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Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

ObjectivesTo identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.MethodsThe GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10(-8)) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.ResultsThe A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10(-8)). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10(-6)). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10(-13)), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.ConclusionsResults from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p

ObjectivesOsteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.MethodsWe performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.ResultsWe accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).ConclusionsNovel genetic loci for hip OA were found in this meta-analysis of GWAS.

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

Abstract Background The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis. Methods In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls. Results The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05). Conclusion This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.

Abstract Background Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk. As vitamin B12 and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration (≥ 12 μmol/L). One group receives daily a tablet with 500 μg vitamin B12 and 400 μg folic acid and the other group receives a placebo tablet. In both tablets 15 μg (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers, physical performance and physical activity including falls, nutritional intake and status, cognitive function, depression, genetics and quality of life. This large multi-center project is carried out by a consortium from the Erasmus MC (Rotterdam, the Netherlands), VUmc (Amsterdam, the Netherlands) and Wageningen University, (Wageningen, the Netherlands), the latter acting as coordinator. Discussion To our best knowledge, the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population. We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013. The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures. Trial Registration The B-PROOF study is registered with the Netherlands Trial (NTR NTR1333) and with ClinicalTrials.gov (NCT00696514).

Abstract Background The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis. Methods In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls. Results The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05). Conclusion This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.

Background: Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology.Methods: We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees.Results: We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci.Conclusions: We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes. [ABSTRACT FROM AUTHOR]

Background: With a number of vaccines against COVID-19 now widely available globally, it is opportune to determine what tips the decision to get vaccinated. In most countries like the Philippines where the government provides these vaccines for free to all its citizens, their COVID-19 vaccine awareness and COVID-19 information sources as well as their socio-demographic profile were considered as primary factors that could possibly affect vaccination decisions. Participants' income level was considered as a possible financial consideration that can affect vaccination decision as transport to vaccination sites might entail costs to them., Methods: This study used a cross sectional survey design wherein participants came from all regions of the Philippines. An online questionnaire was voluntarily answered by Filipinos aged 18-80 years of age., Results: A total of 2,268 participated in the survey with 1,462 having complete responses which were included in the analysis. Those who are younger, with higher educational attainment, with public health insurance, with employers requiring vaccination, high awareness about COVID-19 vaccination, and high vaccine confidence are more likely to get vaccinated. On the other hand, those with long-standing illness and those residing outside the national capital region are less likely to get vaccinated., Conclusion: Vaccination decisions among Filipinos are determined by their age, educational attainment, health insurance, employer requirement, high awareness of the disease, and a high level of vaccine confidence., (© 2023. The Author(s).)

Neuroplasticity enables teleosts to promote or downregulate the growth of their brains regionally. To compensate for the effects of predation pressure, teleosts may alter their brain morphology and behavioral responses to mitigate its impact on individual fitness. High-predation environments often promote specific patterns of brain growth and produce bolder and more proactive populations. Owing to the expense of maintaining neural tissue, relative size indicates the regions most relied upon. In northern redbelly dace Chrosomus eos , as little as 2 weeks of elevated predation pressure, resulted in increased investment in their olfactory bulbs and optic tecta, while the imposition of captivity produced smaller, less symmetric hypothalami. Taken together, these results suggest that an individual could potentially become better able to detect a threat, and simultaneously less inclined to react to it, making the impact of either change in isolation is difficult to discern. Here, we compared interindividual variation in gross brain morphology, risk-taking tactics in a novel arena (shy-bold personality), and responding to olfactory cues (proactive/reactive stress-coping style). We hypothesized that olfactory investment would positively correlate with response intensity to predator cue concentration and respond across a wider range of cue concentrations, while hypothalamus size would correlate with shyness and reactivity. Exposure to heightened risk produced more bold/proactive individuals, with larger olfactory bulbs and smaller hypothalami. However, the direction of the correlation between hypothalamus size and behavior varied by treatment, and olfactory investment only corresponded with response intensity amongst proactive individuals. Our findings illustrate the potential pitfalls of relating gross brain morphology to complex behavior and suggest that stress-coping style is a relevant consideration in future studies., Competing Interests: The authors have no competing interests to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of Editorial Office, Current Zoology.)

This study replicates and extends prior research indicating that individuals with elevated psychopathic traits are better able to identify vulnerability to criminal victimization. Specifically, the current study aims to further assess this finding, examine if criminal experience aids in the assessment in vulnerability to criminal victimization, and determine if the finding generalizes to females and non-Caucasians. Through an online survey, participants (undergraduate students; n = 247) viewed several videos of people walking alone down a hallway and subsequently rated the vulnerability to criminal victimization of the depicted person. Higher levels of psychopathic traits (measured by the Elemental Psychopathy Assessment) correlated with more accurate assessments of vulnerability when males were assessing videos of males of their same race. Prior criminal behavior, however, did not relate to better accuracy, despite its relation to psychopathic traits. Results for females were not consistent with findings for males, indicating the finding may not generalize across gender. The current findings suggest one mechanism that might explain why those with elevated psychopathic traits are more likely to offend is that they are adept at identifying vulnerability. However, this was only true for males of the same race as the "victim."

Ischemic stroke remains the fifth leading cause of death in the United States. Nurses play a pivotal role in the care of patients throughout the continuum. With the advances in stroke care, including mechanical thrombectomy, the American Heart Association/American Stroke Association charged the writing panel to complement the 2009 clinical practice guideline, "Comprehensive Overview of Nursing and Interdisciplinary Care of the Acute Ischemic Stroke Patient," with current evidence-based nursing care. This update is 1 of a 3-part series focusing on emergency medical services/emergency care, endovascular/intensive care unit care, and postacute care. The aim of this scientific statement is to review and present current evidence, complications, best practices, and clinical practice strategies to provide current comprehensive scientific information for nursing care in the neuroendovascular area and intensive care unit in conjunction with medical treatments, including intravenous thrombolysis and mechanical thrombectomy.

Background: Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology., Methods: We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees., Results: We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa , RUNX2 , COL27A1 , ASTN2 , IL11 and GDF5 loci., Conclusions: We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Teleost fish are neuroplastic and are known to alter their brain morphology and behaviour in response to environmental change such as an increase in predation pressure. The hypothalamus plays a key role in regulating behavioural responses to predation risk. In this study, wild-caught northern red bellied dace (Chrosomus eos) developed smaller and less symmetric hypothalami when held in captivity for 14 days; both measures correlated with boldness in a latency to emerge test. This study's results highlight the potential impact of short-term holding conditions on brains and behaviour., (© 2020 The Fisheries Society of the British Isles.)

Accurate diagnosis of vertebral osteoporotic fractures is crucial for the identification of individuals at high risk of future fractures. Different methods for radiological assessment of vertebral fractures exist, but a gold standard is lacking. The aim of our study was to estimate statistical measures of agreement and prevalence of osteoporotic vertebral fractures in the population-based Rotterdam Study, across two assessment methods. The quantitative morphometry assisted by SpineAnalyzer® (QM SA) method evaluates vertebral height loss that affects vertebral shape whereas the algorithm-based qualitative (ABQ) method judges endplate integrity and includes guidelines for the differentiation of vertebral fracture and nonfracture deformities. Cross-sectional radiographs were assessed for 7582 participants aged 45 to 95 years. With QM SA, the prevalence was 14.2% (95% CI, 13.4% to 15.0%), compared to 4.0% (95% CI, 3.6% to 4.5%) with ABQ. Inter-method agreement according to kappa (κ) was 0.24. The highest agreement between methods was among females (κ = 0.31), participants age >80 years (κ = 0.40), and at the L 1 level (κ = 0.40). With ABQ, most fractures were found at the thoracolumbar junction (T 12 -L 1 ) followed by the T 7 -T 8 level, whereas with QM SA, most deformities were in the mid thoracic (T 7 -T 8 ) and lower thoracic spine (T 11 -T 12 ), with similar number of fractures in both peaks. Excluding mild QM SA deformities (grade 1 with QM) from the analysis increased, the agreement between the methods from κ = 0.24 to 0.40, whereas reexamining mild deformities based on endplate depression increased agreement from κ = 0.24 to 0.50 (p <0.001). Vertebral fracture prevalence differs significantly between QM SA and ABQ; reexamining QM mild deformities based on endplate depression would increase the agreement between methods. More widespread and consistent application of an optimal method may improve clinical care. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Aim: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes., Methods: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis., Results: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6., Conclusion: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.

Recent studies have documented that exposure to high levels of background risk can induce neophobic predator avoidance in prey animals, whereby they respond to any novel cue with an anti-predator response. Such phenotypically plastic predator avoidance may allow prey to maximize anti-predator benefits in variable risk environments. It remains poorly understood whether risk assessment information from different sensory modalities can be integrated to induce generalized, cross-sensory system neophobic responses. Here, we directly test this hypothesis by exposing juvenile convict cichlids (Amatitlania nigrofasciata) to high- versus low-risk environments using either conspecific alarm cue (chemosensory risk) or a model avian predator (visual/mechanical risk) and testing their response to a novel chemosensory cue (Experiment 1) or visual cue (Experiment 2). Our results suggest that regardless of the sensory modality used to increased perceived risk, cichlids pre-exposed to high-risk conditions exhibited increased predator avoidance in response to any novel visual or chemical cue. As expected, cichlids pre-exposed to low-risk conditions did not display any neophobic responses. Our results suggest that induced neophobia is not cue specific; rather, it may function as a generalized response to perceived predation risk.