation (SD) (~12.26 mg/dL) increase in HDL resulted in about 25% (95% CI 9.0% ~ 38%, p = 3.31E-3) reduction of gout risk, with 0.09 mg/dL (95% CI: -0.12 -0.05, p = 7.00E-04) decrease in serum urate, and each SD (~112.33 mg/dL) increase of TG was associated with 0.10 mg/dL (95% CI: 0.06 ~ 0.14, p = 9.87E-05) increase in serum urate. Those results were robust against various sensitive analyses. Additionally, independent effects of HDL and TG on gout/serum urate were confirmed. Finally, mediation analysis demonstrated HDL or TG could also indirectly affect gout via the pathway of serum urate. Conclusion:Our study confirmed the causal associations between HDL (and TG) and gout, and further revealed the effect of HDL or TG on gout could also be mediated via serum urate.
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