David P. Strachan

International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.

The aetiology of asthma and allergic disease remains poorly understood, despite considerable research. The International Study of Asthma and Allergies in Childhood (ISAAC), was founded to maximize the value of epidemiological research into asthma and allergic disease, by establishing a standardized methodology and facilitating international collaboration. Its specific aims are: 1) to describe the prevalence and severity of asthma, rhinitis and eczema in children living in different centres, and to make comparisons within and between countries; 2) to obtain baseline measures for assessment of future trends in the prevalence and severity of these diseases; and 3) to provide a framework for further aetiological research into genetic, lifestyle, environmental, and medical care factors affecting these diseases. The ISAAC design comprises three phases. Phase 1 uses core questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations. Phase 2 will investigate possible aetiological factors, particularly those suggested by the findings of Phase 1. Phase 3 will be a repetition of Phase 1 to assess trends in prevalence.

A large-scale, consortium-based genomewide association study of asthma

BACKGROUNDnSusceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease.nnnMETHODSnWe carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma.nnnRESULTSnWe observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma.nnnCONCLUSIONSnAsthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined Pu2009value of Pu2009<u200910-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (Pu2009<u200910-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.

A genome-wide association scan in individuals with Crohns disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 × 10−4, combined P = 2.1 × 10−10) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10−11), IRF8 (P = 3.73 × 10−9) and CD6 (P = 3.79 × 10−9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors.

Abstract Objective: To investigate the relation between seropositivity to chronic infections with Helicobacter pylori and Chlamydia pneumoniae and both coronary heart disease and cardiovascular risk factors. Objective:To investigate the relation between seropositivity to chronic infections with Helicobacter pylori and Chlamydia pneumoniae and both coronary heart disease and cardiovascular risk factors. Setting: General practices in Merton, Sutton, and Wandsworth, south London. Subjects: 388 white south London men aged 50-69. Main outcome measures: Evidence of coronary risk factors and infection with H pylori or C pneumoniae. Results: 47 men (12.1%) had electrocardiographic evidence of ischaemia or infarction. 36 (76.6%) and 18 (38.3%) were seropositive for H pylori and C pneumoniae, respectively, compared with 155 (45.5%) and 62 (18.2%) men with normal electrocardiograms. Odds ratios for abnormal electrocardiograms were 3.82 (95% confidence interval 1.60 to 9.10) and 3.06 (12.33 to 7.01) in men seropositive for H pylori and C pneumoniae, respectively, after adjustment for a range of socioeconomic indicators and risk factors for coronary heart disease. Cardiovascular risk factors that were independently associated with seropositivity to H pylori included fibrinogen concentration and total leucocyte count. Seropositivity to C pneumoniae was independently associated with raised fibrinogen and malondialdehyde concentrations. Conclusions: Both H pylori and C pneumoniae infections are associated with coronary heart disease. These relations are not explained by a wide range of confounding factors. Possible mechanisms include an increase in risk factor levels due to a low grade chronic inflammatory response.

Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort

Abstract Objective: To describe the incidence and prognosis of wheezing illness from birth to age 33 and the relation of incidence to perinatal, medical, social, environmental, and lifestyle factors. Design: Prospective longitudinal study. Setting: England, Scotland, and Wales. Subjects: 18 559 people born on 3-9 March 1958. 5801 (31%) contributed information at ages 7, 11, 16, 23, and 33 years. Attrition bias was evaluated using information on 14 571 (79%) subjects. Main outcome measure: History of asthma, wheezy bronchitis, or wheezing obtained from interview with subjects parents at ages 7, 11, and 16 and reported at interview by subjects at ages 23 and 33. Results: The cumulative incidence of wheezing illness was 18% by age 7, 24% by age 16, and 43% by age 33. Incidence during childhood was strongly and independently associated with pneumonia, hay fever, and eczema. There were weaker independent associations with male sex, third trimester antepartum haemorrhage, whooping cough, recurrent abdominal pain, and migraine. Incidence from age 17 to 33 was associated strongly with active cigarette smoking and a history of hay fever. There were weaker independent associations with female sex, maternal albuminuria during pregnancy, and histories of eczema and migraine. Maternal smoking during pregnancy was weakly and inconsistently related to childhood wheezing but was a stronger and significant independent predictor of incidence after age 16. Among 880 subjects who developed asthma or wheezy bronchitis from birth to age 7, 50% had attacks in the previous year at age 7; 18% at 11, 10% at 16, 10% at 23, and 27% at 33. Relapse at 33 after prolonged remission of childhood wheezing was more common among current smokers and atopic subjects. Conclusion: Atopy and active cigarette smoking are major influences on the incidence and recurrence of wheezing during adulthood. Key messages Incidence of wheezing illness at all ages was strongly and consistently related to a history of hay fever or eczema (atopy). Associations with maternal smoking during pregnancy, abdominal pain, and migraine were largely confined to those without atopy Active smoking was a powerful and potentially avoidable risk factor for wheeze starting in adult life among both atopic and non-atopic subjects A quarter of the children with a history of asthma or wheezy bronchitis by age 7 reported wheeze in the past year at age 33 Recurrence of wheezing after prolonged remis- sion during late adolescence was strongly associ- ated with atopy and cigarette smoking.

Parental smoking and childhood asthma: longitudinal and case-control studies

BACKGROUND The relation of parental smoking to wheezing and asthma occurring after the first year of life was assessed by a systematic quantitative review of case-control and longitudinal studies, complementing earlier reviews of cross sectional surveys and wheezing in early childhood. METHODS Fifty one relevant publications were identified after consideration of 1593 abstracts selected by electronic search of the Embase and Medline databases using keywords relevant to passive smoking in children. The search was completed in April 1997 and identified six studies of asthma incidence, seven of prognosis, 22 case-control studies, and 10 case series addressing disease severity. RESULTS Maternal smoking was associated with an increased incidence of wheezing illness up to age 6 (pooled odds ratio 1.31, 95% CI 1.22 to 1.41), but less strongly thereafter (1.13, 95% CI 1.04 to 1.22). The long term prognosis of early wheezing illness was better if the mother smoked. The pooled odds ratio for asthma prevalence from 14 case-control studies was 1.37 (95% CI 1.15 to 1.64) if either parent smoked. Four studies suggest that parental smoking is more strongly associated with wheezing among non-atopic children. Indicators of disease severity including symptom scores, attack frequency, medication use, hospital attendance, and life threatening bronchospasm were in general positively related to household smoke exposure. CONCLUSIONS The excess incidence of wheezing in smoking households appears to be largely non-atopic “wheezy bronchitis” with a relatively benign prognosis, but among children with established asthma, parental smoking is associated with more severe disease. This apparent paradox may be reconciled if environmental tobacco smoke is considered a co-factor provoking wheezing attacks, rather than a cause of the underlying asthmatic tendency.

Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC).

Background: As part of the International Study of Asthma and Allergies in Childhood (ISAAC), prevalence surveys were conducted among representative samples of school children from locations in Europe, Asia, Africa, Australasia, North and South America.

Helicobacter pylori infection in childhood: risk factors and effect on growth

Abstract Objective: To investigate the current prevalence of Helicobacter pylori infection in childhood, the risk factors for infection, and the effect of infection on growth in preadolescent schoolchildren. Design: Population based sample of 7 year old schoolchildren followed up at age 11; data on risk20factors for infection collected at age 7; presence of infection at age 11 determined by measurement of salivary IgG against H pylori by a newly developed enzyme linked immunosorbent assay (ELISA). Height was measured at 7 and 11 years of age. Subjects: 554 schoolchildren from Edinburgh. Results: 62 (11%) children had H pylori infection.20Independent risk factors for infection were single parent families (adjusted odds ratio=2.5; 95% confidence interval 1.1 to 5.7), the 10% most crowded homes (3.1; 1.3 to 7.2), and schools serving predominantly rented housing estates (2.5; 1.0 to 6.5). School catchment area was more important than parental social class or housing tenure. Growth in height between 7 and 11 was diminished in infected children by a mean of 1.1 cm (0.3 to 2.0 cm) over four years. This growth reduction was largely confined to girls (1.6 cm over four years), among whom it correlated with salivary IgG (P=0.015). Conclusion: Data from salivary assay to investigate the epidemiology of H pylori suggest that factors relating to the type of community in which the child lives may now be as important for acquisition of this infection as features of the family home. The greater reduction of growth among infected girls raises the possibility that H pylori infection may delay or diminish the pubertal growth spurt.