Essentiality of SLC7A11-mediated nonessential amino acids in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) remains a rapidly growing global health burden. Here, we report that the nonessential amino acid (NEAA) transporter SLC7A11 plays a key role in MASLD. In patients with MASLD, we found high expression levels of SLC7A11 that were correlated directly with clinical grade. Using both loss-of-function and gain-of-function genetic models, we found that Slc7a11 deficiency accelerated MASLD progression via classic cystine/cysteine deficiency-induced ferroptosis, while serine deficiency and a resulting impairment in de novo cysteine production were attributed to ferroptosis-induced MASLD progression in mice overexpressing hepatic Slc7a11. Consistent with these findings, we found that both serine supplementation and blocking ferroptosis significantly alleviated MASLD, and the serum serine/glutamate ratio was significantly lower in these preclinical disease models, suggesting that it might serve as a prognostic biomarker for MASLD in patients. These findings indicate that defects in NEAA metabolism are involved in the progression of MASLD and that serine deficiency-triggered ferroptosis may provide a therapeutic target for its treatment.

Predicting the severity of mycoplasma pneumoniae pneumonia in pediatric and adult patients: a multicenter study.

The purpose of this study is to develop a nomogram model for early prediction of the severe mycoplasma pneumoniae pneumonia (SMPP) in Pediatric and Adult Patients. A retrospective analysis was conducted on patients with MPP, classifying them into SMPP and non-severe MPP (NSMPP) groups. A total of 550 patients (NSMPP 374 and SMPP 176) were enrolled in the study and allocated to training, validation cohorts. 278 patients (NSMPP 224 and SMPP 54) were retrospectively collected from two institutions and allocated to testing cohort. The risk factors for SMPP were identified using univariate analysis. For radiomic feature selection, Spearman's correlation and the least absolute shrinkage and selection operator (LASSO) were utilized. Logistic regression was used to build different models, including clinical, imaging, radiomics, and integrated models (combining clinical, imaging, and radiomics features selected). The model's discrimination was evaluated using a receiver operating characteristic curve, its calibration with a calibration curve, and the results were visualized using the Hosmer-Lemeshow goodness-of-fit test. Thirteen clinical features and fourteen imaging features were selected for constructing the clinical and imaging models. Simultaneously, a set of twenty-five radiomics features were utilized to build the radiomics model. The integrated model demonstrated good calibration and discrimination in the training cohorts (AUC, 0.922; 95% CI: 0.900, 0.942), validation cohorts (AUC, 0.879; 95% CI: 0.806, 0.920), and testing cohorts (AUC, 0.877; 95% CI: 0.836, 0.916). The discriminatory and predictive efficacy of the clinical model in testing cohorts increased further after clinical and radiological features were incorporated (AUC, 0.849 vs. 0.922, P = 0.002). The model demonstrated exemplary predictive efficacy for SMPP by leveraging a comprehensive set of inputs, encompassing clinical data, quantitative and qualitative radiological features, along with radiomics features. The integration of these three aspects in the predictive model further enhanced the performance of the clinical model, indicating the potential for extensive clinical applications.

Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.

AIMS: To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). RESULTS: GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. CONCLUSIONS: GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.

Mechanisms of Cinnamomi Cortex against Diabetes Mellitus Explored by Network Pharmacology combined with Molecular Docking and Experimental Validation.

OBJECTIVE: Cinnamomi cortex (CC), a traditional Chinese herbal medicine, exhibits antidiabetic properties, yet the underlying mechanisms are not fully understood. Our study combined network pharmacology, molecular docking, and experimental validation to elucidate the antidiabetic mechanisms of CC. METHODS: Active components of CC and their potential antidiabetic targets were identified through TCMSP, DisGeNET, and GeneCards. The PPI networks were constructed with STRING and analyzed with Cytoscape, while GO and KEGG analyses utilized the DAVID database. Molecular docking with core targets was performed using Autodock Vina. The efficacy of CC in diabetes mellitus was evaluated through H&E staining, qPCR, and Western blot in the T2DM mouse. RESULTS: Eleven active components and sixty-six potential antidiabetic targets of CC were identified. The enrichment analysis revealed 288 GO terms and 37 pathways. The molecular docking showed high affinity for PPAR-γ and IL-6 receptors. In vivo studies further confirmed CC's ability to modulate PPAR-γ and IL-6, contributing to its antidiabetic effects. CONCLUSION: CC manages diabetes by regulating the PPAR-γ pathway and suppressing associated inflammation, providing a multi-pathway therapeutic approach.

TDP-43 ameliorates aging-related cartilage degradation through preventing chondrocyte senescence.

Senescent chondrocytes or signaling mechanisms leading to senescence are promising new therapeutic approaches for ameliorating cartilage degradation. Herein, we show that the transactive response DNA/RNA-binding protein (TDP-43) regulates chondrocyte senescence and ameliorates cartilage degradation. First, a significant decrease in TDP-43 was observed in 16-month-old mice compared with younger mice. Immunohistochemistry (IHC) analysis of mouse articular cartilage showed that p21, p16, p53, and matrix metalloprotein-13 (MMP13) were increased, but laminB1 and Collagen type II alpha1 1 chain (Col2a1) were decreased in 16-month-old mice. Furthermore, TDP-43 levels were decreased in vivo following D-galactose (D-gal) induction. Therefore, we investigated the role of TDP-43 in the senescent chondrocytes. ATDC5 cells were induced to overexpress TDP-43. Western blot analysis showed increased expression of laminB1, Ki67, and PCNA but decreased expression of p21, p16, p53, and MMP13. Senescence-associated-ß-galactosidase (SA-ß-Gal) assay, γH2AX staining, and EdU were performed to assess changes in chondrocytes, showing weaker SA-ß-Gal and γH2AX staining but stronger EdU and Alican Blue staining. However, TDP-43 deficiency had opposing effects, and similar to D-gal stimulation results. Taken together, our data verified that TDP-43 negatively correlated with senescence markers, positively correlated with cell proliferation markers, and could alleviate cartilage degradation induced by D-gal. This may be an essential mechanism of cellular senescence and cartilage degradation.

Iron silicate perovskite and postperovskite in the deep lower mantle.

Ferromagnesian silicates are the dominant constituents of the Earth's mantle, which comprise more than 80% of our planet by volume. To interpret the low shear-velocity anomalies in the lower mantle, we need to construct a reliable transformation diagram of ferromagnesian silicates over a wide pressure-temperature (P-T) range. While MgSiO3 in the perovskite structure has been extensively studied due to its dominance on Earth, phase transformations of iron silicates under the lower mantle conditions remain unresolved. In this study, we have obtained an iron silicate phase in the perovskite (Pv) structure using synthetic fayalite (Fe2SiO4) as the starting material under P-T conditions of the lower mantle. Chemical analyses revealed an unexpectedly high Fe/Si ratio of 1.72(3) for the Pv phase in coexistence with metallic iron particles, indicating incorporation of about 25 mol% Fe2O3 in the Pv phase with an approximate chemical formula (Fe2+0.75Fe3+0.25)(Fe3+0.25Si0.75)O3. We further obtained an iron silicate phase in the postperovskite (PPv) structure above 95 GPa. The calculated curves of compressional (VP) and shear velocity (VS) of iron silicate Pv and PPv as a function of pressure are nearly parallel to those of MgSiO3, respectively. To the best of our knowledge, the iron silicate Pv and PPv are the densest phases among all the reported silicates stable at P-T conditions of the lower mantle. The high ferric iron content in the silicate phase and the spin-crossover of ferric iron at the Si-site above ~55 GPa should be taken into account in order to interpret the seismic observations. Our results would provide crucial information for constraining the geophysical and geochemical models of the lower mantle.

Genetic associations with longevity are on average stronger in females than in males.

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that "one-size-fits-all" for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis.

Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function progressively declines. Currently, whether and how metformin protects the kidney remains unclear. In this study, among longevity drugs, including metformin, nicotinamide, resveratrol, rapamycin, and senolytics, we unexpectedly found that metformin, even at low doses, exacerbated experimentally-induced acute kidney injury (AKI) and increased mortality in mice. By single-cell transcriptomics analysis, we found that death of renal parenchymal cells together with an expansion of neutrophils occurs upon metformin treatment after AKI. We identified programmed cell death by ferroptosis in renal parenchymal cells and blocking ferroptosis, or depleting neutrophils protects against metformin-induced nephrotoxicity. Mechanistically, upon induction of AKI, ferroptosis in renal parenchymal cells initiates the migration of neutrophils to the site of injury via the surface receptor CXCR4-bound to metformin-iron-NGAL complex, which results in NETosis aggravated AKI. Finally, we demonstrated that reducing iron showed protective effects on kidney injury, which supports the notion that iron plays an important role in metformin-triggered AKI. Taken together, these findings delineate a novel mechanism underlying metformin-aggravated nephropathy and highlight the mechanistic relationship between iron, ferroptosis, and NETosis in the resulting AKI.

Design and application of modified CAD/CAM socket-shield preparation template in immediate implantation in the esthetic area.

OBJECTIVE: Designed and applicated a modified customized CAD-CAM socket-shield preparation guide template in immediate implant and followed up for 3 years. CLINICAL CONSIDERATIONS: Socket-shield technique could improve the esthetic effect of immediate implant restorations by preserving the labial fascicular bone-periodontal complex at the implant site. While the socket-shield technique is highly technique-sensitive. A modified customized CAD/CAM guided template was designed and fabricated by 3D printing. The movement of the carbide bur during preparing the socket-shield was limited by the socket-shield preparation template. In this case report, the socket-shield preparation template was used for preparing the socket-shield in the tooth root with irregular morphology and the case was followed up for 3 years. CONCLUSIONS: The modified CAD/CAM socket-shield preparation template effectively improved the accuracy and efficiency of preparing the socket-shield by limiting the movement of the high-speed carbide bur in both in both lip-to-palatal and crown-to-root orientation. The socket-shield with accurate morphology could effectively maintain the gingival marginal level and contour. CLINICAL SIGNIFICANCE: The modified CAD/CAM socket-shield preparation template with the depth-locking ring effectively reduced the technique sensitivity and time consumption of the socket-shield technique, especially for tooth roots with irregular morphology.

Evaluating the effect of preheating on resin composites in pit-and-fissure caries treatments with a digital intraoral scanner.

OBJECTIVE: To evaluate the effect of preheating on the microleakage and surface hardness of resin composites in the treatment of pit-and-fissure caries with various widths, as measured by an intraoral scanner. METHODS: A total of 153 L-shaped cavities with different widths (1 mm, 1.6 mm and 2 mm) were prepared on the buccal or palatal/lingual surfaces of human molars. The cavities were measured in three dimensions by a TRIOS scanner and then filled with various resins (room temperature Z350 flowable resin and room temperature and 60 â„ƒ Z350 universal resin). Microleakage and gap formation at 2 sites were evaluated by stereomicroscopy and scanning electron microscope. Resin samples were prepared, and the top surface Vickers hardness (VHNtop) of all samples was measured at 1 day and 30 days postirradiation. RESULTS: No difference were observed in the 3D scans for the cavities sizes among groups with the same width. For the 1 mm-wide cavity, the lowest microleakage was obtained with the flowable group; for the 1.6 mm-wide cavity, the nonpreheating universal group showed the highest microleakage at site 1, and the preheating group exhibited lower microleakage than that of the nonpreheating universal group at site 2; and for the 2 mm-wide cavity, the preheating group presented lower microleakage at site 2. The gap formations were consistent with the microleakage degrees. The preheating group exhibited the highest VHNtop at 1 day and 30 days postirradiation. SIGNIFICANCE: A digital intraoral scanner could be used to scan the cavities in three dimensions. Preheating technology could reduce the microleakage of Z350 universal resin and enhance its surface hardness.

An Accurate and Individualized Preoperative Estimation Method for the Linear Insertion Depth of Cochlear Implant Electrode Arrays Based on Computed Tomography.

OBJECTIVES: Cochlear implantation or auditory brainstem implantation is currently the only accepted method for improving severe or profound sensorineural hearing loss. The length of the electrodes implanted during cochlear implantation is closely related to the degree of hearing improvement of hearing after the surgery. We aimed to explore new methods to accurately estimate the electrode array (EA) linear insertion depth based on computed tomography (CT) images prior surgery, which could help surgeons select the appropriate EA length for each patient. DESIGN: Previous studies estimated the linear insertion depth by measuring the length of the lateral wall of the cochlea rather than the electrode's path in the cochlea duct. Here, we determined the actual position of the EA on the CT image after cochlear surgery in order to predict the path of the EA, and the length of the predicted EA path was measured by the contouring technique (CoT) to estimate the linear insertion depth of the EA. Because CoT can only measure the length of the estimated EA path on a two-dimensional plane, we further modified the measurement by weighting the height of the cochlea and the length of the EA tail (the length of the last stimulating electrode to the end, which cannot be displayed on the CT image), which we termed the modified CoT + height + tail (MCHT) measurement. RESULTS: Based on our established method, MCHT could reduce the error to the submillimeter range (0.67 ± 0.37 mm) when estimating the linear insertion depth of various kinds of EAs compared with the actual implant length. The correlation coefficient between the linear insertion depth as predicted by MCHT and the actual was 0.958. The linear insertion depth estimated by this method was more accurate than that estimated using the classical CoT technique ( R = 0.442) and using the modified Escudé's method ( R = 0.585). CONCLUSIONS: MCHT is a method based on CT images that can accurately predict the linear insertion depth of cochlear implants preoperatively. This is the first report that we are aware of a method for predicting linear insertion depth before cochlear implantation with only submillimeter errors and that is tailored to different types of EAs.

Causal Effects of Circulating Lipid Traits on Epithelial Ovarian Cancer: A Two-Sample Mendelian Randomization Study.

Ovarian cancer (OC), and particularly epithelial OC (EOC), is an increasing challenge for women. Circulating lipids play different roles in the occurrence and development of OC, but no causal relationship has been confirmed. We used two-sample Mendelian randomization (MR) to evaluate the genetic effects of circulating Apolipoprotein A1 (APOA1), Apolipoprotein B (APOB), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyc-erides (TG) on EOC risks based on summary data obtained from the UK Biobank and the Ovarian Cancer Association Consortium. We used the inverse-variance weight as the main statistical method and the MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. A 1-SD increment in HDL gave odds ratios (OR) and 95% confidence intervals (CI) of OR = 0.80 (95% CI: 0.69-0.93), OR = 0.77 (95% CI: 0.66-0.90), and OR = 0.76 (95% CI: 0.63-0.90) for low malignant potential OC (LMPOC), low-grade low malignant OC (LGLMSOC), and low malignant serous OC (LMSOC), respectively. Genetic liability due to TG was associated with an increased risk of LGLMSOC and LGSOC and a suggestive association with an increased risk of LMSOC (p = 0.001, p = 0.007, and p = 0.027, respectively). Circulating HDL was negatively associated with the risk of LMPOC, LGLMSOC, and LMSOC, while elevated circulating TG levels genetically predicted an increased risk of LGLMSOC and LGSOC. Further research is needed to investigate the causal effects of lipids on EOC and potential intervention and therapeutic targets.

A population-based study of precision health assessments using multi-omics network-derived biological functional modules.

Recent technological advances in multi-omics and bioinformatics provide an opportunity to develop precision health assessments, which require big data and relevant bioinformatic methods. Here we collect multi-omics data from 4,277 individuals. We calculate the correlations between pairwise features from cross-sectional data and then generate 11 biological functional modules (BFMs) in males and 12 BFMs in females using a community detection algorithm. Using the features in the BFM associated with cardiometabolic health, carotid plaques can be predicted accurately in an independent dataset. We developed a model by comparing individual data with the health baseline in BFMs to assess health status (BFM-ash). Then we apply the model to chronic patients and modify the BFM-ash model to assess the effects of consuming grape seed extract as a dietary supplement. Finally, anomalous BFMs are identified for each subject. Our BFMs and BFM-ash model have huge prospects for application in precision health assessment.

Optimal timing of salvage intratympanic steroids in idiopathic sudden sensorineural hearing loss.

Background: Salvage intratympanic steroids (ITS) works in patients with idiopathic sudden sensorineural hearing loss (ISSNHL) after failure of initial therapy, but optimal timing of administration is unknown. Methods: Two hundred and seventy patients with ISSNHL were included. Among them, 180 were treated with ITS and standard medical treatment (SMT) and the other 90 received SMT along. The hearing threshold before and after salvage treatment were compared. The relationship between the salvage starting time and hearing recovery was analyzed. Results: The hearing of ITS group improved more than that of the SMT group in all frequency bands. The effect of both strategies decreases with the delay of the starting time. ITS can improve hearing even if being administrated 5 weeks after onset while SMT failed after 3 weeks. Conclusion: Patients with profound ISSNHL can obtain extra hearing recovery from salvage ITS. The earlier salvage starts, the greater the patient benefits.

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma.

Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both in vitro and in vivo. Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.

Genetic trade-offs between complex diseases and longevity.

Longevity was influenced by many complex diseases and traits. However, the relationships between human longevity and genetic risks of complex diseases were not broadly studied. Here, we constructed polygenic risk scores (PRSs) for 225 complex diseases/traits and evaluated their relationships with human longevity in a cohort with 2178 centenarians and 2299 middle-aged individuals. Lower genetic risks of stroke and hypotension were observed in centenarians, while higher genetic risks of schizophrenia (SCZ) and type 2 diabetes (T2D) were detected in long-lived individuals. We further stratified PRSs into cell-type groups and significance-level groups. The results showed that the immune component of SCZ genetic risk was positively linked to longevity, and the renal component of T2D genetic risk was the most deleterious. Additionally, SNPs with very small p-values (p ≤ 1x10-5 ) for SCZ and T2D were negatively correlated with longevity. While for the less significant SNPs (1x10-5  < p ≤ 0.05), their effects on disease and longevity were positively correlated. Overall, we identified genetically informed positive and negative factors for human longevity, gained more insights on the accumulation of disease risk alleles during evolution, and provided evidence for the theory of genetic trade-offs between complex diseases and longevity.

Causal Associations of Circulating Lipids with Osteoarthritis: A Bidirectional Mendelian Randomization Study.

Osteoarthritis (OA) imposes an increasing social burden due to global activity limitations, especially among the aged. Links between circulating lipids and OA have been reported; however, confounding data from observational studies have hindered causal conclusions. We used Mendelian randomization (MR) approach to evaluate the genetic causal effects of circulating apolipoproteins and lipoprotein lipids on OA risk. Genetic instruments at the genome-wide significance level (p < 5 × 10−8) were selected from genome-wide association studies (n = 393,193−441,016 individuals). Summary-level OA data were obtained from the UK Biobank (39,427 cases, 378,169 controls). Bidirectional two-sample Mendelian randomization (MR) analyses used MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. Genetic predisposition to 1-SD increments of Apolipoprotein B (APOB), and low-density lipoprotein (LDL) was associated with a decreased risk of knee or hip OA (KHOA) (odds ratio (OR) = 0.925, 95% confidence interval (95% CI): 0.881−0.972, p = 0.002; OR = 0.898, 95% CI: 0.843−0.957, p = 0.001) and hip OA (HOA) (OR = 0.894; 95% CI: 0.832−0.961, p = 0.002; OR = 0.870 95% CI: 0.797−0.949, p = 0.002). Genetically predicted APOB showed an association with knee OA (KOA) (OR per SD increase, 0.930, 95% CI: 0.876−0.987, p = 0.016). The OR of KOA was 0.899 (95% CI: 0.835−0.968, p = 0.005) for a 1-SD increase in LDL. Apolipoprotein A1, high-density lipoprotein, and triglycerides showed no association. Inverse MR showed no causal effect of KOA, HOA, or KHOA on these serum lipids. Distinct protective genetic-influence patterns were observed for APOB and LDL on OA, offering new insights into relationships between lipids and OA risk and a better understanding of OA etiology.

Genetic Support of A Causal Relationship Between Iron Status and Type 2 Diabetes: A Mendelian Randomization Study.

CONTEXT: Iron overload is a known risk factor for type 2 diabetes (T2D); however, iron overload and iron deficiency have both been associated with metabolic disorders in observational studies. OBJECTIVE: Using mendelian randomization (MR), we assessed how genetically predicted systemic iron status affected T2D risk. METHODS: A 2-sample MR analysis was used to obtain a causal estimate. We selected genetic variants strongly associated (P < 5 × 10-8) with 4 biomarkers of systemic iron status from a study involving 48 972 individuals performed by the Genetics of Iron Status consortium and applied these biomarkers to the T2D case-control study (74 124 cases and 824 006 controls) performed by the Diabetes Genetics Replication and Meta-analysis consortium. The simple median, weighted median, MR-Egger, MR analysis using mixture-model, weighted allele scores, and MR based on a Bayesian model averaging approaches were used for the sensitivity analysis. RESULTS: Genetically instrumented serum iron (odds ratio [OR]: 1.07; 95% CI, 1.02-1.12), ferritin (OR: 1.19; 95% CI, 1.08-1.32), and transferrin saturation (OR: 1.06; 95% CI, 1.02-1.09) were positively associated with T2D. In contrast, genetically instrumented transferrin, a marker of reduced iron status, was inversely associated with T2D (OR: 0.91; 95% CI, 0.87-0.96). CONCLUSION: Genetic evidence supports a causal link between increased systemic iron status and increased T2D risk. Further studies involving various ethnic backgrounds based on individual-level data and studies regarding the underlying mechanism are warranted for reducing the risk of T2D.

Causal association of childhood obesity with cancer risk in adulthood: A Mendelian randomization study.

In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two-sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long-term cancer risk. Single-nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large-scale genome-wide association studies were used as genetic instruments. Summary-level data for 24 site-specific cancers were obtained from UK Biobank. We found that a 1-SD increase in childhood BMI (kg/m2 ) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12-2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09-1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27-0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64-0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.