Population-specific genotype imputations using minimac or IMPUTE2

In order to meaningfully analyze common and rare genetic variants, results from genome-wide association studies (GWASs) of multiple cohorts need to be combined in a meta-analysis in order to obtain enough power. This requires all cohorts to have the same single-nucleotide polymorphisms (SNPs) in their GWASs. To this end, genotypes that have not been measured in a given cohort can be imputed on the basis of a set of reference haplotypes. This protocol provides guidelines for performing imputations

Predictive associations between lifestyle behaviours and dairy consumption: The IDEFICS study

Background and aim: Physical activity (PA) and sedentary behaviours (SB) are related to obesity and cardiometabolic risk; however, the literature is controversial regarding the effect of dairy consumption on the development of cardiovascular disease (CVD) risk factors. The aim of this study was to assess longitudinally the relationship between specific lifestyle behaviours (PA and SB) and dairy consumption in a sample of European children and adolescents. Methods and results: Children from the IDEFICS study were included in the analyses. Two measurements, with 2 years'' interval, were conducted. A total of 1688 (50.8% boys) children provided information regarding diet, measured by a 24-h dietary recall, PA measured by accelerometers and parent-reported sedentary screen time (SST) at both time points. Different combinations of these behaviours, at each survey and over time, were derived applying specific recommendations. Multilevel ordinal logistic regression and analysis of covariance were used to assess their association with dairy consumption, adjusted for potential confounders. Differences by gender were found regarding dairy product consumption and also adherence to SB and PA recommendations at T0 and T1. Children meeting both lifestyle recommendations, at the two measurement points, had higher probability to consume more milk and yogurt and less cheese than the rest of combinations. Conclusions: These results suggest that European children with a healthy lifestyle, especially regarding PA and SB over time, consumed more milk and yogurt. This study suggests that the protective effect of specific dairy products found in literature could be partially due to the association of their consumption with specific healthy lifestyles

Prospective physical fitness status and development of cardiometabolic risk in children according to body fat and lifestyle behaviours: The IDEFICS study

Background: Elevated cardiometabolic risk (CMR) is an important factor for cardiovascular diseases later in life while physical fitness seems to decrease CMR. Objective: Thus, the aim of the present study is to assess the association between muscular fitness (MF) and cardiorespiratory fitness (CRF) on CMR in European children, both cross-sectional and longitudinally. Methods: A total of 289 children (49.5% males) from eight European countries, aged 6 to 9, with longitudinal information on blood pressure, triglycerides, total cholesterol, HDL-cholesterol, homoeostasis model assessment, body mass index, data on fitness level, objectively measured physical activity (PA), diet quality, and total screen time were included. A CMR score was calculated and dichotomized. MF and CRF were also dichotomized. Cross-sectional and longitudinal multilevel logistic regressions adjusting for lifestyle behaviours were performed. Results: Reaching a high level of MF during childhood as well as remaining in that level over-time were associated with an 82% and 62% lower probability of high CMR at follow-up, respectively. Also, children who became top CRF over time, showed a 77% lower probability (P < 0.05) of being in the highest CMR quartile at follow-up, independently of sociodemographic and lifestyle indicators. Conclusions: A high MF at early childhood and during childhood reduces the odds of having CMR. Same occurs with the improvement of CRF during childhood. These findings highlight the importance of enhancing fitness to avoid CMR already in children. © 2021 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

Fine-scale mapping of Schistosoma mansoni infections and infection intensities in sub-districts of Makenene in the Centre region of Cameroon

BackgroundSchistosomiasis control relies mainly on mass drug administration of Praziquantel (PZQ) to school aged children (SAC). Although precision mapping has recently guided decision making, the sub-districts and the epidemiological differences existing between bio-ecological settings in which infected children come from were not taken into consideration. This study was designed to fill this gap by using POC-CCA and KK to comparatively determine the prevalence and infection intensities of Schistosoma mansoni (S. mansoni) and to perform fine-scale mapping of S. mansoni infections and its infection intensities with the overarching goal of identifying sub-districts presenting high transmission risk where control operations must be boosted to achieve schistosomiasis elimination.MethodologyDuring a cross- sectional study conducted in Makenene, 1773 stool and 2253 urine samples were collected from SAC of ten primary schools. S. mansoni infections were identified using the point of care circulating cathodic antigen (POC-CCA) and Kato-Katz (KK) test respectively on urine and stool samples. Geographical coordinates of houses of infected SAC were recorded using a global position system device. Schistosome infections and infection intensities were map using QGIS software.ResultsThe prevalence of S. mansoni inferred from POC-CCA and KK were 51.3% and 7.3% respectively. Most infected SAC and those bearing heavy infections intensities were clustered in sub-districts of Baloua, Mock-sud and Carriere. Houses with heavily-infected SAC were close to risky biotopes.ConclusionThis study confirms the low sensitivity of KK test compared to POC-CCA to accurately identify children with schistosome infection and bearing different schistosome burden. Fine-scale mapping of schistosome infections and infection intensities enabled to identify high transmission sub-districts where control measures must be boosted to reach schistosomiasis elimination.Host-parasite interactio

Effect of sickle cell trait and apol1 genotype on the association of soluble upar with kidney function measures in black americans

Soluble urokinase plasminogen activator receptor (suPAR) is the circulating form of urokinase plasminogen activator receptor, a glycosyl-phosphatidylinositol–anchored membrane protein expressed in various cell types including kidney podocytes and endothelial cells. suPAR has been associated with a decline in eGFR and the risk of incident CKD or proteinuria in a variety of clinical settings. In the United States, the higher risk of CKD in Black people compared with White people may be at least partially attributable to two genetic susceptibility factors, APOL1 and sickle cell trait, which occur respectively in approximately 13% and 8% of Black people. Hayeketal recently showed that suPAR levels modify the association between APOL1 genotype and eGFR decline in the African American Study of Kidney Disease and Hypertension and a cohort registry of Black people who underwent cardiac catherization

Virological characteristics of the SARS-CoV-2 BA.2.86 variant

オミクロンBA.2.86株のウイルス学的特性の解明. 京都大学プレスリリース. 2024-01-30.A comprehensive systematic characterization of the SARS-CoV-2 strain BA.2.86. 京都大学プレスリリース. 2024-01-31.In late 2023, several SARS-CoV-2 XBB descendants, notably EG.5.1, were predominant worldwide. However, a distinct SARS-CoV-2 lineage, the BA.2.86 variant, also emerged. BA.2.86 is phylogenetically distinct from other Omicron sublineages, accumulating over 30 amino acid mutations in its spike protein. Here, we examined the virological characteristics of the BA.2.86 variant. Our epidemic dynamics modeling suggested that the relative reproduction number of BA.2.86 is significantly higher than that of EG.5.1. Additionally, four clinically available antivirals were effective against BA.2.86. Although the fusogenicity of BA.2.86 spike is similar to that of the parental BA.2 spike, the intrinsic pathogenicity of BA.2.86 in hamsters was significantly lower than that of BA.2. Since the growth kinetics of BA.2.86 are significantly lower than those of BA.2 both in vitro and in vivo, the attenuated pathogenicity of BA.2.86 is likely due to its decreased replication capacity. These findings uncover the features of BA.2.86, providing insights for control and treatment

COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls

Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p , 3.5 3 1024) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95%confidence interval [CI] 1.11-1.24, p 56.62 31028) and deep ICH (lead SNP rs4771674: OR 1.28, 95%CI 1.13-1.44, p 55.76 3 1025). A SNP in HTRA1 was associated (significance threshold p , 5.5 3 1024) with lacunar IS (rs79043147: OR 1.23, 95%CI 1.10-1.37, p 5 1.90 3 1024) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype

The effect on melanoma risk of genes previously associated with telomere length.

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/jnci/dju26

Discovery and fine-mapping of glycaemic and obesity-related trait loci using high-density imputation

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency &ge;0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated