Circulating Metabolite Abundances Associated With Risks of Bipolar Disorder, Schizophrenia, and Depression: A Mendelian Randomization Study.

BACKGROUND: Preventive measures and treatments for psychiatric disorders are limited. Circulating metabolites are potential candidates for biomarker and therapeutic target identification, given their measurability and essential roles in biological processes. METHODS: Leveraging large-scale genome-wide association studies, we conducted Mendelian randomization analyses to assess the associations between circulating metabolite abundances and the risks of bipolar disorder, schizophrenia, and depression. Genetic instruments were selected for 94 metabolites measured in the Canadian Longitudinal Study on Aging cohort (N = 8299). We repeated Mendelian randomization analyses based on the UK Biobank, INTERVAL, and EPIC (European Prospective Investigation into Cancer)-Norfolk studies. RESULTS: After validating Mendelian randomization assumptions and colocalization evidence, we found that a 1 SD increase in genetically predicted circulating abundances of eicosapentaenoate and docosapentaenoate was associated with odds ratios of 0.72 (95% CI, 0.65-0.79) and 0.63 (95% CI, 0.55-0.72), respectively, for bipolar disorder. Genetically increased Ω-3 unsaturated fatty acids abundance and Ω-3-to-total fatty acids ratio, as well as genetically decreased Ω-6-to-Ω-3 ratio, were negatively associated with the risk of bipolar disorder in the UK Biobank. Genetically increased circulating abundances of 3 N-acetyl-amino acids were associated with an increased risk of schizophrenia with a maximum odds ratio of 1.31 (95% CI, 1.18-1.44) per 1 SD increase. Furthermore, a 1 SD increase in genetically predicted circulating abundance of hypotaurine was associated with an odds ratio of 0.85 (95% CI, 0.78-0.93) for depression. CONCLUSIONS: The biological mechanisms that underlie Ω-3 unsaturated fatty acids, NAT8-catalyzed N-acetyl-amino acids, and hypotaurine warrant exploration to identify new biomarkers and potential therapeutic targets.

Machine learning-based integration develops an immunogenic cell death-derived lncRNA signature for predicting prognosis and immunotherapy response in lung adenocarcinoma.

Accumulating evidence demonstrates that lncRNAs are involved in the regulation of the immune microenvironment and early tumor development. Immunogenic cell death occurs mainly through the release or increase of tumor-associated antigen and tumor-specific antigen, exposing "danger signals" to stimulate the body's immune response. Given the recent development of immunotherapy in lung adenocarcinoma, we explored the role of tumor immunogenic cell death-related lncRNAs in lung adenocarcinoma for prognosis and immunotherapy benefit, which has never been uncovered yet. Based on the lung adenocarcinoma cohorts from the TCGA database and GEO database, the study developed the immunogenic cell death index signature by several machine learning algorithms and then validated the signature for prognosis and immunotherapy benefit of lung adenocarcinoma patients, which had a more stable performance compared with published signatures in predicting the prognosis, and demonstrated predictive value for benefiting from immunotherapy in multiple cohorts of multiple cancers, and also guided the utilization of chemotherapy drugs.

Microbes for lung cancer detection: feasibility and limitations.

As the second most common cancer in the world, the development of lung cancer is closely related to factors such as heredity, environmental exposure, and lung microenvironment, etc. Early screening and diagnosis of lung cancer can be helpful for the treatment of patients. Currently, CT screening and histopathologic biopsy are widely used in the clinical detection of lung cancer, but they have many disadvantages such as false positives and invasive operations. Microbes are another genome of the human body, which has recently been shown to be closely related to chronic inflammatory, metabolic processes in the host. At the same time, they are important players in cancer development, progression, treatment, and prognosis. The use of microbes for cancer therapy has been extensively studied, however, the diagnostic role of microbes is still unclear. This review aims to summarize recent research on using microbes for lung cancer detection and present the current shortcomings of microbes in collection and detection. Finally, it also looks ahead to the clinical benefits that may accrue to patients in the future about screening and early detection.

Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers.

Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.

Deciphering the heterogeneity dominated by tumor-associated macrophages for survival prognostication and prediction of immunotherapy response in lung adenocarcinoma.

Tumor-associated macrophages (TAMs) are a specific subset of macrophages that reside inside the tumor microenvironment. The dynamic interplay between TAMs and tumor cells plays a crucial role in the treatment response and prognosis of lung adenocarcinoma (LUAD). The study aimed to examine the association between TAMs and LUAD to advance the development of targeted strategies and immunotherapeutic approaches for treating this type of lung cancer. The study employed single-cell mRNA sequencing data to characterize the immune cell composition of LUAD and delineate distinct subpopulations of TAMs. The "BayesPrism" and "Seurat" R packages were employed to examine the association between these subgroups and immunotherapy and clinical features to identify novel immunotherapy biomarkers. Furthermore, a predictive signature was generated to forecast patient prognosis by examining the gene expression profile of immunotherapy-associated TAMs subsets and using 104 machine-learning techniques. A comprehensive investigation has shown the existence of a hitherto unidentified subgroup of TAMs known as RGS1 + TAMs, which has been found to have a strong correlation with the efficacy of immunotherapy and the occurrence of tumor metastasis in LUAD patients. CD83 was identified CD83 as a distinct biomarker for the expression of RGS1 + TAMs, showcasing its potential utility as an indicator for immunotherapeutic interventions. Furthermore, the prognostic capacity of the RTMscore signature, encompassing three specific mRNA (NR4A2, MMP14, and NPC2), demonstrated enhanced robustness when contrasted against the comprehensive collection of 104 features outlined in the published study. CD83 has potential as an immunotherapeutic biomarker. Meanwhile, The RTMscore signature established in the present study might be beneficial for survival prognostication.

Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG. METHODS: By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk. RESULTS: We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in TH2 cells and MG risk. CONCLUSIONS: This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.

From target discovery to clinical drug development with human genetics.

The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.

Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection.

BACKGROUND: Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. METHODS: Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p < 0.05). Of these, 62 proteins were validated in an external cohort (p < 0.05, N = 261). RESULTS: We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p < 0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. CONCLUSIONS: Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Acute kidney injury (AKI) is a sudden, sometimes fatal, episode of kidney failure or damage. It is a known complication of COVID-19, albeit through unclear mechanisms. COVID-19 is also associated with kidney dysfunction in the long term, or chronic kidney disease (CKD). There is a need to better understand which patients with COVID-19 are at risk of AKI or CKD. We measure levels of several thousand proteins in the blood of hospitalized COVID-19 patients. We discover and validate sets of proteins associated with severe AKI and CKD in these patients. The markers identified suggest that kidney injury in COVID-19 patients involves damage to kidney cells that reabsorb fluid from urine and reduced blood flow to the heart, causing damage to heart muscles. Our findings might help clinicians to predict kidney injury in patients with COVID-19, and to understand its mechanisms.

Proteomic Characterization of Acute Kidney Injury in Patients Hospitalized with SARS-CoV2 Infection.

Background Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Methods Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 higher plasma abundances of protein targets and 40 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). Results We demonstrate that COVID-AKI is associated with increased markers of tubular injury ( NGAL ) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2 , trefoil factor 3 , transmembrane emp24 domain-containing protein 10 , and cystatin-C indicating tubular dysfunction and injury. Conclusions Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Proteomic Characterization of Acute Kidney Injury in Patients Hospitalized with SARS-CoV2 Infection.

Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using measurements of ∼4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 higher plasma abundances of protein targets and 40 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements.

BACKGROUND: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. MATERIALS AND METHODS: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). RESULTS: An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes. CONCLUSIONS: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. IMPACT: Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.

Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF. METHODS: To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments, we used genetic determinants of circulating proteins which reside cis to the encoded gene (cis-single nucleotide polymorphisms (SNPs)), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalisation analyses to ensure that both the circulating proteins and IPF shared a common genetic signal. RESULTS: MR analyses of 834 proteins found that a 1 sd increase in circulating galactoside 3(4)-l-fucosyltransferase (FUT3) and α-(1,3)-fucosyltransferase 5 (FUT5) was associated with a reduced risk of IPF (OR 0.81, 95% CI 0.74-0.88; p=6.3×10-7 and OR 0.76, 95% CI 0.68-0.86; p=1.1×10-5, respectively). Sensitivity analyses including multiple cis-SNPs provided similar estimates both for FUT3 (inverse variance weighted (IVW) OR 0.84, 95% CI 0.78-0.91; p=9.8×10-6 and MR-Egger OR 0.69, 95% CI 0.50-0.97; p=0.03) and FUT5 (IVW OR 0.84, 95% CI 0.77-0.92; p=1.4×10-4 and MR-Egger OR 0.59, 95% CI 0.38-0.90; p=0.01). FUT3 and FUT5 signals colocalised with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%, respectively. Further transcriptomic investigations supported the protective effects of FUT3 for IPF. CONCLUSIONS: An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.

Health Effects of Calcium: Evidence From Mendelian Randomization Studies.

Calcium is widely used in conjunction with vitamin D to prevent osteoporosis. The use of calcium supplementation is also promoted for its potential benefits in lowering the risk for metabolic syndromes and cancers. However, the causal link between calcium and various health outcomes remains unclear. This review focuses on the evidence from 24 Mendelian randomization (MR) studies that were designed to minimize bias from confounding and reverse causation. These MR studies evaluated the effect of lifelong genetically higher serum calcium levels on various health outcomes. Overall, available MR studies found no conclusive effects of serum calcium levels on bone mineral density and fracture, ischemic stroke and heart failure, cancers, type 2 diabetes, Parkinson disease, or offspring birth weight. However, a higher serum calcium concentration was reported to have estimated causal effects on increased risks for coronary artery disease (especially myocardial infarction), migraine, renal colic, allergy/adverse effect of penicillin, and reduced risks for osteoarthrosis and osteoarthritis. In conclusion, supplementation of calcium in individuals from the general population is not predicted to influence the risk of most investigated diseases to date. Moreover, long-term high serum calcium concentrations may result in adverse health outcomes. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Polygenic Risk Score for Low-Density Lipoprotein Cholesterol Is Associated With Risk of Ischemic Heart Disease and Enriches for Individuals With Familial Hypercholesterolemia.

BACKGROUND: The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH). METHODS: We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41 748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers among individuals with severe hypercholesterolemia and low LDL-C PRS. Last, we contrasted the effect of the LDL-C PRS, measured LDL-C and FH variant carrier status on risk of ischemic heart disease among 3010 cases and 38 738 controls. RESULTS: Among the 41 748 whole-exome sequenced White British individuals, 1-SD increase in the LDL-C PRS was associated with elevated LDL-C among both FH variant carriers (0.34 [95% CI, 0.22-0.47] mmol/L) and noncarriers (0.42 [95% CI, 0.42-0.43] mmol/L). Among individuals with severe hypercholesterolemia, FH variant carriers were enriched in those with a low LDL-C PRS (odds ratio, 2.20 [95% CI, 1.66-2.71] per SD). Each SD increase in the LDL-C PRS was associated with risk of ischemic heart disease to the comparable magnitude as measured LDL-C (odds ratio, 1.24 [95% CI, 1.20-1.29] and odds ratio, 1.15 [95% CI, 1.09-1.23], respectively). The LDL-C PRS was not strongly associated with other traditional ischemic heart disease risk factors. CONCLUSIONS: An LDL-C PRS could be used to identify individuals with a higher probability of harboring FH variants. The association between ischemic heart disease and the LDL-C PRS was comparable to measured LDL-C, likely because the PRS reflects lifetime exposure to LDL-C levels.

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

Genetically Decreased Circulating Vascular Endothelial Growth Factor and Osteoporosis Outcomes: A Mendelian Randomization Study.

Vascular endothelial growth factor (VEGF) is important for bone formation and has been associated with osteoporosis in humans. Therefore, we conducted a two-sample Mendelian randomization study to test whether genetically decreased circulating VEGF was associated with decreased bone mineral density (BMD) and increased risk of fracture. Summary statistics from a genomewide association study (GWAS) meta-analysis of circulating VEGF level (n = 16,112) were used to identify 10 genetic variants explaining up to 52% of the variance in circulating VEGF levels. GWAS meta-analyses on dual-energy X-ray absorptiometry (DXA)-derived BMD of forearm, lumbar spine, and femoral neck (n = up to 32,735) and BMD estimated from heel calcaneus ultrasound (eBMD) (n = 426,824) were used to assess the effect of genetically lowered circulating VEGF levels on BMD. A GWAS meta-analysis including a total of 76,549 cases and 470,164 controls was used to assess the effect of genetically lowered circulating VEGF levels on risk of fracture. A natural log-transformed pg/mL decrease in circulating VEGF levels was not associated with a decrease in forearm BMD (0.02 standard deviation [SD], 95% confidence interval [CI] -0.024 to 0.064, p = 0.38), lumbar spine BMD (-0.005 SD, 95% CI -0.03 to 0.019, p = 0.67), femoral neck BMD (0.004 SD, 95% CI -0.017 to 0.026, p = 0.68), eBMD (-0.006 SD, 95% CI -0.012 to -0.001, p = 0.031) or risk of fracture (odds ratio = 0.99, 95% CI 0.98 to 1.0, p = 0.37) in inverse-variance-weighted Mendelian randomization analyses. Sensitivity analyses did not provide evidence that our results were influenced by pleiotropy. Genetically lowered circulating VEGF was not associated with a decrease in BMD or increased risk of fracture, suggesting that efforts to influence circulating VEGF level are unlikely to have beneficial effects on osteoporosis outcomes and that previous observational associations of circulating VEGF with BMD were influenced by confounding or reverse causation. © 2019 American Society for Bone and Mineral Research.

Associations between iron status and insulin resistance in Chinese children and adolescents: findings from the China Health and Nutrition Survey.

BACKGROUND AND OBJECTIVES: Iron homeostasis abnormalities are associated with insulin resistance (IR), but studies on such associations in children and adolescents are limited and have contrasting results. The purpose of this study was to determine the associations between indicators of iron status and IR, and assesse if there are sex disparities in these associations. METHODS AND STUDY DESIGN: We selected data of 689 children and adolescents (367 boys and 322 girls) aged 6-18 years in the analysis. Serum ferritin, transferrin, and soluble transferrin receptor (sTfR) levels were determined. The level of glycated hemoglobin (HbA1c) was assessed using highperformance liquid chromatography. Homeostasis model assessment of insulin resistance (HOMA-IR) was used to indicate the status of insulin resistance. Stepwise and multivariate logistic regression analyses were computed to evaluate associations between iron status and glucose parameters. RESULTS: The prevalence of IR (HOMAIR >3.16) and high HbA1c (HbA1c ≥5.7%) were 29.8% and 16.4%, respectively. Serum transferrin and sTfR were significant associated with HbA1c (p<0.001), while serum transferrin was associated with HOMA-IR (p<0.001). Furthermore, the highest transferrin concentrations were associated with higher risks of both HOMAIR and high HbA1c, while decreased sTfR concentrations were associated with a risk of higher HbA1c in both children and adolescents. CONCLUSIONS: Serum transferrin and sTfR were statistically significantly associated with glucose parameters, which may suggest that transferrin and sTfR levels should be taken into consideration when studying IR in both boys and girls.

Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study.

OBJECTIVE: To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. DESIGN: Mendelian randomisation study. SETTING: Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). PARTICIPANTS: A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. RESULTS: A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm2, 95% confidence interval -0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. CONCLUSIONS: Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.

Osteochondral repair using scaffolds with gradient pore sizes constructed with silk fibroin, chitosan, and nano-hydroxyapatite.

BACKGROUND: One of the main problems associated with the development of osteochondral reparative materials is that the accurate imitation of the structure of the natural osteochondral tissue and fabrication of a suitable scaffold material for osteochondral repair are difficult. The long-term outcomes of single- or bilayered scaffolds are often unsatisfactory because of the absence of a progressive osteochondral structure. Therefore, only scaffolds with gradient pore sizes are suitable for osteochondral repair to achieve better proliferation and differentiation of the stem cells into osteochondral tissues to complete the repair of defects. METHODS: A silk fibroin (SF) solution, chitosan (CS) solution, and nano-hydroxyapatite (nHA) suspension were mixed at the same weight fraction to obtain osteochondral scaffolds with gradient pore diameters by centrifugation, freeze-drying, and chemical cross-linking. RESULTS: The scaffolds prepared in this study are confirmed to have a progressive structure starting from the cartilage layer to bone layer, similar to that of the normal osteochondral tissues. The prepared scaffolds are cylindrical in shape and have high internal porosity. The structure consists of regular and highly interconnected pores with a progressively increasing pore distribution as well as a progressively changing pore diameter. The scaffold strongly absorbs water, and has a suitable degradation rate, sufficient space for cell growth and proliferation, and good resistance to compression. Thus, the scaffold can provide sufficient nutrients and space for cell growth, proliferation, and migration. Further, bone marrow mesenchymal stem cells seeded onto the scaffold closely attach to the scaffold and stably grow and proliferate, indicating that the scaffold has good biocompatibility with no cytotoxicity. CONCLUSION: In brief, the physical properties and biocompatibility of our scaffolds fully comply with the requirements of scaffold materials required for osteochondral tissue engineering, and they are expected to become a new type of scaffolds with gradient pore sizes for osteochondral repair.

Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population.

Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.