A Non-Toxic Binuclear Vanadium(IV) Complex as Insulin Adjuvant Improves the Glycemic Control in Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus (DM) complications are a burden to health care systems due to the associated consequences of poor glycemic control and the side effects of insulin therapy. Recently. adjuvant therapies, such as vanadium compounds, have gained attention due to their potential to improve glucose homeostasis in patients with diabetes. In order to determine the anti-diabetic and antioxidant effects of the oxidovanadium(IV) complex (Et3NH)2[{VO(OH}2)(ox)2(µ-ox)] or Vox2), rats with streptozotocin (STZ)-induced diabetes were treated with 30 and 100 mg/kg of Vox2, orally administered for 12 days. Vox2 at 100 mg/kg in association with insulin caused a 3.4 times decrease in blood glucose in STZ rats (424 mg/dL), reaching concentrations similar to those in the normoglycemic animals (126 mg/dL). Compared to insulin alone, the association with Vox2 caused an additional decrease in blood glucose of 39% and 65% at 30 and 100 mg/kg, respectively, and an increased pancreatic GSH levels 2.5 times. Vox2 alone did not cause gastrointestinal discomfort, diarrhea, and hepatic or renal toxicity and was not associated with changes in blood glucose level, lipid profile, or kidney or liver function. Our results highlight the potential of Vox2 in association with insulin in treating diabetes.

Apolipoprotein M gene polymorphisms in childhood-onset type 1 diabetes in southern Brazil.

Type 1 diabetes mellitus (T1DM), associated with autoimmune destruction of pancreatic ß cells, is observed in children and adolescents. OBJECTIVE: We investigated the potential association of the apolipoprotein M (APOM) polymorphisms rs707921, rs805264, rs805296, rs805297, and rs9404941 in childhood-onset T1DM (n = 144) and compared them to those in healthy (mostly Euro-Brazilian) children (n = 168). METHODS: This project was approved by the Ethics Committee of the Federal University of Parana (CAAE 24676613.6.0000.0102). Genotyping was performed using PCR-restriction fragment length polymorphisms (rs805296 and rs9404941) and TaqMan probes (rs707921, rs805264, and rs805297). RESULTS: All polymorphisms were in Hardy-Weinberg equilibrium. In the codominant model, no significant differences (P > 0.05) were observed in genotype and allele frequencies between healthy controls and children with T1DM. The minor allele frequencies (95% CI) for healthy subjects were rs707921 (A, 10.7%; 7-14%), rs805264 (A, 6.5%; 4-9%), rs805296 (C, 3.6%; 2-6%), rs805297 (A, 22.6%; 22-31%), and rs9404941 (C, 2.7%; 1-4%). The frequencies of the rs805297 A allele and rs805296 C allele were similar to those of other Caucasian populations; both the rs707921 and rs805264 A alleles were similar to American and Latin American populations, whereas that of the rs9404941 C allele was lower than that observed in the Caucasian and Asian populations. CONCLUSIONS: Haplotype analysis suggests that rs805297-C, rs9404941-T, rs805296-T, rs805264-G, and rs707921-C conferred risk (OR: 4.25; 95% CI: 1.81-10.1) to childhood-onset T1DM in the Euro-Brazilian population.

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores.

BACKGROUND: Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. METHODS: We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10-18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). RESULTS: MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. CONCLUSIONS: Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Cell-Type Heterogeneity in Adipose Tissue Is Associated with Complex Traits and Reveals Disease-Relevant Cell-Specific eQTLs.

Adipose tissue is an important endocrine organ with a role in many cardiometabolic diseases. It is comprised of a heterogeneous collection of cell types that can differentially impact disease phenotypes. Cellular heterogeneity can also confound -omic analyses but is rarely taken into account in analysis of solid-tissue transcriptomes. Here, we investigate cell-type heterogeneity in two population-level subcutaneous adipose-tissue RNA-seq datasets (TwinsUK, n = 766 and the Genotype-Tissue Expression project [GTEx], n = 326) by estimating the relative proportions of four distinct cell types (adipocytes, macrophages, CD4+ T cells, and micro-vascular endothelial cells). We find significant cellular heterogeneity within and between the TwinsUK and GTEx adipose datasets. We find that adipose cell-type composition is heritable and confirm the positive association between adipose-resident macrophage proportion and obesity (high BMI), but we find a stronger BMI-independent association with dual-energy X-ray absorptiometry (DXA) derived body-fat distribution traits. We benchmark the impact of adipose-tissue cell composition on a range of standard analyses, including phenotype-gene expression association, co-expression networks, and cis-eQTL discovery. Our results indicate that it is critical to account for cell-type composition when combining adipose transcriptome datasets in co-expression analysis and in differential expression analysis with obesity-related traits. We applied gene expression by cell-type proportion interaction models (G × Cell) to identify 26 cell-type-specific expression quantitative trait loci (eQTLs) in 20 genes, including four autoimmune disease genome-wide association study (GWAS) loci. These results identify cell-specific eQTLs and demonstrate the potential of in silico deconvolution of bulk tissue to identify cell-type-restricted regulatory variants.

Epigenetic findings in periodontitis in UK twins: a cross-sectional study.

BACKGROUND: Genetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease. METHODS: Self-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples. RESULTS: Epigenome-wide analyses in blood identified one CpG-site (cg21245277 in ZNF804A) associated with gingival bleeding (FDR = 0.03, nominal p value = 7.17e-8) and 58 sites associated with tooth mobility (FDR < 0.05) with the top signals in IQCE and XKR6. Epigenetic variation at 28 candidate regions (247 CpG-sites) for chronic periodontitis showed an enrichment for association with periodontal traits, and signals in eight genes (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, and CXCL1) were significant in both traits. The methylation-phenotype association signals validated in buccal samples, and a subset (25%) also validated in adipose tissue. CONCLUSIONS: Epigenome-wide analyses in adult female twins identified specific DNA methylation changes linked to self-reported periodontal disease. Future work will explore the environmental basis and functional impact of these results to infer potential for strategic personalized treatments and prevention of chronic periodontitis.

Fasting and time of day independently modulate circadian rhythm relevant gene expression in adipose and skin tissue.

BACKGROUND: Intermittent fasting and time-restricted diets are associated with lower risk biomarkers for cardio-metabolic disease. The shared mechanisms underpinning the similar physiological response to these events is not established, but circadian rhythm could be involved. Here we investigated the transcriptional response to fasting in a large cross-sectional study of adipose and skin tissue from healthy volunteers (N = 625) controlling for confounders of circadian rhythm: time of day and season. RESULTS: We identified 367 genes in adipose and 79 in skin whose expression levels were associated (FDR < 5%) with hours of fasting conditionally independent of time of day and season, with 19 genes common to both tissues. Among these genes, we replicated 38 in human, 157 in non-human studies, and 178 are novel associations. Fasting-responsive genes were enriched for regulation of and response to circadian rhythm. We identified 99 genes in adipose and 54 genes in skin whose expression was associated to time of day; these genes were also enriched for circadian rhythm processes. In genes associated to both exposures the effect of time of day was stronger and in an opposite direction to that of hours fasted. We also investigated the relationship between fasting and genetic regulation of gene expression, including GxE eQTL analysis to identify personal responses to fasting. CONCLUSION: This study robustly implicates circadian rhythm genes in the response to hours fasting independently of time of day, seasonality, age and BMI. We identified tissue-shared and tissue-specific differences in the transcriptional response to fasting in a large sample of healthy volunteers.

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

Shared genetic variants suggest common pathways in allergy and autoimmune diseases.

BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Analysis with the exome array identifies multiple new independent variants in lipid loci.

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Farm environment during infancy and lung function at the age of 31: a prospective birth cohort study in Finland.

OBJECTIVES: Farming as an occupation is considered a risk factor for asthma and reduced lung function. By contrast, living on a farm during infancy has been reported to be associated with lower risk of asthma in adulthood. However, little is known about the association between farming environment during infancy and lung function in adulthood. We aimed to study the prospective longitudinal association between farming environment during infancy and lung function in adulthood. DESIGN: A prospective birth cohort study. SETTING: Northern Finland. PARTICIPANTS: 5666 participants born in 1966 were followed up at the age of 31 years. PRIMARY OUTCOME MEASURES: Spirometry at the age of 31 years. RESULTS: To be born into a farmer's family was associated with higher forced expiratory volume in 1 s (FEV1) (36 mL; 95% CI 6 to 67 mL) and forced vital capacity (FVC) (40 mL; 95% CI 5 to 75 mL) at the age of 31 years. Contact with farm animals during infancy was associated with higher FEV1. No associations were seen with FEV1/FVC (FEV1/FVC ratio). Having dogs in childhood revealed similar associations. There was a suggestive dose-dependent association with the number of animal species during childhood and higher FEV1 and FVC at adulthood, especially among women. CONCLUSIONS: Farming environment in early life may have a positive impact on lung function in adulthood.

Multiple measures of adiposity are associated with mean leukocyte telomere length in the northern Finland birth cohort 1966.

Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.

Dysregulation of complement system and CD4+ T cell activation pathways implicated in allergic response.

Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.

Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of ß = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

A new scoring system derived from base excess and platelet count at presentation predicts mortality in paediatric meningococcal sepsis.

INTRODUCTION: The aim of this study was to derive a novel prognostic score for mortality in paediatric meningococcal sepsis (MS) based on readily available laboratory markers. METHODS: A multicentre retrospective cohort study for the consortium set and a single centre retrospective study for replication set. The consortium set were 1,073 children (age 1 week to 17.9 years) referred over a 15-year period (1996 to 2011), who had an admission diagnosis of MS, referred to paediatric intensive care units (PICUs) in six different European centres. The consortium set was split into a development set and validation set to derive the score. The replication set were 134 children with MS (age 2 weeks to 16 years) referred over a 4-year period (2007 to 2011) to PICUs via the Children's Acute Transport Service (CATS), London. RESULTS: A total of 85/1,073 (7.9%) children in the consortium set died. A total of 16/134 (11.9%) children in the replication set died. Children dying in the consortium set had significantly lower base excess, C-reactive protein (CRP), platelet and white cell count, more deranged coagulation and higher lactate than survivors. Paediatric risk of mortality (PRISM) score, Glasgow meningococcal septicaemia prognosis score (GMSPS) and Rotterdam score were also higher. Using the consortium set, a new scoring system using base excess and platelet count at presentation, termed the BEP score, was mathematically developed and validated. BEP predicted mortality with high sensitivity and specificity scores (area under the curve (AUC) in the validation set=0.86 and in the replication set=0.96). In the validation set, BEP score performance (AUC=0.86, confidence interval (CI): 0.80 to 0.91) was better than GMSPS (AUC=0.77, CI: 0.68, 0.85), similar to Rotterdam (AUC=0.87, CI: 0.81 to 0.93) and not as good as PRISM (AUC=0.93, CI: 0.85 to 0.97). CONCLUSIONS: The BEP score, relying on only two variables that are quickly and objectively measurable and readily available at presentation, is highly sensitive and specific in predicting death from MS in childhood.

Correction: Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA.

[This corrects the article DOI: 10.1371/journal.pone.0044008.].