Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.

CCRK is a candidate oncogene in glioblastoma multiforme tumorigenesis.

Objectives The aim of this meta-analysis is to comprehensively evaluate the effects of lean mass on all-cause mortality across different cancer types. Methods This is a meta-analysis. Cohort studies on lean mass and mortality published before December 20, 2017 were obtained by systematic search on PubMed, Cochrane Library, and Embase. Inclusion criteria were cohort studies reporting lean mass measurements by dual-energy X-ray absorptiometry, bioimpedance analysis or computed tomography, and with all-cause mortality as the study outcome. Exclusion criteria were studies using muscle mass surrogates, anthropometric measurement of muscle, rate of change in muscle mass, and sarcopenia defined by composite criteria. Hazard ratios (HRs) and 95% confidence intervals (CIs) of low/reduced lean mass on cancer mortality were pooled with a random-effects model. Subgroup analysis stratifying studies according to cancer type and measurement index was performed. Results Altogether 100 studies evaluated the association between lean mass and cancer mortality. The overall pooled HR on cancer mortality was 1.41 (95% CI, 1.24 to 1.59) for every standard deviation decrease in lean mass and 1.69 (95% CI, 1.56 to 1.83) for patients with sarcopenia (binary cutoffs). Overall mortality was also significantly associated with sarcopenia in across various cancer types, except for hematopoietic, breast, ovarian and endometrial, and prostate cancer. Conclusions The robust association of decreased lean mass with increased mortality further justified the importance of developing clinical guidelines for managing sarcopenia in cancer patients. Public health initiatives aiming at promoting awareness of muscle health in susceptible individuals are urgently needed.

Background Growth differentiation factor 15 (GDF15) is a key regulator of body weight in animals by regulating food intake. Its receptor, glial cell-derived neurotrophic factor receptor alpha-like (GFRAL), was identified recently. Pre-clinical studies showed that it is a promising therapeutic target for cardiometabolic diseases and anorexia/cachexia. Although many pharmaceutical companies are developing drugs targeting GFRAL, whether the findings from animal studies can be extrapolated to man is unknown. Mendelian randomization (MR) is useful in investigating the relationship between risk factors and disease outcomes. We aimed to use a two-sample MR approach to evaluate the clinical usefulness of targeting GDF15 for cardiometabolic diseases. Methods Genetic instruments and summary statistics for MR analyses were obtained from a large genome-wide association study (GWAS) of GDF15 and cardiometabolic outcomes ( n = 27,394 to 644,875), including body mass index, waist-hip ratio, waist circumference, whole-body lean mass, fat percentage, Type 2 Diabetes, fasting glucose, glycated haemoglobin, fasting insulin, LDL-cholesterol, HDL-cholesterol, total cholesterol, triglycerides, coronary artery disease, and estimated BMD (eBMD). Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of GDF-15 with different outcomes; weighted median and MR-egger were used for sensitivity analyses. Findings There was null association between GDF15 levels and anthropometric outcomes. One SD increase in genetically-determined GDF15 was significantly associated with reduced HDL-C (beta: -0.048SD; SE: 0.014; P = .001) but the result was not significant in sensitivity analyses. A consistent significant causal association was observed between GDF15 and eBMD in IVW (beta: 0.026 SD; SE: 0.005; P < .001) and subsequent sensitivity analyses. Interpretation This study sheds lights on the potential of drugs targeting the GDF15/GFRAL axis. It suggested that the effect of targeting GDF15/GFRAL axis for weight control in human may be different from the effects observed in animal studies. GDF15 treatment may improve BMD in humans. Fund No specific funding was received for this study.

Background Low-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to bone mineral density (BMD) and assess the effects of LDL-C-lowering drugs on BMD. Methods Association between blood lipid levels and BMD was examined by epidemiological observation analyses in a US representative cohort NHANES III (n = 3638) and the Hong Kong Osteoporosis Study (HKOS; n = 1128). Two-sample Mendelian randomization (MR), employing genetic data from a large-scale genome-wide association study (GWAS) of blood lipids (n = 188 577), total body BMD (TB-BMD) (n = 66 628) and estimated BMD (eBMD) (n= 142 487), was performed to infer causality between LDL-C and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs’ effects on BMD. Results In the NHANES III cohort, each standard deviation (SD) decrease in LDL-C was associated with a 0.045 SD increase in femoral neck BMD (95% CI: 0.009 − 0.081; P = 0.015). A similar increase in BMD was observed in the HKOS at femoral neck and lumbar spine. In MR analysis, a decrease in genetically predicted LDL-C was associated with an increase in TB-BMD {estimate per SD decrease, 0.038 [95% confidence interval (CI): 0.002 − 0.074]; P = 0.038} and eBMD [0.076 (0.042 − 0.111); P = 1.20x10−5]. Reduction in TB-BMD was causally associated with increased LDL-C [0.035 (0.033 − 0.066); P = 0.034]. Statins’ LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 − 0.316); P = 9.600x10−3] and eBMD [0.143 (0.062 − 0.223); P = 5.165x10−4]. Conclusions Negative causal association exists between LDL-C level and BMD. Statins’ LDL-C-lowering effect increases BMD, suggesting their protective effect on bone.

Context Previous studies suggested a potential link of maternal thyroid dysfunction with adverse neurocognitive outcomes and impaired development of internal organs in offspring. Objective To review the association between maternal thyroid dysfunction and the risk of adverse outcomes in offspring. Data Sources PubMed, EMBASE and Cochrane Library. Study Selections Eligible studies reported the association between maternal thyroid hormone function and the risk of adverse outcomes in their children. Data Extraction Reviewers extracted data on study characteristics and results independently. Data Synthesis Estimates were pooled and reported as odds ratio (OR) with 95% confidence interval (CI). I2 tests were applied to assess the heterogeneity across studies. Results We identified 29 eligible articles and found an association between maternal hyperthyroidism and attention deficit hyperactivity disorder (ADHD) (OR: 1.18, 95% CI: 1.04 - 1.34, I2 = 0%) and epilepsy (OR: 1.19, 95% CI: 1.08 - 1.31, I2 = 0%) in offspring; as well as an association of maternal hypothyroidism with increased risk of ADHD (OR: 1.14, 95% CI: 1.03 - 1.26, I2 = 25%), autism spectrum disorder (OR: 1.41, 95% CI: 1.05 - 1.90, I2 = 63%) and epilepsy (OR: 1.21, 95% CI: 1.06 - 1.39, I2 = 0%) in offspring. Conclusion Routine measurement and timely treatment on thyroid function should be considered for pregnant women.

The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen‐containing bisphosphonates (N‐BPs), non‐N‐BP anti‐osteoporosis medications, and no anti‐osteoporosis medications after hip fracture. We studied a historical cohort using a population‐wide database. Patients with first hip fracture during 2005–2015 were identified and matched by time‐dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox‐proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N‐BPs and 11,802 without anti‐osteoporosis medication were propensity score–matched. N‐BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person‐years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N‐BPs were compared with non‐N‐BP anti‐osteoporosis medications, the association remained significant. N‐BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N‐BPs, non–vaccine‐based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.

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