Family Asthma Research Articles

Evidence for gene × smoking exposure interactions in a genome-wide linkage screen of asthma and bronchial hyper-responsiveness in EGEA families

Asthma and bronchial hyper-responsiveness (BHR), an asthma-related phenotype, result from many genetic (G) and environmental (E) factors. Passive exposure to tobacco smoke (ETS) in early life is one of these risk factors. Following a genome scan for asthma and associated phenotypes conducted in 295 French Epidemiological study on the Genetics and Environment of Asthma, our present aim was to investigate interactions between genetic susceptibility to asthma and to BHR with passive ETS using two different methods: the predivided sample test (PST) and the mean interaction test (MIT). PST and MIT consider the identical by descent (identity by descent) distribution at all markers in affected sib-pairs with 2, 1 or 0 sib(s) exposed to ETS. While the PST allows detection of both linkage and G x E interaction, the MIT tests for linkage by taking into account a possible interaction. Among the six regions detected at P</=0.005, three of them (1q43-q44, 4q34, 17p11) were revealed by both PST and MIT for BHR. The three other regions were detected by only one method: 5p15 for BHR using PST; 14q32 and 17q21 for asthma using MIT, underlying the importance of using concomitantly different approaches. None of these regions was revealed for asthma and bronchial responsiveness by previous linkage analyses of these data, supporting the idea that taking into account gene-environment interactions can substantially increase power of linkage detection. Our results also showed evidence for G x ETS interactions underlying BHR in all four regions detected by PST.

Factors associated with the duration of exclusive breast-feeding in asthmatic families

This study was part of a randomized controlled trial in which verbal and written advice about exclusive breast-feeding for 6 months was provided to Dutch women expecting a child with a high risk of developing asthmatic traits. Eighty-nine women completed a theory-based self-report questionnaire between the third and sixth months of pregnancy, which served as the baseline measurement. The aim of this study was to examine the factors that influence the duration of exclusive breast-feeding. Cox multiple regression analysis showed a positive significant association between the duration of exclusive breast-feeding and the mother's breast-feeding knowledge (P < 0.01), her intended hours of work per week after maternity leave (P < 0.01) and her age (P <or= 0.05). Short-term, that is <5 weeks, or no previous breast-feeding experience of multiparous women appeared to be negatively associated with the duration of breast-feeding (P < 0.001). Furthermore, women who received the educational programme were more likely to succeed in breast-feeding exclusively for 6 months than the control group (48% versus 27%, P < 0.05). This study suggests that extra educational support is beneficial, and especially necessary for multiparous women with an earlier short-term, <5 weeks, or no breast-feeding experience, since they are at risk of discontinuing exclusive breast-feeding before completing the advisable 6-month period.

Lower inhaled steroid requirement with a fluticasone/salmeterol combination in family practice patients with asthma or COPD

Previous studies on inhaled steroid and long-acting beta2-agonist combination products may not be representative for the asthma and chronic obstructive pulmonary disease (COPD) patients in family practice. To compare in a group of doctor-diagnosed patients with asthma or COPD, the effects of a lower dose of fluticasone in a combination product with salmeterol with conventional treatment (i.e. a higher dose of fluticasone), both supplemented with as-needed use of a short-acting bronchodilator. The study was a 12-week multicentre, randomized controlled, double-blind trial. In all, 41 family practices recruited 137 patients diagnosed with asthma and 40 patients diagnosed with COPD. Primary outcome was the forced expiratory volume in 1 second (FEV1) as percentage of predicted. Morning peak expiratory flow (PEF), symptom-free days, health status [Asthma Quality of Life Questionnaire (AQLQ) and St. George's Respiratory Questionnaire (SGRQ)], exacerbations, use of short-acting bronchodilators and adverse events were secondary outcomes. FEV1% predicted increased 2.6% (SD 8.3) in fluticasone/salmeterol- and 0.01% (SD 6.6) in fluticasone-treated patients (overall: P=0.036, asthma: P=0.025 and COPD: P=0.700). PEF increased in favour of fluticasone/salmeterol in asthma patients only (P=0.016). Fluticasone/salmeterol-treated asthma patients had 1.1 more symptom-free days per week (P=0.044); no such effect was observed for COPD (P=0.769). There were no differences in total AQLQ and SGRQ scores, exacerbations, use of reliever puffs or adverse effects. In family practice patients diagnosed with asthma, several treatment goals were better achieved with a lower dose of fluticasone and salmeterol in a combination product than with a higher dose of fluticasone. We found no differences between the two approaches for patients with COPD.

The Success of an Educational Program to Promote Exclusive Breastfeeding for 6 Months in Families with a History of Asthma: A Randomized Controlled Trial

The objective was to investigate the effect of a theory-based educational program in promoting exclusive breastfeeding for at least 6 months in asthmatic families. 89 families in which the woman was less than 7 months pregnant and at least one first-degree relative (mother, biological father, or sibling) had asthma that had been diagnosed by a doctor were recruited by means of posters in the practices of midwives and participated in a randomized controlled trial. When the families in the intervention group were visited (twice before the births of their babies and once after), they received written and oral advice about all aspects of breastfeeding and storing and expressing milk. The proportion of women breastfeeding exclusively at 6 months was significantly higher in the intervention group than among the control group (21/44 [48%] versus 12/45 [27%]; odds ratio 2.91; 95% Confidence Interval [1.10-7.71] (p = 0.03), controlled for maternal age, education level, and breastfeeding experience. This study provides evidence that the new program (written and oral advice about breastfeeding) is effective in improving the exclusive breastfeeding rates at 6 months in asthmatic families. A next step would be to make this program available for health professionals who support pregnant women who have a familial history of asthma. (Pediatr Asthma Allergy Immunol 2006; 19[4]:214–222.)

Factors Associated with the Initiation of Breastfeeding in Asthmatic Families: The Attitude–Social Influence–Self-Efficacy Model

Exclusive breastfeeding for the first 6 months postpartum is promoted internationally as the preferred method of feeding infants. Infants of parents with a history of asthma in particular could benefit from a longer period (6 months) of breastfeeding, because this may reduce the chance of developing an allergic disease. The aim of this study was to identify psychosocial behavioral determinants of the intended duration and actual initiation of breastfeeding in families with a predisposition to asthma. This prospective study was part of a randomized trial in which breastfeeding for 6 months was promoted. The 89 women participating completed a breastfeeding questionnaire based on the Attitude-Social Influence-Self-Efficacy model in the second trimester of their pregnancy. This served as the baseline measurement. Multiple linear and logistic regression analyses showed that attitudinal beliefs were significantly associated with the intended duration to breastfeed (p = 0.01) and the intention was the strongest predictor for the actual initiation of breastfeeding (OR: 8.2; 95% CI: 1.5 to 44.3). Breastfeeding promotion needs to focus on the health advantages and other advantages of breastfeeding for 6 months, especially in high-risk groups, in order to increase the intention to breastfeed, which appeared to be a strong predictor for actual behavior.

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Meeting program

Coping with asthma in immigrant Hispanic families: a focus group study

Little is known about how childhood asthma affects immigrant Hispanic families in the United States. Qualitative research is effective for understanding the social, cultural, functional, and structural aspects of asthma in the family context. Furthermore, such knowledge is necessary to develop culturally appropriate interventions for these families. To describe participants' perceptions of their roles in caring for an asthmatic child, to compare family patterns of caring for an asthmatic child by parents' country of origin, to identify barriers to caring for an asthmatic child, and to evaluate specific coping needs of low-income immigrant Hispanic families caring for an asthmatic child. Five focus groups were conducted with low-income, immigrant, Spanish-speaking Hispanic adults caring for an asthmatic child, including community health workers, mothers, fathers, and grandparents, along with women with asthma. Audiotaped focus groups were transcribed verbatim in Spanish, forward translated into English, and back translated into Spanish. Data analysis was performed using qualitative analytic methods. Forty-one participants represented a range of countries of origin. Different themes emerged for community health workers vs parents and grandparents and for women vs men caring for a child with asthma. All the participants reported strong beliefs in using folk medicines. Barriers identified included language, culture, poverty, lack of health insurance, and poor living conditions. Results highlight the lack of asthma self-management skills, diagnostic uncertainty, and the use of folk medicine as factors that should be taken into consideration when tailoring interventions to improve asthma outcomes in this vulnerable population.

Determinants of cockroach and mouse exposure and associations with asthma in families and elderly individuals living in New York City public housing

Asthma prevalence is high in the inner city, and morbidity has been associated with cockroach and mouse allergens. To characterize the relationships among pests, allergens, pesticides, and asthma in New York City public housing. In 324 apartments, dust samples collected from beds and kitchens were analyzed for cockroach (Bla g 2) and mouse (mouse urinary protein [MUP]) allergens, pest populations were monitored, and residents were interviewed about home characteristics and asthma symptoms. Cockroaches were found in 77% of the apartments, and evidence of mice was found in 13%. Allergens and pesticide use were associated with pest infestation, and 15% of residents reported using illegal pesticides. The percentage of apartments with high allergen levels varied significantly by building (Bla g 2: P = .002; MUP: P = .03), as did the percentage of apartments with cockroaches (P = .002) and daily mouse sightings (P = .02). Thirty-seven percent of the apartments had at least 1 resident with physician-diagnosed asthma. In family buildings, apartments with high Bla g 2 levels had 1.7 times greater odds of having an asthmatic resident (95% confidence interval, 1.2-2.3). In senior citizen buildings, apartments with high MUP levels had 6.6 times greater odds of having an asthmatic resident (95% confidence interval, 1.4-31.7), controlling for smoking and other potential confounders. Previous studies have identified home characteristics associated with the presence of cockroaches and mice, but the present findings suggest that building-level characteristics can affect high pest exposure. Furthermore, the high asthma prevalence in residents and the use of illegal pesticides highlight the need for safe and effective building-wide pest control strategies.

Home Visiting for Intervention Delivery to Improve Rural Family Asthma Management

The focus of this article is on the use of home visits in an asthma self-management intervention study with rural families who have a school-aged child with asthma. The study design involved randomization of the sample by elementary schools, then baseline (pretest) and postintervention data collection.1 The purpose of this article is to describe challenges with, and pose solutions for, implementing home visits for asthma self-management in rural areas. Home visiting is a strategy for program delivery that takes advantage of the home context for tailoring services to address the family's individual needs. The advantages of intervening in the home include being able to (a) use actual home conditions for individualizing the asthma education to meet families' needs; (b) match home visitors with family in terms of ethnicity and language; (c) retain a high percentage of families over the year-long duration of the study; and (d) not add to family burden of managing asthma.

The cysteinyl‐leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma

The cysteinyl-leukotriene receptor type 1 (CysLT1) mediates the bronchoconstrictor and pro-inflammatory actions of cysteinyl-leukotrienes (LTC4, LTD4, LTE4) in asthma and is the molecular target of the lukast class of oral anti-leukotriene drugs. We screened the CYSLTR1 gene on chromosome Xq13-21 for coding region polymorphisms, and investigated their associations with allergy and asthma. Solid-phase chemical cleavage was used to screen polymorphisms in the coding region of CYSLTR1. A TaqMan allelic discrimination assay was used to genotype a 927T/C SNP and oligonucleotide ligation assays were used to genotype the previously reported 617T/C and 898G/A SNPs of CYSLTR1 in 341 asthmatic families from the UK. Associations with asthma diagnosis, atopic status, serum-specific IgE and severity of allergy and asthma were examined. Family-based association tests showed that the 927 T allele was associated with atopy severity, especially in female subjects, but not with asthma diagnosis or severity, atopic status, bronchial hyper-responsiveness to methacholine or forced expiratory volume in 1 s. Mutation screening identified only one polymorphism, 927T/C, in the coding region of the CysLT1 receptor. This polymorphsim is predictive of atopy severity, but not associated with asthma.

Pediatric Asthma Morbidity: The Importance of Symptom Perception and Family Response to Symptoms

To determine whether family response to asthma symptoms mediates the relationship between child symptom perception and morbidity. A total of 122 children with asthma, aged between 7 and 17 years (47% females; 25% ethnic minorities), were recruited from three sites. Participants completed a family asthma management interview and 5-6 weeks of symptom perception assessment. Family response to symptoms mediated the relationship between child underestimation of symptoms and asthma morbidity and partially mediated the relationship between accurate symptom perception and morbidity. In contrast, although child overestimation of symptoms and family response to symptoms were independently related to asthma morbidity, a mediational model was not supported. Our study found support for the role of family response to symptoms in mediating the relationship between child symptom perception and morbidity, particularly with regard to underestimation of symptoms, underscoring the need for behavioral tools to accurately recognize and optimally respond to exacerbations.

Coping with Asthma in Immigrant Hispanic Families: A Focus Group Study

RATIONALE: Little is known about how childhood asthma impacts low income immigrant (LII) Hispanic families within the United States. Qualitative research is effective for understanding the social, cultural, functional, and structural aspects of asthma within the family context. We aimed to describe participants' perceptions of their role in caring for an asthmatic child; to compare the patterns of family caring for an asthmatic child by parents' country of origin; to identify barriers to caring for an asthmatic child; and to assess specific coping needs of LII Hispanic families caring for an asthmatic child. METHODS: Five focus groups were conducted with LII Spanish-speaking Hispanic adults caring for an asthmatic child, including community health workers (CHWs), mothers, fathers, and grandparents. Audiotaped focus groups were transcribed verbatim in Spanish, forward translated into English, and back translated into Spanish. Data analysis was performed using qualitative analytic methodology. RESULTS: Forty-one participants represented diverse countries of origin. Different themes emerged for CHWs versus parents and grandparents. Similarly, women and men had slightly different perspectives on their roles in caring for the child. All participants reported strong beliefs in using folk medicines to treat asthma. Immigrant mothers described a lack of adequate social support for having a child with asthma. Barriers identified included fear, language, culture, poverty, lack of health insurance, and poor living conditions. CONCLUSIONS: Results highlight the lack of asthma self-management skills, diagnostic uncertainty, and use of folk medicines as factors that should be taken into consideration when tailoring interventions to improve asthma outcomes in this vulnerable population.

Association between interleukin‐1 receptor antagonist gene and asthma‐related traits in a German adult population

A recent study in German and Italian families associated variants in the interleukin-1 receptor antagonist (IL1RA) gene with asthma. The aim of the present study was to further investigate the role of single nucleotide polymorphisms (SNPs) in the IL1RA gene in the development of atopy and lifelong asthma in a population-based study. DNA samples from the German centres of the European Community Respiratory Health Survey were analysed for genetic variants in the IL1RA gene and the development of asthma, atopy and bronchial hyperreactivity. Carriers of the rare G allele of SNP rs447713 had a significantly increased risk of developing asthma (P = 0.0013) and allergic sensitization (P = 0.0119). Carriers of the rare C allele of SNP rs3087271 had an increased risk of asthma (P = 0.0227) and high immunoglobulin E (IgE) levels (P = 0.0232). A haplotype built from eight SNPs in the IL1RA gene (A-C-A-G-A-C-G-A) was associated with a higher prevalence of asthma (P = 0.007) and high total IgE (P = 0.02). Bronchial hyperreactivity was positively associated with the haplotype A-C-G-G-A-C-G-C (P = 0.02) and negatively with the A-C-G-G-A-C-T-C (P = 0.03). A previously described association between IL1RA and asthma in families could be reproduced in a population-based sample. The genetic variants of IL1RA gene do not to seem to affect asthma alone, but to act as modulators of asthma-related traits as well, where different haplotypes drive the development of different phenotypes.

T-bet polymorphisms are associated with asthma and airway hyperresponsiveness.

T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR. To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association. Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels. We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR. These data suggest that T-bet variation contributes to airway responsiveness in asthma.

Effects of glutathione S‐transferase M1, T1 and P1 on lung function in asthmatic families

Previous data have suggested that glutathione-S-transferase (GST) genotypes are important in determining the rate of lung function growth in childhood. This effect was most marked in Caucasian children with asthma. We investigated the association of lung function with GSTM1, GSTP1 and GSTT1 genotypes in Caucasian families with asthma. Four hundred and eighteen children and 316 parents from 224 Caucasian families were recruited via a child with asthma, the proband. Associations between lung function and GST genotype were determined using multilevel models. There were no observed associations between lung function and GST genotype in parents. However, in the children, the GSTP1 val(105)/val(105) and GSTM1 null genotypes were associated with significantly higher forced expiratory volume in 1 s (FEV(1)) and FVC values as percentage of predicted. This effect was not statistically significant in the probands but was marked in their siblings in whom GSTP1 val(105)/val(105) was associated with 9.4% higher FEV(1) and 10.7% higher FVC (P=0.005 and 0.001, respectively). The GSTM1 null genotype was associated with a 6.7% higher FEV(1) and 4.1% higher FVC (P=0.003 and 0.063, respectively). These effects remained significant after correcting for the confounders of individual atopic status, tobacco smoke exposure and familial aggregation of lung function values. GSTM1 and GSTP1 genotypes are important determinants of lung function in childhood. The smaller differences seen in probands are predicted by a simple model in which more rapid decline in lung function is seen in these individuals.

Pediatric Asthma Management in the Family Context: The Family Asthma Management System Scale

To examine psychometric properties of a revised version of the Family Asthma Management System Scale (FAMSS), a clinical interview to assess asthma management. The FAMSS was administered to 115 children with asthma and their primary caregivers, along with a measure of asthma morbidity. A subset of families (n = 53) participated also in objective-adherence monitoring and completed measures of asthma knowledge and self-efficacy. The FAMSS demonstrated good internal consistency (alpha = .84). The FAMSS summary score was unrelated to age, gender, race, or minority status, but was related to socioeconomic status (SES) and to functional morbidity at baseline and prospectively. Convergent validity of the FAMSS was documented. The FAMSS explained additional variance in concurrent-asthma morbidity beyond self-reports or objective adherence monitoring. The FAMSS is a valuable tool to assess family-based asthma management that addresses gaps in available assessment methodologies and holds promise for research and clinical applications.

ADAM33 Enzyme Properties and Substrate Specificity

ADAM33 is an asthma susceptibility gene recently identified through a genetic study of asthmatic families [van Eerdewegh, et al. (2002) Nature 418, 426-430]. To understand the function of the gene product, the recombinant metalloproteinase domain of human ADAM33 was purified and tested for its substrate cleavage specificity using peptides derived from beta-amyloid precursor protein (APP). A single Ala substitution at the P2 position of a 10-residue APP peptide, YEVHHQKLVF, yielded a 20-fold more efficient substrate. Terminal truncation studies identified a minimal nine-residue core (P5-P4') important for ADAM33 recognition and cleavage. Full positional scanning of the 10-mer peptide using the 19 naturally occurring l-amino acids (excluding Cys) revealed a substrate specificity profile. A strong preference for Val or Ile at P3, Ala at P2, and Gln at P1' was observed. The substrate binding model based on the X-ray structure of the ADAM33-inhibitor complex supported the observed substrate specificity profile. On the basis of this, an improved substrate was designed and a fluorescence resonance energy transfer (FRET) assay was developed using a fluorogenic derivative of this substrate. Kinetic studies confirmed that the best substrate, FRET-P2 [K(Dabcyl)YRVAFQKLAE(Edans)K], was approximately 100-fold more efficient than the wild-type APP peptide substrate, with a k(cat)/K(m) value of (3.6 +/- 0.1) x 10(4) s(-)(1) M(-)(1). Using this substrate and the FRET assay, ADAM33 enzyme activity and thermal stability were characterized. ADAM33 dependence on buffer conditions, detergents, and temperature was examined, and optimal conditions were defined. Accurate K(i) values for tissue inhibitors of metalloproteinase and small molecule compounds were obtained.

Reexamining the Familial Association Between Asthma and ADHD in Girls

The objective of this study is to further evaluate the association between asthma and ADHD, addressing issues of familiality in female probands. A case control study of referred ADHD proband girls, controls, and relatives are used. Participants include 140 ADHD proband girls and 122 non-ADHD comparisons, with 417 and 369 first-degree biological relatives, respectively. Relatives are stratified into four groups according to proband ADHD and asthma status. The authors compare rates of asthma and ADHD in relatives. ADHD does not increase the risk for asthma in probands. Patterns of familial aggregation are mostly consistent with independent transmission of ADHD and asthma in families of girl probands. The results extend to female probands’ previously reported findings that asthma and ADHD are independently transmitted in families. These findings further support the conclusion that ADHD symptoms should not be dismissed as part of asthma symptomatology or a consequence of its treatment.

Family asthma management routines: Connections to medical adherence and quality of life

To develop a reliable measure of asthma management routines and examine its association with health care utilization, medical adherence, and quality of life. Families (n = 153) with a child with asthma, drawn from two sites, participated in the study. Parents completed the Asthma Routines Questionnaire, Adherence to Clinical Trials interview, Functional Severity of Asthma Questionnaire, and Caregiver Quality of Life. Children completed the Pediatric Quality of Life. Electronic monitoring of medication use over a period of 12 months was available for children at one study site. A principal component factor analysis revealed two dimensions to the Asthma Routines Questionnaire: Medication Routines and Routine Burden. Medication Routines were related to medical adherence and to health care utilization. Routine Burden was related to caregiver and child quality of life. The Asthma Routine Questionnaire holds promise as a reliable assessment of family practices related to medication use. The emotional burden of daily care can be distinguished from medication use, which is more closely linked to adherence issues. Targeted questions during regular care may reveal family routine practices amenable to intervention.

Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13q14 and atopic asthma.

Cysteinyl leukotriene receptor 2 (CYSLTR2) is one of the receptors for the cysteinyl leukotrienes (CYSLTs), which cause bronchoconstrictions, vascular hyperpermeability and mucus hypersecretion in asthmatic patients. CYSLTR1 antagonists have been shown to be effective in the treatment of chronic asthma. CYSLTR2 is located approximately 300 kb from D13S153, which is reportedly linked to asthma in several populations. We characterized the genomic structure of humans CYSLTR2, determined the putative major promoter region and conducted association studies pertaining to polymorphisms in CYSLTR2 and asthma. We identified three novel exons in the 5' untranslated region of CYSLTR2 by rapid amplification of cDNA ends and identified eight novel polymorphisms in CYSLTR2 by direct sequencing. A transmission disequilibrium test with 137 Japanese asthmatic families revealed that the -1220A > C polymorphism is associated with the development of asthma (P = 0.0066). In addition, a polymorphism in the putative promoter region caused different promoter activities in vitro. Our results suggest that CYSLTR2 is one of the genes that contributes to susceptibility to asthma in the Japanese population.