Linkage to atopy on chromosome 19 in north-eastern Italian families with allergic asthma.

BACKGROUND: Allergic asthma is a multifactorial disease for which there is a widely assessed, although poorly understood, genetic involvement. Genome-wide screens reported evidence for linkage of allergic asthma-related phenotypes to several chromosomal locations. Markers on chromosome 19 have been linked to allergic asthma phenotypes in different populations in independent studies. OBJECTIVE: The aim of this study was to perform a genetic linkage analysis on chromosome 19 to search for DNA markers linked to phenotypes related to allergic asthma. METHODS: Using non-parametric multipoint linkage analysis on a total of 22 random DNA markers in 2 stages, a sample of 111 families (542 subjects) from north-eastern Italy, recruited through an asthmatic allergic proband, was investigated. Phenotypes examined were: clinical asthma, total serum elevated IgE, skin prick test positivity, bronchial hyper-responsiveness, and atopy defined as skin prick test positivity and/or elevated IgE. Simulation studies were performed to confirm the significance of the results. RESULTS: A novel linkage of atopy and skin prick test positivity to marker D19S601 (19q13.3) was found. Modest evidence for linkage of atopy, skin prick test positivity, and IgE was also found to marker D19S591 (19p13.3). Simulation analysis for atopy gave an NPL-Z > 3.326 in 2 replicates out of 1000 (P = 0.002) for D19S601, and an NPL-Z > 2.56 in 16 replicates out of 1000 (P = 0.016) for D19S591. CONCLUSIONS: On chromosome 19, suggestive linkage of atopy and skin prick test positivity with marker D19S601 (19q13.3) and modest evidence of linkage of marker D19S591 (19p13.3) to the atopic phenotypes investigated were found. These results suggest that these regions may contain susceptibility loci associated to atopic phenotypes.

Chromosome 14 linkage analysis and mutation study of 2 serpin genes in allergic asthmatic families.

BACKGROUND: Genome and chromosome screens reported DNA markers on chromosome 14 linked to allergic asthma or intermediate phenotypes in several populations. OBJECTIVE: We sought to perform a linkage study on chromosome 14 and a further association study on candidate genes mapped in the region found to be linked to allergic asthma or intermediate phenotypes. METHODS: The study consisted of a sample of 189 families (847 genotyped individuals) from a restricted geographic area in northeastern Italy. The subjects were characterized for the following phenotypes: allergic asthma, total serum IgE levels, skin prick test responses, and bronchial hyperresponsiveness (BHR) to methacholine. Genotyping was done with 14 DNA markers and 4 polymorphisms in the genes encoding alpha(1)-anti-trypsin and alpha(1)-antichymotrypsin (ACT). RESULTS: Multipoint analysis indicated a potential linkage of BHR with marker D14S617 (nonparametric linkage z score = 2.32, P =.01). Transmission disequilibrium of Thr -15Ala in the gene encoding ACT was observed with all the phenotypes investigated: allergic asthma, BHR, total IgE levels, or skin prick test responses (P =.041,.02,.0053, or.026, respectively). CONCLUSION: Chromosome 14 screening and transmission disequilibrium testing on the gene encoding ACT suggest that it or a closely located gene may be involved in susceptibility to allergic asthma in the Italian population.

Linkage analysis of chromosome 12 markers in Italian families with atopic asthmatic children.

We investigated 116 Italian atopic families (560 individuals) for linkage with 13 DNA markers on chromosome 12. All the subjects were phenotyped for asthma, total serum IgE, bronchial hyperresponsiveness, skin-prick positivity to common aeroallergens, and atopy. A relative location map of the markers was prepared from Centre d'Etude du Polymorphisme Humain families. Affected sib pair multipoint linkage methods were used to perform the statistical analyses. We report suggestive linkage for asthma with markers on chromosome 12. The region of interest centers around marker D12S390 (maximum logarithm of odds [mlod] = 2.81; p = 0.003). These results provide additional support that asthma susceptibility factors are located on chromosome 12q.

Association of a lymphotoxin alpha gene polymorphism and atopy in Italian families.

Tumour necrosis factor (TNF) is a proinflammatory cytokine that increases human airway tissue responsiveness and is considered a candidate gene for asthma. Two common polymorphisms (LTalphaNcoI and TNFalpha-308) in the TNF gene complex were studied in 600 subjects from 131 Italian families with atopic asthmatic children. Skin prick test (SPT), total IgE levels, atopy (defined as increased IgE levels or SPT positivity or both), bronchial hyperresponsiveness, and clinical asthma were investigated. The observed distribution of the identical by descent alleles at the LTalphaNcoI locus was different from expected for SPT and atopy (p=0.015). The LTalphaNcoI genotype distribution for increased IgE levels was different between males and females (p=0.0011), and an association of the 2.2 genotype with increased IgE levels was observed in females (p=0.0032). The results indicate that the LTalpha gene, or a closely linked locus, is associated with atopy, and suggest a sex difference in the effect of the gene.

Asthma and bronchial hyperresponsiveness linked to the XY long arm pseudoautosomal region.

We examined the long arm XY pseudoautosomal region for linkage to asthma, serum IgE, and bronchial hyperresponsiveness. In 57 Caucasian families multipoint nonparametric analyses provide evidence for linkage between DXYS154 and bronchial hyperresponsiveness (P = 0.000057) or asthma (P = 0.00065). This genomic region is approximately 320 kb in size and contains the interleukin-9 receptor gene. These results suggest that a gene controlling asthma and bronchial hyperresponsiveness maybe located in this region and that the interleukin-9 receptor is a potential candidate.

Longitudinal evaluation of bone mass in asthmatic children treated with inhaled beclomethasone dipropionate or cromolyn sodium.

Inhaled corticosteroids are recommended as first-line therapy in patients with moderate to severe asthma. The use of these agents in the milder form of asthma is controversial because of their potential adverse effects, especially in growing children. We investigated 49 asthmatic children (38 treated with beclomethasone dipropionate (BDP) at a daily dose of 276+/-125 microg/day and 11 treated with cromolyn sodium (CS) at a daily dose of 30+/-10 mg/day) for 7.4 months, with bone-mass measurements at baseline and after the treatment period. Evaluation of changes in cortical and trabecular bone mass (bone mineral density [BMD]; m/cm2) was performed by absorptiometry at the proximal forearm and at the lumbar spine, respectively. Furthermore, to correct for bone size changes due to growth, we calculated volumetric BMD (VOL-BMD; mg/cm3). At the end of the treatment period, the children who had received regular inhaled BDP had grown as well as children treated with CS, from 120+/-1.4 to 123+/-1.3 cm and from 118+/-3.2 to 120.3+/-2.8 cm, respectively. No children showed deviation from their percentile level of growth. Trabecular and cortical BMD increased after 7 months of follow-up in both groups to the same extent. When BMD was adjusted for body size (VOL-BMD; mg/cm3), bone mass was found not to have changed after BDP or CS treatment course within and between the two groups.

Association of the FcepsilonRIbeta gene with bronchial hyper-responsiveness in an Italian population.

A study of two DNA polymorphisms (i2 RsaI, E237G) in the gene for the beta subunit of the IgE high affinity receptor (FcepsilonRIbeta) was performed in 168 Italian families with atopic asthmatic children. The prevalence of the E237G allele in the Italian population was 4%, so this polymorphism was unsuitable for this study. The i2 RsaI polymorphism minor allele frequency was 44%, and it had a PIC value of 0.37. Linkage analysis indicated a significant allele sharing in affected sib pairs for bronchial hyper-responsiveness (BHR, p=0.048), but not for allergic asthma. These data indicate an association of bronchial hyper-responsiveness with the FcepsilonRIbeta gene.

Monitoring of bronchial asthma.

Assessment of asthma severity is important for disease management. Analysis of symptoms past and present, and previous and actual lung function measurements (including variability) is the usual method of evaluation and classification of asthma disease severity and activity. However, symptoms and lung function alterations are the result of pathophysiological processes including inflammation in the bronchial wall which, in chronic phases, precedes the clinical measurements, and are risk factors for disease progression and worsening. Tools for more precise determination of asthma disease processes in the airway wall would be of importance for prophylactic intervention to avoid chronic damage to the airways and acute worsenings to occur.

Optimum treatment of allergic rhinitis in children.

Allergic rhinitis is a very common disease, occurring in 10% of children and up to 20% of adolescents. The effects of the disease are frequently underestimated and not regarded as a serious health problem. However, if not properly treated, the disease is associated with harmful sequelae and poor quality of life. The treatment of allergic rhinitis in children depends on 3 therapeutic approaches: avoidance of provoking factors, pharmacological therapy and immunotherapy. Environmental control measures should be directed against allergens as well as against nonspecific irritating factors such as tobacco smoke. Conventional therapy depends on the appropriate selection and combination of antihistamines, mast cell stabilisers, decongestants and topical corticosteroids. Immunotherapy must not be used indiscriminately and should be prescribed only when clearly indicated. Compliance with the treatment regimen is an essential element of therapeutic success.

Nebulized flunisolide in infants and young children with asthma: a pilot study.

The role of nebulized flunisolide solution in controlling recurrent respiratory symptoms was assessed in a double-blind placebo-controlled parallel study on 23 infants and small children (mean age, 14.2 months) with bronchial asthma. Five of the 12 children in the placebo group and 1 of the 11 patients on active treatment had to be withdrawn from the study. Flunisolide significantly improved symptom scores of wheezing and cough. The rescue treatments with salbutamol did not differ between the two groups during the study. Parents considered the active treatment effective in all the patients, while the placebo was considered useful in 4 of 7 children. No side effects were detected with either treatments. This study indicates that nebulized flunisolide may be an effective treatment for infants with recurrent wheezing and cough.

Affected sib-pair and mutation analyses of the high affinity IgE receptor beta chain locus in Italian families with atopic asthmatic children.

Previous studies reported linkage between maternally inherited atopy and the beta subunit of the high affinity IgE receptor (Fc epsilon RI-beta) located on chromosome 11q13. We have investigated 45 Italian families with atopic asthmatic children, for a total of 213 subjects, including 148 patients. Genotyping was carried out with two microsatellite DNA markers: one (Fc epsilon RI-beta CA) located inside the gene, and one (CI11-319 CA) closely linked to it. Affected sib-pair analysis in families with several affected children indicated 128 pairs in which either both markers were informative. An excess of maternal allele sharing was observed, although not significant. The allele-specific DNA amplification test for the FcRI-beta Ile181Leu mutation, described previously in 17% of atopic English families by Shirakawa and coworkers, was negative in all our families, as well as in 42 Italian children with atopic asthma and without family histories of the disease.

Effect on cortical and trabecular bone mass of different anti-inflammatory treatments in preadolescent children with chronic asthma.

Bone metabolism and density have been shown to be abnormal in adult asthmatic patients treated with inhaled corticosteroids. Because the largest increases in bone growth and mineral deposition occur during childhood and adolescence, we performed a cross-sectional evaluation of cortical and trabecular bone mass by dual-photon absorptiometry at the proximal one third of the radius (cortical bone) and by dual-energy X-ray absorptiometry at the L2-L4 lumbar spine (trabecular bone) in 64 prepubertal asthmatic children receiving beclomethasone dipropionate (BDP) or cromolyn sodium (CS). Dual-energy X-ray absorptiometry was performed by anteroposterior scan and also by lateral vertebral scan in order to exclude the posterior elements of the vertebrae, which are composed mainly of cortical bone and which are less sensitive to the negative effect of steroids. Furthermore, we calculated "volumetric" bone density, dividing lateral mineral content by the vertebral volume. Bone mineral areal density and volume bone density did not differ in children receiving BDP for 6.7 +/- 1.3 mo at a mean dose of 319.3 +/- 130 micrograms/d compared with those in children treated with CS. Furthermore, anteroposterior bone density in our study population was in agreement with published normative data and with that of normal age-related healthy nonasthmatic children living in the same area and with the same dietary intake of calcium. No normal values are available for lateral and calculated-volume bone density. In conclusion, treatment with BDP does not appear to have an adverse effect on bone mass in prepubertal children with mild moderate asthma. Longitudinal studies should be performed in order to evaluate the effect of early introduction of inhaled corticosteroids in children with mild asthma.

[Beta-2 agonists, exposure to allergens and bronchial hyperreactivity in children with allergic asthma]. / beta 2-agonisti, esposizione ad allergeni e iperreattività bronchiale nel bambino con asma allergico.

The contribution of beta 2-agonist treatment per se and the effect of beta 2-agonists plus allergen exposure was evaluated in two groups of thirteen asthmatic children being treated respectively at sea level during the period of maximal allergen exposure and at high altitude in an environment free of the offending allergens. Bronchial hyperreactivity was evaluated by standardised exercise tests before and after treatment with salbutamol controlled release tablets (4 mg). Challenges were performed at the beginning and after 2 and 4 weeks of treatment. A fourth test was performed 2 days after stopping the treatment. Children treated with salbutamol at sea level (exposure to allergen) showed baseline delta PEF of 16.9 +/- 3.4 and 13.7 +/- 4.2, 20.7 +/- 4.3, 26.0 +/- 5.1 respectively for the second, third and fourth test. Children treated at high altitude showed respectively delta PEF of 34.9 +/- 5.1, 31.1 +/- 4.9, 26.5 +/- 5.4, 27.9 +/- 5.0. These data suggest that oral salbutamol per se is not responsible for an increase in bronchial responsiveness, but eventually suggest that treatment with beta 2-agonists at the same time as continued allergen exposure may be responsible for an increase in bronchial hyperresponsiveness.

Double-blind trial of house-dust mite immunotherapy in asthmatic children resident at high altitude.

Twenty-three Dermatophagoides pteronyssinus (Dpt)-sensitive asthmatic children aged 7-14 years entered a double-blind, placebo-controlled trial of standardized immunotherapy (IT) (Alpare) while resident at high altitude. Dpt sensitivity was evaluated by skin prick tests at different allergen concentrations at the enrollment and after 6 and 12 months of treatment. Bronchial hyperreactivity was evaluated at the same time points, and on each occasion, histamine challenge and, the following day, Dpt bronchial challenge were performed. All patients, irrespective of active treatment, improved clinically and in lung function with increased PC20 and Dpt-PD20. Alpare-treated patients had a significantly decreased sensitivity on Dpt skin testing (P < 0.009) and felt that their asthma had improved (P < 0.001) compared with placebo-treated subjects, but there was no difference between the treatment groups in lung function or bronchial challenge response. IT neither increased nor decreased bronchial histamine sensitivity. Our results indicate that Dpt IT benefits asthmatic children, but improvement by allergen avoidance at high altitude is even greater.