The effect of parental allergy on childhood allergic diseases depends on the sex of the child.

BACKGROUND: The parent-of-origin effect is important in understanding the genetic basis of childhood allergic diseases and improving our ability to identify high-risk children. OBJECTIVE: We sought to investigate the parent-of-origin effect in childhood allergic diseases. METHODS: The Isle of Wight Birth Cohort (n= 1456) has been examined at 1, 2, 4, 10, and 18 years of age. Information on the prevalence of asthma, eczema, rhinitis, and environmental factors was obtained by using validated questionnaires. Skin prick tests were carried out at ages 4, 10, and 18 years, and total IgE measurement was carried out at 10 and 18 years. Parental history of allergic disease was assessed soon after the birth of the child, when maternal IgE levels were also measured. Prevalence ratios (PRs) and their 95% CIs were estimated, applying log-linear models adjusted for confounding variables. RESULTS: When stratified for sex of the child, maternal asthma was associated with asthma in girls (PR, 1.91; 95% CI, 1.34-2.72; P= .0003) but not in boys (PR, 1.29; 95% CI, 0.85-1.96; P= .23), whereas paternal asthma was associated with asthma in boys (PR, 1.99; 95% CI, 1.42-2.79; P< .0001) but not in girls (PR, 1.03; 95% CI, 0.59-1.80; P= .92). Maternal eczema increased the risk of eczema in girls (PR, 1.92; 95% CI, 1.37-2.68; P= .0001) only, whereas paternal eczema did the same for boys (PR, 2.07; 95% CI, 1.32-3.25; P = .002). Similar trends were observed when the effect of maternal and paternal allergic disease was assessed for childhood atopy and when maternal total IgE levels were related to total IgE levels in children at ages 10 and 18 years. CONCLUSIONS: The current study indicates a sex-dependent association of parental allergic conditions with childhood allergies, with maternal allergy increasing the risk in girls and paternal allergy increasing the risk in boys. This has implications for childhood allergy prediction and prevention.

Air pollutant exposure and preterm and term small-for-gestational-age births in Detroit, Michigan: long-term trends and associations.

Studies in a number of countries have reported associations between exposure to ambient air pollutants and adverse birth outcomes, including low birth weight, preterm birth (PTB) and, less commonly, small for gestational age (SGA). Despite their growing number, the available studies have significant limitations, e.g., incomplete control of temporal trends in exposure, modest sample sizes, and a lack of information regarding individual risk factors such as smoking. No study has yet examined large numbers of susceptible individuals. We investigated the association between ambient air pollutant concentrations and term SGA and PTB outcomes among 164,905 singleton births in Detroit, Michigan occurring between 1990 and 2001. SO(2), CO, NO(2), O(3) and PM(10) exposures were used in single and multiple pollutant logistic regression models to estimate odds ratios (OR) for these outcomes, adjusted for the infant's sex and gestational age, the mother's race, age group, education level, smoking status and prenatal care, birth season, site of residence, and long-term exposure trends. Term SGA was associated with CO levels exceeding 0.75ppm (OR=1.14, 95% confidence interval=1.02-1.27) and NO(2) exceeding 6.8ppb (1.11, 1.03-1.21) exposures in the first month, and with PM(10) exceeding 35µg/m(3) (1.22, 1.03-1.46) and O(3) (1.11, 1.02-1.20) exposure in the third trimester. PTB was associated with SO(2) (1.07, 1.01-1.14) exposure in the last month, and with (hourly) O(3) exceeding 92ppb (1.08, 1.02-1.14) exposure in the first month. Exposure to several air pollutants at modest concentrations was associated with adverse birth outcomes. This study, which included a large Black population, suggests the importance of the early period of pregnancy for associations between term SGA with CO and NO(2), and between O(3) with PTB; and the late pregnancy period for associations between term SGA and O(3) and PM(10), and between SO(2) with PTB. It also highlights the importance of accounting for individual risk factors such as maternal smoking, maternal race, and long-term trends in air pollutant levels and adverse birth outcomes in evaluating relationships between pollutant exposures and adverse birth outcomes.

What does adolescent undiagnosed wheeze represent? Findings from the Isle of Wight Cohort.

We sought to characterise adolescent wheeze in the absence of asthma, which we termed "undiagnosed wheeze". The Isle of Wight Birth Cohort (n=1,456) was reviewed at 1, 2, 4, 10 and 18 yrs. Using questionnaire responses, "asthma" was defined as "ever had asthma" plus either "wheezing in the last 12 months" or "taking asthma treatment in the last 12 months"; "undiagnosed wheeze" as "wheeze in the last 12 months" but "no" to "ever had asthma"; and remaining subjects termed "non-wheezers". Undiagnosed wheeze (prevalence 4.9%) accounted for 22% of wheezing at 18 yrs. This was largely adolescent-onset with similar symptom frequency and severity to diagnosed asthma. However, undiagnosed wheezers had significantly higher forced expiratory volume in 1 s to forced vital capacity ratio, less bronchodilator reversibility and bronchial hyperresponsiveness, and were less frequently atopic than asthmatics. Undiagnosed wheezers had earlier smoking onset, higher smoking rates and monthly paracetamol use than non-wheezers. Logistic regression identified paracetamol use (OR 1.11, 95% CI 1.01-1.23; p=0.03), smoking at 18 yrs (OR 2.54, 95% CI 1.19-5.41; p=0.02), rhinitis at 18 yrs (OR 2.82, 95% CI 1.38-5.73; p=0.004) and asthmatic family history (OR 2.26, 95% CI 1.10-4.63; p=0.03) as significant independent risk factors for undiagnosed wheeze. Undiagnosed wheeze is relatively common during adolescence, differs from diagnosed asthma and has strong associations with smoking and paracetamol use. Better recognition of undiagnosed wheeze and assessment of potential relevance to adult health is warranted.

Do symptoms predict COPD in smokers?

BACKGROUND: The US Preventive Services Task Force recommends against spirometry in the absence of symptoms. However, as much as 50% of COPD cases in the United States remain undiagnosed. METHODS: Report of symptoms, smoking history, and spirometric data were collected from subjects screened for a work-related medical evaluation (N = 3,955). Prevalence of airflow obstruction and respiratory symptoms were assessed. Sensitivity, specificity, positive and negative predictive values, and relative risks of predicting symptoms and smoking history for COPD were calculated. RESULTS: Forty-four percent of smokers in our sample had airways obstruction (AO). Of these, 36% reported a diagnosis of or treatment for COPD. Odds ratio (95% CI) for AO with smoking (> or = 20 pack-years) was 3.73 (3.12- 4.45), 1.98 (1.73-2.27) for cough, 1.79 (1.55-2.08) for dyspnea, 1.95 (1.70-2.34) for sputum, and 2.59 (2.26-2.97) for wheeze. Respiratory symptoms were reported by 92% of smokers with AO, 86% smokers with restriction, 76% smokers with normal spirometry, and 73% of nonsmokers. Sensitivity (92% vs 90%), specificity (19% vs 22%), positive (47% vs 40%) and negative (75% vs 80%) predictive values for the presence of one or more symptoms were similar between smokers and all subjects. CONCLUSIONS: COPD is underdiagnosed in the United States. Symptoms are frequent in subjects with AO and increase their risk for COPD, but add little beyond age and smoking history to the predictive value of spirometry. In view of the high prevalence of symptoms and their poor predictive value, a simpler and more effective approach would be to screen older smokers.

COPD is associated with a macrophage scavenger receptor-1 gene sequence variation.

BACKGROUND: Macrophages play an important role in COPD. We genotyped at-risk smokers to evaluate the role of polymorphisms in the macrophage scavenger receptor-1 gene (MSR1) in COPD susceptibility and related measures of lung function. Then, in macrophages from donors with specific MSR1 genotypes, we determined the effect of MSR1 single nucleotide polymorphisms (SNPs) on macrophage function by examining in vitro adhesion, receptor expression, and cell number in culture as an index of increased survival/reduced apoptosis. METHODS: Smokers (> or = 20 pack-years) who were > 40 years (n = 714) were genotyped for seven SNPs; one nonsense change (ex6R293x_C/T), four missense changes (ex4V113A_T/C, ex4P174Y_G/T, ex11H441R_A/G, and in the ligand binding site ex6P275A_C/G), -176511_A/G in the promoter region, and IVS5-59_C/A in the intron. Nonsmoking healthy volunteers (n = 85) were genotyped, and peripheral blood monocytes were isolated from seven P275A_CG/GG and eight P275A_CC controls and cultured to generate monocyte-derived macrophages (MDM). The effectiveness of trypsin and scraping to dislodge MDM was scored on a four-point subjective scale. MDM were counted on a Z1 particle counter and surface expression of MSR1 was determined by fluorescence-activated cell sorting analysis using secondary staining of antibodies against human macrophage scavenger receptor (MSR1). RESULTS: The MSR1-coding SNP P275A was associated with susceptibility to COPD in smokers (P < .005) and a lower percent predicted (pp) FEV(1), FEV(1)/FVC, and pp forced expiratory flow (FEF)(25-75) (P = .03). P275A_CG/GG was also associated with increases in maintenance of cell number in culture (increased survival/reduced apoptosis), MSR1 expression, and adhesion of macrophages to plastic in vitro (P < .05). CONCLUSIONS: The MSR1 association with COPD susceptibility, COPD-related measures of lung function, and abnormalities of macrophage function may account for significant COPD morbidity.

Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers.

BACKGROUND: Variation in ADAM33 has been shown to be important in the development of asthma and altered lung function. This relationship however, has not been investigated in the population susceptible to COPD; long term tobacco smokers. We evaluated the association between polymorphisms in ADAM33 gene with COPD and lung function in long term tobacco smokers. METHODS: Caucasian subjects, at least 50 year old, who smoked >or= 20 pack-years (n = 880) were genotyped for 25 single nucleotide polymorphisms (SNPs) in ADAM33. COPD was defined as an FEV1/FVC ratio < 70% and percent-predicted (pp)FEV1 < 75% (n = 287). The control group had an FEV1/FVC ratio >or= 70% and ppFEV(1) >or= 80% (n = 311) despite >or= 20 pack years of smoking. Logistic and linear regressions were used for the analysis. Age, sex, and smoking status were considered as potential confounders. RESULTS: Five SNPs in ADAM33 were associated with COPD (Q-1, intronic: p < 0.003; S1, Ile --> Val: p < 0.003; S2, Gly --> Gly: p < 0.04; V-1 intronic: p < 0.002; V4, in 3' untranslated region: p < 0.007). Q-1, S1 and V-1 were also associated with ppFEV1, FEV1/FVC ratio and ppFEF25-75 (p values 0.001 - 0.02). S2 was associated with FEV1/FVC ratio (p < 0.05). The association between S1 and residual volume revealed a trend toward significance (p value < 0.07). Linkage disequilibrium and haplotype analyses suggested that S1 had the strongest degree of association with COPD and pulmonary function abnormalities. CONCLUSION: Five SNPs in ADAM33 were associated with COPD and lung function in long-term smokers. Functional studies will be needed to evaluate the biologic significance of these polymorphisms in the pathogenesis of COPD.

IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study.

BACKGROUND: Tobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13) polymorphisms and tobacco smoke on persistent childhood wheezing and asthma. METHODS: In the Isle of Wight birth cohort (UK, 1989-1999), five IL13 single nucleotide polymorphisms (SNPs): rs1800925 (-1112C/T), rs2066960, rs1295686, rs20541 (R130Q) and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy. RESULTS: Maternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p < 0.0001); polymorphisms in IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair). However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014). Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02). Comparable results were observed for persistent childhood asthma (p for interaction = 0.03). CONCLUSION: This is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.

Patterns of GATA3 and IL13 gene polymorphisms associated with childhood rhinitis and atopy in a birth cohort.

BACKGROUND: GATA3 activates transcription of the T(H)2 cytokines, including IL13, an important step in the allergic inflammatory pathway. OBJECTIVE: We sought to identify associations of single nucleotide polymorphisms of the genes GATA3 and IL13 and their interactions with rhinitis and allergic sensitization during childhood. METHODS: We performed genetic association studies in a cohort of children (n = 923) who have been evaluated for the development of rhinitis and allergic sensitization by means of skin prick tests (SPTs) at age 10 years. Pyrosequencing was used to genotype 7 polymorphisms from GATA3 and 5 from IL13. A novel model-selection procedure combining logistic regression models and classification was used to study the contributions of the polymorphisms and their interactions. RESULTS: Combinations of polymorphisms and their interactions increase the risk for rhinitis and allergic sensitization at age 10 years. A model with rs1058240, rs379568, and rs4143094 (GATA3) and rs1800925 (IL13) and their interactions was selected to predict rhinitis and positive SPT responses. rs1058240 was associated with rhinitis and allergic rhinitis (P < .05), and the gene-gene interaction rs1058240:rs1800925 was associated with rhinitis (P = .043). The odds ratios for 4 genotype combinations were significant for rhinitis or SPTs (P < .044). CONCLUSION: Gene-gene interaction between GATA3 and IL13 polymorphisms can influence the risk of childhood rhinitis. Our study suggests that set associations of polymorphisms are important in studying genetic associations for complex phenotypes, such as rhinitis and atopy.

IL13 promoter polymorphism 1112C/T modulates the adverse effect of tobacco smoking on lung function.

RATIONALE: Although the duration and amount of cigarette smoking correlate with reduction in pulmonary function, there is still variation among individual responses. IL-13 is involved in pulmonary inflammation, remodeling, and susceptibility to chronic obstructive pulmonary disease (COPD). OBJECTIVES: We investigated whether the relationships between smoking and the lung function measures FEV(1) and FEV(1)/FVC ratio are modulated by IL13 polymorphisms. METHODS: Smokers (>or=20 pack-years), aged at least 40 years old (n = 1,073), were genotyped for three single nucleotide polymorphisms (SNPs; -1112C/T [rs1800925], +2044G/A [rs20541, R130Q], and +2525G/A [rs1295685]) in the IL13 gene. Linear, quantile, and logistic regression methods were used to assess the effect of cigarette smoking (pack-years), IL13 polymorphisms, and their interaction on %predicted FEV(1) and FEV(1)/FVC ratio. Age, sex, and current smoking status were included as confounders. MEASUREMENTS AND MAIN RESULTS: The number of pack-years smoked was associated with a lower value for both %predicted FEV(1) and FEV(1)/FVC (P < 0.001). The three SNPs were not associated with lung function measures; however, there was a significant combined effect between smoking and the promoter polymorphism -1112C/T on %predicted FEV(1) (P for interaction < 0.03 for mean %predicted FEV(1) and < 0.0001 for 90th percentile %predicted FEV(1)). Every 20-pack-year increment in smoking was associated with a 2.4% reduction in mean %predicted FEV(1) in the common homozygous (CC) or heterozygous (CT) promoter genotypes, and an 8.2% reduction in mean %predicted FEV(1) in minor allele homozygotes (TT, recessive model). CONCLUSIONS: An IL13 polymorphism in the promoter region may modulate the adverse effects of cigarette smoking on pulmonary function in long-term cigarette smokers.

IL13 gene polymorphism association with cord serum immunoglobulin E.

Interleukin-13 (IL-13) has a pivotal role in the pathway of immunoglobulin E (IgE). Cord serum IgE has been suggested to be associated with allergy later in life, yet less affected by environmental exposures. We investigated the association of the interleukin-13 gene (IL13) polymorphisms on cord serum IgE. In the Isle of Wight birth cohort (UK, 1989-1990), cord serum IgE was measured using the ULTRA EIA kit and was dichotomized at 0.5 kU/l (n = 1358). Five single nucleotide polymorphisms (SNPs: rs1800925 in promoter, rs2066960 in intron 1, rs1295686 in intron 3, rs20541 in exon 4 and rs1295685 in exon 4) in IL13 were genotyped by pyrosequencing method. Linkage analysis using Haploview software revealed that rs1295686, rs20541 and rs1295685 were in strong linkage disequilibrium. Logistic regression and Armitage-Cochran test were used and gene association analysis included 798 children. Confounders were maternal age; maternal smoking, household dog, and household cat during pregnancy; season of birth; sex; position of child in family; and birth weight. SNP rs1295685 was associated with raised cord serum IgE (p = 0.031). This is the first report that shows an association between IL13 polymorphism and cord serum IgE.

Prevention of allergic disease during childhood by allergen avoidance: the Isle of Wight prevention study.

BACKGROUND: Early life allergen exposure may increase the risk of childhood allergy, but the protective effect of reduction in allergen exposure remains uncertain. OBJECTIVE: To evaluate the effect of reduction in food and house dust mite (HDM) allergen exposure in infancy in preventing asthma and allergy. METHODS: Infants, at higher risk because of family predisposition, were recruited prenatally and randomized to prophylactic (n = 58) and control (n = 62) groups. Prophylactic group infants were either breast-fed with mother on a low allergen diet or given an extensively hydrolyzed formula. Exposure to HDM was reduced by the use of an acaricide and mattress covers. The control group followed standard advice. Development of allergic diseases and sensitization to common allergens (atopy) was assessed blindly at ages 1, 2, 4, and 8 years in all 120 children. RESULTS: Repeated measurement analysis, adjusted for all relevant confounding variables, confirmed a preventive effect on asthma: adjusted odds ratio (OR), 0.24; 95% CI, 0.09-0.66; P = .005; atopic dermatitis, OR, 0.23; CI, 0.08-0.64; P = .005; rhinitis, OR, 0.42; CI, 0.19-0.92; P = .03; and atopy, OR, 0.13; CI, 0.05-0.32; P < .001. The protective effect was primarily observed in the subgroup of children with persistent disease (symptoms at all visits) and in those with evidence of allergic sensitization. CONCLUSION: Allergic diseases can be reduced, for at least the first 8 years of life, by combined food and HDM allergen avoidance in infancy. CLINICAL IMPLICATIONS: Strict food and HDM allergen avoidance should be considered for prevention of allergy in high-risk infants.