GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa.

Retinal microvascular associations with cardiometabolic risk factors differ by diabetes status: results from the UK Biobank.

AIMS/HYPOTHESIS: The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status. METHODS: The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering). RESULTS: A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction <0.01) for total fat mass index, HbA1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a -0.92 µm difference (95% CI -0.96 to -0.88 µm) in arteriolar diameter for those without diabetes, and a -0.58 µm difference (95% CI -0.76 to -0.41 µm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters. CONCLUSIONS/INTERPRETATION: We provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications. DATA AVAILABILITY: The data supporting the results reported here are available through the UK Biobank ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study.

BACKGROUND: Asthma is the most common chronic disease in children globally. The Global Asthma Network (GAN) Phase I study aimed to determine if the worldwide burden of asthma symptoms is changing. METHODS: This updated cross-sectional study used the same methods as the International study of Asthma and Allergies in Childhood (ISAAC) Phase III. Asthma symptoms were assessed from centres that completed GAN Phase I and ISAAC Phase I (1993-95), ISAAC Phase III (2001-03), or both. We included individuals from two age groups (children aged 6-7 years and adolescents aged 13-14 years) who self-completed written questionnaires at school. We estimated the 10-year rate of change in prevalence of current wheeze, severe asthma symptoms, ever having asthma, exercise wheeze, and night cough (defined by core questions in the questionnaire) for each centre, and we estimated trends across world regions and income levels using mixed-effects linear regression models with region and country income level as confounders. FINDINGS: Overall, 119 795 participants from 27 centres in 14 countries were included: 74 361 adolescents (response rate 90%) and 45 434 children (response rate 79%). About one in ten individuals of both age groups had wheeze in the preceding year, of whom almost half had severe symptoms. Most centres showed a change in prevalence of 2 SE or more between ISAAC Phase III to GAN Phase I. Over the 27-year period (1993-2020), adolescents showed a significant decrease in percentage point prevalence per decade in severe asthma symptoms (-0·37, 95% CI -0·69 to -0·04) and an increase in ever having asthma (1·25, 0·67 to 1·83) and night cough (4·25, 3·06 to 5·44), which was also found in children (3·21, 1·80 to 4·62). The prevalence of current wheeze decreased in low-income countries (-1·37, -2·47 to -0·27], in children and -1·67, -2·70 to -0·64, in adolescents) and increased in lower-middle-income countries (1·99, 0·33 to 3·66, in children and 1·69, 0·13 to 3·25, in adolescents), but it was stable in upper-middle-income and high-income countries. INTERPRETATION: Trends in prevalence and severity of asthma symptoms over the past three decades varied by age group, country income, region, and centre. The high worldwide burden of severe asthma symptoms would be mitigated by enabling access to effective therapies for asthma. FUNDING: International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca Educational Grant, National Institute for Health Research, UK Medical Research Council, European Research Council, and Instituto de Salud Carlos III.

The burden of asthma, hay fever and eczema in adults in 17 countries: GAN Phase I study.

AIMS: Asthma, hay fever and eczema are three common chronic conditions. There have been no recent multi-country data on the burden of these three conditions in adults; the aims of this study are to fill this evidence gap. METHODS: The Global Asthma Network Phase I is a multi-country cross-sectional population-based study using the same core methodology as the International Study of Asthma and Allergies in Childhood Phase III. It provides data on the burden of asthma, hay fever and eczema in children and adolescents, and, for the first time, in their parents/guardians. RESULTS: Data were available from 193 912 adults (104 061 female; mean±sd age 38±7.5 years) in 43 centres in 17 countries. The overall prevalence (range) of symptoms was 6.6% (0.9-32.7%) for current wheeze, 4.4% (0.9-29.0%) for asthma ever, 14.4% (2.8-45.7%) for hay fever ever and 9.9% (1.6-29.5%) for eczema ever. Centre prevalence varied considerably both between countries and within countries. There was a moderate correlation between hay fever ever and asthma ever, and between eczema ever and hay fever ever at the centre level. There were moderate to strong correlations between indicators of the burden of disease reported in adults and the two younger age groups. CONCLUSION: We found evidence for a substantial burden of asthma, hay fever ever and eczema ever in the countries examined, highlighting the major public health importance of these diseases. Prevention strategies and equitable access to effective and affordable treatments for these three conditions would help mitigate the avoidable morbidity they cause.

The burden of asthma, hay fever and eczema in children in 25 countries: GAN Phase I study.

AIMS: There have been no worldwide standardised surveys of prevalence and severity of asthma, rhinoconjunctivitis and eczema in school children for 15 years. The present study aims to provide this information. METHODS: Following the exact International Study of Asthma and Allergies in Childhood (ISAAC) methodology (cross-sectional questionnaire-based survey), Global Asthma Network (GAN) Phase I was carried out between 2015 and 2020 in many centres worldwide. RESULTS: The study included 157 784 adolescents (13-14 years of age) in 63 centres in 25 countries and 101 777 children (6-7 years of age) in 44 centres in 16 countries. The current prevalence of symptoms, respectively, was 11.0% and 9.1% for asthma, 13.3% and 7.7% for rhinoconjunctivitis and 6.4% and 5.9% for eczema. The prevalence of asthma ever was 10.5% and 7.6%, hay fever ever was 15.2% and 11.1% and eczema ever was 10.6% and 13.4%, respectively. Centres in low or lower middle gross national income countries (LICs or LMICs) had significantly lower prevalence of the three disease symptoms and diagnoses (except for hay fever). In children, the prevalence of asthma and rhinoconjunctivitis symptoms was higher in boys, while the reverse occurred among adolescents. For eczema, while the prevalence among female adolescents was double that of males, there was no sex difference among children. Centre accounted for non-negligible variability in all disease symptoms (10-20%). CONCLUSION: The burdens of asthma, rhinoconjunctivitis and eczema vary widely among the limited number of countries studied. Although symptom prevalence is lower in LICs and LMICs, it represents a considerable burden everywhere studied.

Worldwide time trends in prevalence of symptoms of rhinoconjunctivitis in children: Global Asthma Network Phase I.

BACKGROUND: The Global Asthma Network (GAN), by using the International Study of Asthma and Allergies in Childhood (ISAAC) methodology, has updated trends in prevalence of symptoms of childhood allergic diseases, including non-infective rhinitis and conjunctivitis ('rhinoconjunctivitis'), which is reported here. METHODS: Prevalence and severity of rhinoconjunctivitis were assessed by questionnaire among schoolchildren in GAN Phase I and ISAAC Phase I and III surveys 15-23 years apart. Absolute rates of change in prevalence were estimated for each centre and modelled by multi-level linear regression to compare trends by age group, time period and per capita national income. RESULTS: Twenty-seven GAN centres in 14 countries surveyed 74,361 13- to 14-year-olds ('adolescents') and 45,434 6- to 7-year-olds ('children'), with average response proportions of 90% and 79%, respectively. Many centres showed highly significant (p < .001) changes in prevalence of rhinoconjunctivitis in the past year ('current rhinoconjunctivitis') compared with ISAAC. The direction and magnitude of centre-level trends varied significantly (p < .001) both within and between countries. Overall, current rhinoconjunctivitis prevalence decreased slightly from ISAAC Phase III to GAN: -1.32% per 10 years, 95% CI [-2.93%, +0.30%] among adolescents; and -0.44% [-1.29%, +0.42%] among children. Together, these differed significantly (p < .001) from the upward trend within ISAAC. Among adolescents, centre-level trends in current rhinoconjunctivitis were highly correlated with those for eczema symptoms (rho = 0.72, p < .0001) but not with centre-level trends in asthma symptoms (rho = 0.15, p = .48). Among children, these correlations were positive but not significant. CONCLUSION: Symptoms of non-infective rhinoconjunctivitis among schoolchildren may no longer be on the increase globally, although trends vary substantially within and between countries.

Genome-wide associations for birth weight and correlations with adult disease.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Gut microbiota development during infancy: Impact of introducing allergenic foods.

BACKGROUND: The gut microbiota potentially plays an important role in the immunologic education of the host during early infancy. OBJECTIVE: We sought to determine how the infant gut microbiota evolve during infancy, particularly in relation to hygiene-related environmental factors, atopic disorders, and a randomized introduction of allergenic solids. METHODS: A total of 1303 exclusively breast-fed infants were enrolled in a dietary randomized controlled trial (Enquiring About Tolerance study) from 3 months of age. In this nested longitudinal study, fecal samples were collected at baseline, with additional sampling of selected cases and controls at 6 and 12 months to study the evolution of their gut microbiota, using 16S ribosomal RNA gene-targeted amplicon sequencing. RESULTS: In the 288 baseline samples from exclusively breast-fed infant at 3 months, the gut microbiota was highly heterogeneous, forming 3 distinct clusters: Bifidobacterium-rich, Bacteroides-rich, and Escherichia/Shigella-rich. Mode of delivery was the major discriminating factor. Increased Clostridium sensu stricto relative abundance at 3 months was associated with presence of atopic dermatitis on examination at age 3 and 12 months. From the selected cases and controls with longitudinal samples (n = 70), transition to Bacteroides-rich communities and influx of adult-specific microbes were observed during the first year of life. The introduction of allergenic solids promoted a significant increase in Shannon diversity and representation of specific microbes, such as genera belonging to Prevotellaceae and Proteobacteria (eg, Escherichia/Shigella), as compared with infants recommended to exclusively breast-feed. CONCLUSIONS: Specific gut microbiota characteristics of samples from 3-month-old breast-fed infants were associated with cesarean birth, and greater Clostridium sensu stricto abundance was associated with atopic dermatitis. The randomized introduction of allergenic solids from age 3 months alongside breast-feeding was associated with differential dynamics of maturation of the gut microbial communities.

Impact of early life geohelminths on wheeze, asthma and atopy in Ecuadorian children at 8 years.

BACKGROUND: Early-life exposures to geohelminths may protect against development of wheeze/asthma and atopy. OBJECTIVE: To study the effect of maternal geohelminths and infections in children during the first 5 years on atopy, wheeze/asthma and airways reactivity/inflammation at 8 years. METHODS: Birth cohort of 2404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO) and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy. RESULTS: 1933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and 45.5% of children to 5 years. Frequencies of outcomes at 8 years were as follows: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%) and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced SPT prevalence (OR 0.72). Childhood Trichuris trichiura infections during the first 5 years were associated with reduced wheeze (OR 0.57) but greater parasite burdens with Ascaris lumbricoides at 5 years were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite-specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non-atopic children. CONCLUSIONS: Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways. Registered as an observational study (ISRCTN41239086).

The rising tide of dementia deaths: triangulation of data from three routine data sources using the Clinical Practice Research Datalink.

BACKGROUND: Dementia is currently the leading certified underlying cause of death in England. We assess how dementia recording on Office for National Statistics death certificates (ONS) corresponded to recording in general practice records (GP) and Hospital Episode Statistics (HES). METHODS: Retrospective study of deaths (2001-15) in 153 English General Practices contributing to the Clinical Practice Research Datalink, with linked ONS and HES records. RESULTS: Of 207,068 total deaths from any cause, 19,627 mentioned dementia on the death certificate with 10,253 as underlying cause; steady increases occurred from 2001 to 2015 (any mention 5.3 to 15.4 %, underlying cause 2.7 to 10 %). Including all data sources, recording of any dementia increased from 13.2 to 28.6 %. In 2015, only 53.8 % of people dying with dementia had dementia recorded on their death certificates. Among deaths mentioning dementia on the death certificate, the recording of a prior diagnosis of dementia in GP and HES rose markedly over the same period. In 2001, only 76.3 % had a prior diagnosis in GP and/or HES records; by 2015 this had risen to 95.7 %. However, over the same period the percentage of all deaths with dementia recorded in GP or HES but not mentioned on the death certificate rose from 7.9 to 13.3 %. CONCLUSIONS: Dementia recording in all data sources increased between 2001 and 2015. By 2015 the vast majority of deaths mentioning dementia had supporting evidence in primary and/or secondary care. However, death certificates were still providing an inadequate picture of the number of people dying with dementia.

Trends in worldwide asthma prevalence.

This review of trends in worldwide asthma prevalence starts with defining how asthma prevalence is measured in populations and how it is analysed. Four population studies of asthma across at least two regions are described: European Community Respiratory Health Survey (ECRHS), the International Study of Wheezing in Infants (EISL), the International Study of Asthma and Allergies in Childhood (ISAAC) and the World Health Survey (WHS). Two of these (ISAAC and WHS) covered all the regions of the world; each using its own standardised questionnaire-based methodology with cross-sectional study design, suitable for large populations. EISL (2005 and 2012) and ISAAC (1996-1997 and 2002-2003) have undertaken a second cross-sectional population survey from which trends are available: EISL in three centres in two countries; ISAAC 106 centres in 56 countries (13-14 year olds) and 66 centres in 37 countries (6-7 year olds). Key results from these studies are presented. Unfortunately, there is no new worldwide data outside of EISL since 2003. Global Burden of Disease estimates of asthma prevalence have varied greatly. Recent reliable worldwide data on asthma prevalence and trends is needed; the Global Asthma Network Phase I will provide this in 2021.

Clinical onset of atopic eczema: Results from 2 nationally representative British birth cohorts followed through midlife.

BACKGROUND: Atopic eczema onset is described primarily in early childhood, and the frequency and characteristics of adult-onset disease remain controversial. OBJECTIVE: We sought to determine the proportion of subjects who report atopic eczema symptoms between birth and midadulthood and to examine demographic, immunologic, and genetic factors associated with period of symptom onset. METHODS: We conducted a longitudinal study using data from 2 nationally representative community-based birth cohorts from the United Kingdom: the British Cohort Studies 1958 and 1970. Subjects were followed from birth through age 42 to 50 years. The primary outcome was the age period of self-reported atopic eczema symptom onset based on repeated measures of self-reported atopic eczema at each survey wave. RESULTS: The annual period prevalence of atopic eczema ranged from 5% to 15% in 2 cohorts of more than 17,000 participants each followed from birth through middle age. There was no clear trend in prevalence by age, and among adults reporting active atopic eczema during a given year, only 38% had symptom onset reported in childhood. When compared with subjects whose eczema started in childhood, those with adult-onset disease were more likely to be women, from Scotland or Northern England, of lower childhood socioeconomic group, smokers in adulthood, and less likely to have a history of asthma. In a subanalysis using data from the 1958 cohort only, genetic mutations previously associated with atopic eczema, including filaggrin-null mutations, and allergen-specific IgE were more common among those with childhood-onset disease. CONCLUSION: Rates of self-reported atopic eczema remain high after childhood, and adult-onset atopic eczema has different risk factor associations than childhood-onset eczema.

Are environmental risk factors for current wheeze in the International Study of Asthma and Allergies in Childhood (ISAAC) phase three due to reverse causation?

BACKGROUND: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global prevalence of symptoms of asthma in children. We undertook comprehensive analyses addressing risk factors for asthma symptoms in combination, at both the individual and the school level, to explore the potential role of reverse causation due to selective avoidance or confounding by indication. OBJECTIVE: To explore the role of reverse causation in risk factors of asthma symptoms. METHODS: We compared two sets of multilevel logistic regression analyses, using (a) individual level exposure data and (b) school level average exposure (ie prevalence), in two different age groups. In individual level analyses, reverse causation is a possible concern if individual level exposure statuses were changed as a result of asthma symptoms or diagnosis. School level analyses may suffer from ecologic confounding, but reverse causation is less of a concern because individual changes in exposure status as a result of asthma symptoms would only have a small effect on overall school exposure levels. RESULTS: There were 131 924 children aged 6-7 years (2428 schools, 25 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (odds ratio = 2.06; 95% confidence interval 1.97-2.16), early life antibiotic use (1.65; 1.58-1.73) and open fire cooking (1.44; 1.26-1.65). In school level analyses, these risk factors again showed increased risks. There were 238 586 adolescents aged 13-14 years (2072 schools, 42 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (1.80; 1.75-1.86), cooking on an open fire (1.32; 1.22-1.43) and maternal tobacco use (1.23; 1.18-1.27). In school level analyses, these risk factors again showed increased risks. CONCLUSIONS & CLINICAL RELEVANCE: These analyses strengthen the potentially causal interpretation of previously reported individual level findings, by providing evidence against reverse causation.

Retinal Vasculometry Associations with Cardiometabolic Risk Factors in the European Prospective Investigation of Cancer-Norfolk Study.

PURPOSE: To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women. DESIGN: Retinal imaging examination as part of the European Prospective Investigation into Cancer-Norfolk Eye Study. PARTICIPANTS: Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry. METHODS: Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width. MAIN OUTCOMES MEASURES: Retinal arteriolar and venular tortuosity and width. RESULTS: In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%-3.3% per 5 kg/m2), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%-3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%-10.4%); wider venules were associated with older age (2.6 µm; 95% CI, 2.2-2.9 µm per decade), higher triglyceride levels (0.6 µm; 95% CI, 0.3-0.9 µm per 1 mmol/l), BMI (0.7 µm; 95% CI, 0.4-1.0 per 5 kg/m2), HbA1c level (0.4 µm; 95% CI, -0.1 to 0.9 per 1%), and being a current smoker (3.0 µm; 95% CI, 1.7-4.3 µm); smoking also was associated with wider arterioles (2.1 µm; 95% CI, 1.3-2.9 µm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 µm; 95% CI, 0.7-2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%-7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%-1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%-6.4%), and in those with prevalent stroke (8.3%; 95% CI, -0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 µm; 95% CI, 0.6-1.0 µm per decade), higher systolic blood pressure (0.5 µm; 95% CI, 0.4-0.6 µm per 10 mmHg), total cholesterol level (0.2 µm; 95% CI, 0.0-0.3 µm per 1 mmol/l), and HDL (1.2 µm; 95% CI, 0.7-1.6 µm per 1 mmol/l). CONCLUSIONS: Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.

Can environment or allergy explain international variation in prevalence of wheeze in childhood?

Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8-12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence.

Effect of Early-Life Geohelminth Infections on the Development of Wheezing at 5 Years of Age.

RATIONALE: Exposures to geohelminths during gestation or early childhood may reduce risk of wheezing illness/asthma and atopy during childhood in tropical regions. OBJECTIVES: To investigate the effect of maternal and early childhood geohelminths on development of wheeze/asthma and atopy during the first 5 years of life. METHODS: A cohort of 2,404 neonates was followed to 5 years of age in a rural district in coastal Ecuador. Data on wheeze were collected by questionnaire and atopy was measured by allergen skin prick test reactivity to 10 allergens at 5 years. Stool samples from mothers and children were examined for geohelminths by microscopy. MEASUREMENTS AND MAIN RESULTS: A total of 2,090 (86.9%) children were evaluated at 5 years. Geohelminths were observed in 45.5% of mothers and in 34.1% of children by 3 years. Wheeze and asthma were reported for 12.6% and 5.7% of children, respectively, whereas 14.0% had skin test reactivity at 5 years. Maternal geohelminths were associated with an increased risk of wheeze (adjusted odds ratio, 1.41; 95% confidence interval, 1.06-1.88), whereas childhood geohelminths over the first 3 years of life were associated with reduced risk of wheeze (adjusted odds ratio, 0.70; 95% confidence interval, 0.52-0.96) and asthma (adjusted odds ratio, 0.60; 95% confidence interval, 0.38-0.94) but not skin prick test reactivity. The effects on wheeze/asthma were greatest with later age of first infection, were observed only in skin test-negative children, but were not associated with parasite burden or specific geohelminths. CONCLUSIONS: Although maternal exposures to geohelminths may increase childhood wheeze, childhood geohelminths during the first 3 years may provide protection through a nonallergic mechanism. Registered as an observational study (ISRCTN41239086).

Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development.

Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r(2) ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10(-8)) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10(-40)). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases.

Persistent variations in national asthma mortality, hospital admissions and prevalence by socioeconomic status and region in England.

BACKGROUND: The UK-wide National Review of Asthma Deaths sought to identify avoidable factors from the high numbers of deaths, but did not examine variation by socioeconomic status (SES) or region. METHODS: We used asthma deaths in England over the period 2002-2015 obtained from national deaths registers, summarised by quintiles of Index of Multiple Deprivation (IMD) and Government Office Region. Emergency asthma admissions were obtained from Hospital Episode Statistics for England 2001-2011. The prevalence of asthma was derived from the Health Survey for England 2010. Associations of mortality, admissions and prevalence with IMD quintile and region were estimated cross-sectionally using incidence rate ratios (IRRs) adjusted for age and sex and, where possible, smoking. RESULTS: Asthma mortality decreased among more deprived groups at younger ages. Among 5-44 year olds, those in the most deprived quintile, mortality was 19% lower than those in the least deprived quintile (IRR 0.81 (95% CI 0.69 to 0.96). In older adults, this pattern was reversed (45-74 years: IRR 1.37 (1.24-1.52), ≥75 years: IRR 1.30 (1.22-1.39)). In 5-44 year olds the inverse trend with asthma mortality contrasted with large positive associations for admissions (IRR 3.34 (3.30-3.38)) and prevalence of severe symptoms (IRR 2.38 (1.70-3.33)). Prevalence trends remained after adjustment for smoking. IRRs for asthma mortality, admissions and prevalence showed significant heterogeneity between English regions. CONCLUSIONS: Despite asthma mortality, emergency admissions and prevalence decreasing over recent decades, England still experiences significant SES and regional variations. The previously undocumented inverse relation between deprivation and mortality in the young requires further investigation.

Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank.

RATIONALE: The prevalence of chronic obstructive pulmonary disease (COPD) is increasing faster among women than among men. OBJECTIVES: To examine sex differences in the risk of airflow obstruction (a COPD hallmark) in relation to smoking history. METHODS: We analyzed 149,075 women and 100,252 men taking part in the UK Biobank who had provided spirometry measurements and information on smoking. The association of airflow obstruction with smoking characteristics was assessed by sex using regression analysis. The shape of this relationship was examined using restricted cubic splines. MEASUREMENTS AND MAIN RESULTS: The association of airflow obstruction with smoking status was stronger in women (odds ratio for ex-smokers [ORex], 1.44; ORcurrent, 3.45) than in men (ORex, 1.25; ORcurrent, 3.06) (P for interaction = 5.6 × 10-4). In both sexes, the association of airflow obstruction with cigarettes per day, smoking duration, and pack-years did not follow a linear pattern, with the increase in risk at lower doses being steeper among women. For equal doses of exposure, sex differences were present in both ex-smokers and current smokers for cigarettes per day (P for interactionex = 6.0 × 10-8; P for interactioncurrent = 1.1 × 10-5), smoking duration (P for interactionex = 7.9 × 10-4; P for interactioncurrent = 0.004), and pack-years (P for interactionex = 6.6 × 10-18; P for interactioncurrent = 1.3 × 10-6). Overall, those who started smoking before age 18 years were more likely to have airflow obstruction, but a sex difference in this association was not clear. For equal time since quitting, the reduction in risk among women seemed less marked than among men. CONCLUSIONS: Exposed to the same dose of smoking, women showed a higher risk of airflow obstruction than men. This could partly explain the increasingly smaller sex difference in the prevalence of COPD, especially in countries where smoking patterns have become similar between women and men.

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.