Erratum: Epigenome-wide association of father's smoking with offspring DNA methylation: a hypothesis-generating study.

[This corrects the article DOI: 10.1093/eep/dvz023.][This corrects the article DOI: 10.1093/eep/dvz023.].

Epigenome-wide association of father's smoking with offspring DNA methylation: a hypothesis-generating study.

Epidemiological studies suggest that father's smoking might influence their future children's health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers' smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11-54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006-0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR) < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers' smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers' exposures might persistently modify their future offspring's epigenome.

Acquisition, remission, and persistence of eczema, asthma, and rhinitis in children.

BACKGROUND: Allergic sensitization is associated with eczema, asthma, and rhinitis. However, it is unknown whether and how allergic sensitization is associated over time with acquisition, remission, and persistence of these diseases and their comorbidity. OBJECTIVE: To gain a better understanding of factors including allergic sensitization transitions that influence the temporal pattern of asthma, eczema, and rhinitis and their comorbidity during childhood. METHODS: In the Isle of Wight birth cohort, information on allergic sensitization to common allergens was collected at ages 4, 10, and 18 years along with asthma, rhinitis, and eczema status determined by clinical diagnosis. Logistic regressions were used to estimate subsequent and concurrent odds ratios of diseases transition with allergic sensitization transition status as the main independent variable. Two transition periods were considered, 4 to 10 years of age and 10 to 18 years of age. RESULTS: The odds of new diagnosis of allergic disease (no-yes) was increased among subjects with acquired or persistent allergic sensitization to common allergens compared to subjects with no sensitization (acquisition of sensitization odds ratio [OR]=3.22, P < .0001; persistence of sensitization, OR=6.33, P < .0001). The odds of remission of allergic diseases (yes-no) was lower among subjects with acquired or sustained allergic sensitization (acquisition, OR=0.18, P = .0001; persistence, OR=0.085, P < .0001), compared to subjects not sensitized. Subjects with acquired or persistent allergic sensitization were also had higher odds for persistence of disease (yes-yes) than subjects not sensitized (acquisition, OR=5.49, P = .0001; persistence, OR=11.79, P < .0001). CONCLUSION: Transition of allergic sensitizations to common allergens is a prognostic factor for subsequent or concurrent transition of eczema, asthma, and rhinitis. Prevention or reduction in allergic sensitization has a potential to lead to remission of these conditions.

Zoonotic helminth exposure and risk of allergic diseases: A study of two generations in Norway.

BACKGROUND: Animal and human studies indicate that definitive host helminth infections may confer protection from allergies. However, zoonotic helminths, such as Toxocara species (spp.), have been associated with increased allergies. OBJECTIVE: We describe the prevalence of Toxocara spp. and Ascaris spp. seropositivity and associations with allergic diseases and sensitization, in 2 generations in Bergen, Norway. METHODS: Serum levels of total IgG4, anti-Toxocara spp. IgG4 and Ascaris spp. IgG4 were established by ELISA in 2 cohorts: parents born 1945-1972 (n = 171) and their offspring born 1969-2003 (n = 264). Allergic outcomes and covariates were recorded through interviews and clinical examinations including serum IgEs and skin prick tests. RESULTS: Anti-Ascaris spp. IgG4 was detected in 29.2% of parents and 10.3% of offspring, and anti-Toxocara spp. IgG4 in 17.5% and 8.0% of parents and offspring, respectively. Among offspring, anti-Toxocara spp. IgG4 was associated with pet keeping before age 15 (OR = 6.15; 95% CI = 1.37-27.5) and increasing BMI (1.16[1.06-1.25] per kg/m2 ). Toxocara spp. seropositivity was associated with wheeze (2.97[1.45- 7.76]), hayfever (4.03[1.63-9.95]), eczema (2.89[1.08-7.76]) and cat sensitization (5.65[1.92-16.6]) among offspring, but was not associated with allergic outcomes among parents. Adjustment for childhood or current pet keeping did not alter associations with allergies. Parental Toxocara spp. seropositivity was associated with increased offspring allergies following a sex-specific pattern. CONCLUSIONS & CLINICAL RELEVANCE: Zoonotic helminth exposure in Norway was less frequent in offspring than parents; however, Toxocara spp. seropositivity was associated with increased risk of allergic manifestations in the offspring generation, but not among parents. Changes in response to helminth exposure may provide insights into the increase in allergy incidence in affluent countries.

Maternal and fetal genetic contribution to gestational weight gain.

BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Expression of the filaggrin gene in umbilical cord blood predicts eczema risk in infancy: A birth cohort study.

BACKGROUND: Filaggrin gene (FLG) expression, particularly in the skin, has been linked to the development of the skin barrier and is associated with eczema risk. However, knowledge as to whether FLG expression in umbilical cord blood (UCB) is associated with eczema development and prediction is lacking. OBJECTIVE: This study sought to assess whether FLG expression in UCB associates with and predicts the development of eczema in infancy. METHODS: Infants enrolled in a birth cohort study (n=94) were assessed for eczema at ages 3, 6, and 12 months. Five probes measuring FLG transcripts expression in UCB were available from genomewide gene expression profiling. FLG genetic variants R501X, 2282del4, and S3247X were genotyped. Associations were assessed using Poisson regression with robust variance estimation. Area under the curve (AUC), describing the discriminatory/predictive performance of fitted models, was estimated from logistic regression. RESULTS: Increased level of FLG expression measured by probe A_24_P51322 was associated with reduced risk of eczema during the first year of life (RR=0.60, 95% CI: 0.38-0.95). In contrast, increased level of FLG antisense transcripts measured by probe A_21_P0014075 was associated with increased risk of eczema (RR=2.02, 95% CI: 1.10-3.72). In prediction models including FLG expression, FLG genetic variants, and sex, discrimination between children who will and will not develop eczema at 3 months of age was high (AUC: 0.91, 95% CI: 0.84-0.98). CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrated, for the first time, that FLG expression in UCB is associated with eczema development in infancy. Moreover, our analysis provided prediction models that were capable of discriminating, to a great extent, between those who will and will not develop eczema in infancy. Therefore, early identification of infants at increased risk of developing eczema is possible and such high-risk newborns may benefit from early stratification and intervention.

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients.

RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n = 9) and asthmatic (n = 27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels were determined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial (P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

Association of season of birth with DNA methylation and allergic disease.

BACKGROUND: Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long-lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy. METHODS: In a subset of 18-year-old participants from the Isle of Wight (IoW) birth cohort (n = 367), the risks of birth season on allergic outcomes were estimated. Whole blood epigenome-wide DNA methylation was measured, and season-associated CpGs detected using a training-and-testing-based technique. Validation method examined the 8-year-old Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. The relationships between DNA methylation, season of birth and allergy were examined. CpGs were analysed in IoW third-generation cohort newborns. RESULTS: Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with season of birth in the epigenome-wide association study. In validation, significantly more CpGs had the same directionality than expected by chance, and four were statistically significant. Season-associated methylation was enriched among networks relating to development, the cell cycle and apoptosis. Twenty CpGs were nominally associated with allergic outcomes. Two CpGs were marginally on the causal pathway to allergy. Season-associated methylation was largely absent in newborns, suggesting it arises post-natally. CONCLUSIONS: This study demonstrates that DNA methylation in adulthood is associated with season of birth, supporting the hypothesis that DNA methylation could mechanistically underlie the effect of season of birth on allergy, although other mechanisms are also likely to be involved.

Relation of FTO gene variants to fetal growth trajectories: Findings from the Southampton Women's survey.

INTRODUCTION: Placental function is an important determinant of fetal growth, and fetal growth influences obesity risk in childhood and adult life. Here we investigated how FTO and MC4R gene variants linked with obesity relate to patterns of fetal growth and to placental FTO expression. METHODS: Southampton Women's Survey children (n = 1990) with measurements of fetal growth from 11 to 34 weeks gestation were genotyped for common gene variants in FTO (rs9939609, rs1421085) and MC4R (rs17782313). Linear mixed-effect models were used to analyse relations of gene variants with fetal growth. RESULTS: Fetuses with the rs9939609 A:A FTO genotype had faster biparietal diameter and head circumference growth velocities between 11 and 34 weeks gestation (by 0.012 (95% CI 0.005 to 0.019) and 0.008 (0.002-0.015) standard deviations per week, respectively) compared to fetuses with the T:T FTO genotype; abdominal circumference growth velocity did not differ between genotypes. FTO genotype was not associated with placental FTO expression, but higher placental FTO expression was independently associated with larger fetal size and higher placental ASCT2, EAAT2 and y + LAT2 amino acid transporter expression. Findings were similar for FTO rs1421085, and the MC4R gene variant was associated with the fetal growth velocity of head circumference. DISCUSSION: FTO gene variants are known to associate with obesity but this is the first time that the risk alleles and placental FTO expression have been linked with fetal growth trajectories. The lack of an association between FTO genotype and placental FTO expression adds to emerging evidence of complex biology underlying the association between FTO genotype and obesity.

Evaluating the efficacy of breastfeeding guidelines on long-term outcomes for allergic disease.

BACKGROUND: WHO guidelines advocate breastfeeding for 6 months, and EAACI guideline recommends exclusive breastfeeding for 4-6 months. However, evidence for breastfeeding to prevent asthma and allergic disease is conflicting. We examined whether following recommended breastfeeding guidelines alters the long-term risks of asthma, eczema, rhinitis or atopy. METHODS: The effect of nonexclusive (0, >0-6, >6 months) and exclusive breastfeeding (0, >0-4, >4 months) on repeated measures of asthma (10, 18 years), eczema, rhinitis, and atopy (1-or-2, 4, 10, 18 years) risks was estimated in the IoW cohort (n = 1456) using log-linear models with generalized estimating equations. The Food Allergy and Intolerance Research (FAIR) cohort (n = 988), also from the IoW, was examined to replicate results. RESULTS: Breastfeeding (any or exclusive) had no effect on asthma and allergic disease in the IoW cohort. In the FAIR cohort, any breastfeeding for >0-6 months protected against asthma at 10 years (RR = 0.50, 95% CI = 0.32-0.79, P = 0.003), but not other outcomes, whilst exclusive breastfeeding for >4 months protected against repeated rhinitis (RR = 0.36, 95% CI = 0.18-0.71, P = 0.003). Longer breastfeeding was protective against late-onset wheeze in the IoW cohort. CONCLUSION: The protective effects of nonexclusive and exclusive breastfeeding against long-term allergic outcomes were inconsistent between these colocated cohorts, agreeing with previous observations of heterogeneous effects. Although breastfeeding should be recommended for other health benefits, following breastfeeding guidelines did not appear to afford a consistent protection against long-term asthma, eczema, rhinitis or atopy. Further research is needed into the long-term effects of breastfeeding on allergic disease.

Identifying CpG sites associated with eczema via random forest screening of epigenome-scale DNA methylation.

BACKGROUND: The prevalence of eczema is increasing in industrialized nations. Limited evidence has shown the association of DNA methylation (DNA-M) with eczema. We explored this association at the epigenome-scale to better understand the role of DNA-M. Data from the first generation (F1) of the Isle of Wight (IoW) birth cohort participants and the second generation (F2) were examined in our study. Epigenome-scale DNA methylation of F1 at age 18 years and F2 in cord blood was measured using the Illumina Infinium HumanMethylation450 Beadchip. A total of 307,357 cytosine-phosphate-guanine sites (CpGs) in the F1 generation were screened via recursive random forest (RF) for their potential association with eczema at age 18. Functional enrichment and pathway analysis of resulting genes were carried out using DAVID gene functional classification tool. Log-linear models were performed in F1 to corroborate the identified CpGs. Findings in F1 were further replicated in F2. RESULTS: The recursive RF yielded 140 CpGs, 88 of which showed statistically significant associations with eczema at age 18, corroborated by log-linear models after controlling for false discovery rate (FDR) of 0.05. These CpGs were enriched among many biological pathways, including pathways related to creating transcriptional variety and pathways mechanistically linked to eczema such as cadherins, cell adhesion, gap junctions, tight junctions, melanogenesis, and apoptosis. In the F2 generation, about half of the 83 CpGs identified in F1 showed the same direction of association with eczema risk as in F1, of which two CpGs were significantly associated with eczema risk, cg04850479 of the PROZ gene (risk ratio (RR) = 15.1 in F1, 95 % confidence interval (CI) 1.71, 79.5; RR = 6.82 in F2, 95 % CI 1.52, 30.62) and cg01427769 of the NEU1 gene (RR = 0.13 in F1, 95 % CI 0.03, 0.46; RR = 0.09 in F2, 95 % CI 0.03, 0.36). CONCLUSIONS: Via epigenome-scaled analyses using recursive RF followed by log-linear models, we identified 88 CpGs associated with eczema in F1, of which 41 were replicated in F2. Several identified CpGs are located within genes in biological pathways relating to skin barrier integrity, which is central to the pathogenesis of eczema. Novel genes associated with eczema risk were identified (e.g., the PROZ and NEU1 genes).

Developmental determinants in non-communicable chronic diseases and ageing.

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.

Allergic sensitization and filaggrin variants predispose to the comorbidity of eczema, asthma, and rhinitis: results from the Isle of Wight birth cohort.

BACKGROUND: Allergic sensitization and filaggrin gene (FLG) variants are important risk factors for allergic disorders; however, knowledge on their individual and interactive effects on the coexistence of eczema, asthma, and rhinitis is lacking. OBJECTIVE: This study aimed at investigating the single and combined effects of allergic sensitization and FLG variants on the development of single and multiple allergic disorders. METHODS: The Isle of Wight birth cohort (n = 1456) has been examined at 1, 2, 4, 10, and 18 years of age. Repeated measurements of eczema, asthma, rhinitis, and skin prick tests were available for all follow-ups. FLG variants were genotyped in 1150 participants. Associations of allergic sensitization and FLG variants with single and multiple allergic disorders were tested in log-binomial regression analysis. RESULTS: The prevalence of eczema-, asthma-, and rhinitis-only ranged from 5.6% to 8.5%, 4.9% to 10.2%, and 2.5% to 20.4%, respectively, during the first 18 years of life. The coexistence of allergic disorders is common, with approximately 2% of the population reporting the comorbidity of 'eczema, asthma, and rhinitis' during the study period. In repeated measurement analyses, allergic sensitization and FLG variants, when analysed separately, were associated with having single and multiple allergic disorders. Of particular significance, their combined effect increased the risk of 'eczema and asthma' (RR = 13.67, 95% CI: 7.35-25.42), 'asthma and rhinitis' (RR = 7.46, 95% CI: 5.07-10.98), and 'eczema, asthma, and rhinitis' (RR = 23.44, 95% CI: 12.27-44.78). CONCLUSIONS AND CLINICAL RELEVANCE: The coexistence of allergic disorders is frequent, and allergic sensitization and FLG variants jointly increased risk of allergic comorbidities, which may represent more severe and complex clinical phenotypes. The interactive effect and the elevated proportion of allergic comorbidities associated with allergic sensitization and FLG variants emphasize their joint importance in the pathogenesis of allergic disorders.

Alpha-tryptase gene variation is associated with levels of circulating IgE and lung function in asthma.

BACKGROUND: Tryptase, a major secretory product of human mast cells has been implicated as a key mediator of allergic inflammation. Genetic variation in the tryptases is extensive, and α-tryptase, an allelic variant of the more extensively studied ß-tryptase, is absent in substantial numbers of the general population. The degree to which α-tryptase expression may be associated with asthma has not been studied. We have investigated the α-tryptase gene copy number variation and its potential associations with phenotypes of asthma. OBJECTIVES: Caucasian families (n = 341) with at least two asthmatic siblings (n = 1350) were genotyped for the α-tryptase alleles, using high-resolution melting assays. Standards for the possible α-/ß-tryptase ratios were constructed by cloning α-and ß-tryptase PCR products to generate artificial templates. Association analysis of asthma affection status and related phenotypes [total and allergen-specific serum IgE, bronchial hyperresponsiveness to methacholine, forced expiratory volume in 1s (FEV1 ) and atopy and asthma severity scores] was undertaken using family-based association tests (FBAT). RESULTS: Four consistent melting patterns for the α-tryptase genotype were identified with alleles carrying null, one or two copies of the α-tryptase allele. Possessing one copy of α-tryptase was significantly associated with lower serum levels of total and dust mite-specific IgE levels and higher FEV1 measurements, while two copies were related to higher serum concentrations of total and dust mite-specific IgE and greater atopy severity scores. CONCLUSIONS AND CLINICAL RELEVANCE: Associations of α-tryptase copy number with serum IgE levels, atopy scores and bronchial function may reflect roles for tryptases in regulating IgE production and other processes in asthma.

DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants.

BACKGROUND: Loss-of-function variants within the filaggrin gene (FLG) are associated with a dysfunctional skin barrier that contributes to the development of eczema. Epigenetic modifications, such as DNA methylation, are genetic regulatory mechanisms that modulate gene expression without changing the DNA sequence. OBJECTIVES: To investigate whether genetic variants and adjacent differential DNA methylation within the FLG gene synergistically act on the development of eczema. METHODS: A subsample (n = 245, only females aged 18 years) of the Isle of Wight birth cohort participants (n = 1456) had available information for FLG variants R501X, 2282del4 and S3247X and DNA methylation levels for 10 CpG sites within the FLG gene. Log-binomial regression was used to estimate the risk ratios (RRs) of eczema associated with FLG variants at different methylation levels. RESULTS: The period prevalence of eczema was 15.2% at age 18 years and 9.0% of participants were carriers (heterozygous) of FLG variants. Of the 10 CpG sites spanning the genomic region of FLG, methylation levels of CpG site 'cg07548383' showed a significant interaction with FLG sequence variants on the risk for eczema. At 86% methylation level, filaggrin haploinsufficient individuals had a 5.48-fold increased risk of eczema when compared to those with wild type FLG genotype (P-value = 0.0008). CONCLUSIONS: Our novel results indicated that the association between FLG loss-of-function variants and eczema is modulated by DNA methylation. Simultaneously assessing the joint effect of genetic and epigenetic factors within the FLG gene further highlights the importance of this genomic region for eczema manifestation.

EAACI position statement on asthma exacerbations and severe asthma.

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.

Relationships between feed efficiency, scrotal circumference, and semen quality traits in yearling bulls.

A meta-analysis was conducted to examine phenotypic relationships between feed efficiency, scrotal circumference, and semen quality traits in yearling bulls. Data evaluated were obtained from 5 postweaning trials involving Angus (n = 92), Bonsmara (n = 62), and Santa Gertrudis (n = 50) bulls fed diets that ranged from 1.70 to 2.85 Mcal ME/kg DM. After an adaptation period of 24 to 28 d, feed intake was measured daily, and BW was measured at 7- or 14-d intervals during the 70- to 77-d trials. Ultrasound carcass traits (12th-rib back fat thickness, BF; LM area, LMA) and scrotal circumference (SC) were measured at the start and end of each trial. Semen samples were collected by electroejaculation within 51 d of the end of the trials when the age of bulls averaged from 365 to 444 d and were evaluated for progressive sperm motility and morphology. Residual feed intake (RFI) was calculated as the difference between actual DMI and expected DMI from linear regression of DMI on ADG and midtest BW(0.75), with trial, trial by ADG, and trial by midtest BW(0.75) as random effects. Across all studies, bulls with low RFI phenotypes (<0.5 SD below the mean RFI of 0) consumed 20% less DM and had 10% less BF but had similar ADG, SC, and semen quality traits compared with high-RFI bulls (>0.5 SD above the mean RFI of 0). Gain to feed ratio was strongly correlated with ADG (0.60) and weakly correlated with initial BW (-0.17) and DMI (-0.26). Residual feed intake was not correlated with ADG, initial age, or BW but was correlated with DMI (0.71), G:F (-0.70), and BF (0.20). Initial SC (-0.20), gain in SC (-0.28), and percent normal sperm (-0.17) were correlated with G:F, but only sperm morphology was found to be weakly associated with RFI (0.13). These data suggest that RFI is not phenotypically associated with SC or sperm motility but is weakly associated with sperm morphology.

Genome-wide association study to identify genetic determinants of severe asthma.

BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

I have taken my umbrella, so of course it does not rain.

Spirometry is used worldwide to diagnose respiratory disease, and it is a validated measure to assess airway obstruction. Irreversible airway obstruction is the defining feature of chronic obstructive pulmonary disease (COPD). Thus, an FEV(1)/FVC ratio <70% is used to diagnose COPD, and the severity is thereafter based on the level of FEV(1). This definition is widely used in clinical practice and research, yet may lead to confusion with respect to the diagnosis associated with the presence of airway obstruction. The three main reasons are the following: (1) fixed airflow obstruction may be the result of specific diagnoses such as cystic fibrosis; (2) FEV(1)/FVC ratio changes with ageing, and it is therefore inappropriate to use the same ratio at 40 and 90 years, leaving aside gender differences; (3) even when specific diagnoses are excluded, fixed airflow obstruction may be the end-stage of many different underlying processes. The authors believe that they have strong arguments that a COPD diagnosis based solely on spirometric values is nonsense. More sophisticated lung function tests, such as plethysmography, forced oscillation and lung clearance index, may help further to delineate the characteristics of low lung function. However, these are not feasible in most clinical contexts and in epidemiologic studies. Therefore, the authors throw down the gauntlet: spirometry is an essential tool in patient evaluation but dangerous for disease diagnosis, and the term COPD should only be used in the appropriate clinical (diagnostic) context.