Effects of prednisone on the cellular responses and release of cytokines and mediators after segmental allergen challenge of asthmatic subjects.

BACKGROUND: Systemic glucocorticoids are a major therapy for the management of allergic inflammation and asthma; however, information about their effects in vivo are limited. OBJECTIVE: This study was performed to examine the effects of prednisone on inflammatory mediators, cytokines, and cellular responses in the model of segmental allergen challenge (SAC) of allergic asthmatic subjects. METHODS: The effects of a 3-day pretreatment with oral prednisone (30 mg twice daily) on the physiologic and inflammatory responses to SAC were studied in 10 allergic asthmatic subjects in a double-blind, placebo-controlled, crossover protocol. RESULTS: Prednisone improved baseline FEV(1) by 10% and modestly inhibited the SAC-induced fall in FEV(1) at 30 minutes and at 6 to 8 hours. Five minutes after challenge, levels of histamine, PGD(2), 9alpha,11beta-PGF(2), and thromboxane B(2) increased in bronchoalveolar lavage fluid (median increase, 5- to 14-fold); prednisone did not inhibit these responses. Prednisone inhibited (median decrease, 66%-97%) the total influx of inflammatory cells, specifically eosinophils, basophils, and some subsets of T lymphocytes (CD4, CD45RA, and CD45RO cells) assessed 19 hours after SAC, but it did not inhibit the influx of neutrophils. Increases in soluble E-selectin, kinins, and albumin were also inhibited by the glucocorticoid (median decrease, 36%-74%). Prednisone treatment inhibited the appearance of mRNA, protein, or both for T(H)2 cytokines (IL-4 and IL-5), as well as for IL-2 and transforming growth factor alpha, but did not inhibit increases of immunoreactive GM-CSF in bronchoalveolar lavage fluid. CONCLUSION: These studies indicate that prednisone suppresses multiple components of allergic airway inflammation, including cell recruitment, adhesion molecule expression or release, airway permeability, and production of cytokines potentially involved in airway immunity or remodeling.

Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families.

Variance components models were used to analyze total IgE levels in families ascertained though the Collaborative Study of the Genetics of Asthma (CSGA) using a genome-wide array of polymorphic markers. While IgE levels are known to be associated with clinical asthma and recognized to be under strong genetic control (here the heritability was estimated at 44-60% in the three racial groups), specific genes influencing this trait are still largely unknown. Multipoint analysis of 323 markers yielded little indication of specific regions containing a trait locus controlling total serum IgE levels (adjusted for age and gender). Although a number of regions showed LOD statistics above 1.5 in Caucasian families (chromosome 4) and in African-American families (chromosomes 2 and 4), none yielded consistent evidence in all three racial groups. Analysis of total IgE adjusted for gender, age and Allergy Index (a quantitative score of skin test sensitivity to 14 common aeroallergens) was conducted on these data. In this analysis, a much stronger signal for a trait locus controlling adjusted log[total IgE] was seen on the telomeric end of chromosome 18, but only in Caucasian families. This region accounted for most of the genetic variation in log[total IgE], and may represent a quantitative trait locus for IgE levels independent of atopic response. Oligogenic analysis accounting simultaneously for the contribution of this locus on chromosome 18 and other chromosomal regions showing some evidence of linkage in these Caucasian families (on chromosomes 2, 4 and 20) failed to yield significant evidence for interaction.

Testing for gene-gene interaction controlling total IgE in families from Barbados: evidence of sensitivity regarding linkage heterogeneity among families.

Genetic heterogeneity has been proposed as a hallmark feature of allergic disease. To test the hypothesis that total IgE levels are jointly influenced by a locus on chromosome 12q21.1-q21.31 and a locus on 17q11.2-q21.2, we conducted multipoint allele-sharing analyses using nonparametric linkage (NPL) methods on Afro-Caribbean families from Barbados to test for evidence of gene-gene interactions. Significant correlations were observed between NPL scores at D12S1052 and both D17S1293 and D17S1299 for a dichotomized phenotype of total IgE. An analysis of family-specific NPL scores revealed that evidence for interaction was being driven largely by one multiplex pedigree (NPL = 12.01, 12.23, and 12.16 at D12S1052, D17S1293, and D17S1299, respectively). Using the programs SIMWALK (v2.0) and GOLD, a different set of haplotypes in this influential family was observed around D12S1052 and the 17q loci compared to the other Barbados pedigrees. Our findings are a classic example of founder effect, provide evidence for sensitivity of this type of linkage analysis to unusual pedigrees, and highlight an element of genetic heterogeneity that has been given little attention in the study of complex traits.

Association and linkage of atopic dermatitis with chromosome 13q12-14 and 5q31-33 markers.

Atopic dermatitis is a chronic inflammatory skin disease that affects 10-20% of the population. Linkage of atopy, asthma, allergic rhinitis, and total serum IgE levels to several different chromosomal regions have been described extensively, but little is known about the genetic control of atopic dermatitis. We tested for the association and linkage between atopic dermatitis and five chromosomal regions: 5q31-33, 6p21.3, 12q15-24.1, 13q12-31, and 14q11.2/14q32.1-32.3. Marker analysis was performed in two Caucasian populations: (i) 192 unrelated German children with atopic dermatitis and 59 non-atopic children from a German birth cohort study (MAS'90), parental DNA was tested in 77 of 192 children with atopic dermatitis; (ii) 40 Swedish families with at least one family member with atopic dermatitis selected from the International Study of Asthma and Allergy in Children. Evidence for linkage and allelic association for atopic dermatitis was observed for markers on chromosome 13q12-14 and 5q31-33.

An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90).

BACKGROUND: Allergic diseases are one of the major causes of morbidity in the developed countries today, and the prevalence of these diseases is increasing steadily. Study of total serum gE level is important in understanding the genetics of allergic iseases because IgE levels are considered to be a crucial pathogenic component. IL-13 plays an important role in the induction of IgE synthesis and in the pathogenesis of allergic diseases. OBJECTIVE: We sought to examine potential variation at the IL13 gene and estimate its effect on elevated IgE level and atopic dermatitis (AD). METHODS: We conducted mutational analyses of the IL13 gene by using single-stranded conformation polymorphism and DNA sequencing. Case control studies for high-IgE phenotype and AD were performed by using subjects from the German MAS-90 cohort. RESULTS: A novel IL13 coding region variant at 4257 bp (G to A, fourth exon) was identified. Case control studies of a German sample from the MAS-90 cohort showed significant associations between the presence of the A allele and two atopic phenotypes: high IgE (odds ratio, 2.38; 95% confidence interval, 1.35-4.21; P =.0026) and AD (odds ratio, 1.77; 95% confidence interval, 1.06-2.96; P =.03). CONCLUSION: This IL13 coding region variant may be involved in the pathogenesis of AD and high total serum IgE level in a study population of white subjects.

Atopic dermatitis is associated with a functional mutation in the promoter of the C-C chemokine RANTES.

Up-regulation of C-C chemokine expression characterizes allergic inflammation and atopic diseases. A functional mutation in the proximal promoter of the RANTES gene has been identified, which results in a new consensus binding site for the GATA transcription factor family. A higher frequency of this allele was observed in individuals of African descent compared with Caucasian subjects (p < 0.00001). The mutant allele was associated with atopic dermatitis in children of the German Multicenter Allergy Study (MAS-90; p < 0.037), but not with asthma. Transient transfections of the human mast cell line HMC-1 and the T cell line Jurkat with reporter vectors driven by either the mutant or wild-type RANTES promoter showed an up to 8-fold higher constitutive transcriptional activity of the mutant promoter. This is the first report to our knowledge of a functional mutation in a chemokine gene promoter. Our findings suggest that the mutation contributes to the development of atopic dermatitis. Its potential role in other inflammatory and infectious disorders, particularly among individuals of African ancestry, remains to be determined.

Physician-derived asthma diagnoses made on the basis of questionnaire data are in good agreement with interview-based diagnoses and are not affected by objective tests.

BACKGROUND: Defining the phenotype is critical for investigating the genetic etiology of asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), the primary objective of which is to identify asthma susceptibility loci, an algorithm was designed to determine diagnoses of definite asthma, probable asthma, less than probable asthma, or no asthma. A respiratory questionnaire was designed to assist in the process of characterizing the asthma phenotype. OBJECTIVE: This study was designed to determine the validity of the CSGA algorithm for the diagnosis of asthma, to determine agreement in assessing an asthma diagnosis between the information obtained by the CSGA questionnaire versus a patient interview by a panel of specialist physicians, and to determine the degree to which objective tests would alter the questionnaire-based certainty of asthma diagnosis. METHODS: An expert panel of asthma clinicians (n = 4) indicated to what degree they were certain that a subject (n = 48) had asthma as determined by using a 6-point Likert scale based on a 20-minute interview (phase I), a review of the CSGA questionnaire (phase II), a review of the questionnaire plus skin test and peripheral blood eosinophilia data (phase III), and a review of phase III information plus pulmonary data (spirometry and methacholine-reversibility testing; IV). Intraclass correlation coefficients (ICCs) were calculated between the physicians' interpretation of the likelihood of asthma based on the information they received during each of the phases and between the CSGA algorithm and each of the phases. RESULTS: Interjudge reliability with regard to the degree of certainty with which an asthma diagnosis could be made by interview was excellent (ICC, 98; 95% confidence intervals [95% CIs], 0.87-0.99). We also found that the agreement between the physicians' interview with the patients (phase I) and the CSGA algorithm was good and at least as good with the addition of the CSGA questionnaire data and objective data (ICC, 0. 65-0.75). Good agreement was also observed between the average certainty score from the interview and the CSGA questionnaire (ICC, 92; 95% CI, 0.76-0.93), and ICCs determining the agreement on asthma diagnosis between phase I and phases III and IV, in which objective data were introduced, did not change from the ICCs comparing phase I with phase II (ICC of 0.93 [95% CI, 0.79-0.96] and ICC of 0.91 [95% CI 0.73-0.95], respectively). CONCLUSION: We conclude that the CSGA algorithm is a valid tool for which the diagnosis of asthma can be made at an acceptable level of certainty and that the CSGA questionnaire, interpreted by an asthma specialist, is a useful tool for the diagnosis of asthma in clinical or epidemiologic studies.

Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides.

The expression of the Duffy Antigen/Receptor for Chemokines (DARC) on red blood cells (RBC) has been commonly determined using hemagglutination tests. Because the vast majority of African individuals are Duffy-negative, screening for DARC expression on RBC is a valuable tool to assess Caucasian admixture in populations of African descent. Furthermore, blood group antigens have been frequently tested as potential risk factors for complex diseases. We established a dot-blotting protocol using sequence-specific oligonucleotides (SSOs) for the DARC-46T ("Duffy-positive") and -46C ("Duffy-negative") alleles. With this method, but not with serological methods, Duffy-positive individuals can be further characterized as homozygous or heterozygous for the dominant Duffy-positive allele, allowing more precise estimation of allele frequencies and admixture in heterogeneous populations. In unrelated African American (n = 235), Afro-Caribbean (n = 90) and Colombian (n = 93) subjects, the frequency of the -46T allele was 21.7%, 12.2% and 74.7%, respectively. The percentage of Duffy-positive individuals (homozygous or heterozygous for the -46T allele) in each population was in accordance with published frequencies. As expected, the -46C allele was not detected in 20 Caucasian subjects. This sensitive and specific method allows for the rapid and inexpensive screening of large samples for Duffy genotypes using small quantities of genomic DNA.

Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy.

BACKGROUND: Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg, rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease. OBJECTIVE: To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN-gamma (IFNG ) and one of the signal transducers and activators of transcription (STAT6 ), we conducted further linkage studies among 33 multiplex families. METHODS: We characterized 528 subjects from Barbados for asthma; 82% were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning approximately 79 centimorgan) was performed. RESULTS: Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P <.05 to.002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P =.002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = 0.006, and IFNGCA, P =.01, respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric linkage analysis score at D12S326 (nonparametric linkage score = 3.8, P =.0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (P =.036). CONCLUSIONS: Our findings suggest that (1) one or more loci in the chromosome 12q13. 12-q23.3 region are contributing to the expression of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.

Positional candidate gene approach and functional genomics strategy in atopy gene discovery.

As part of our effort in searching for genetic factors contributing to the susceptibility to atopy and asthma, we have focused on a 'positional candidate' approach in identifying CC chemokine gene polymorphisms and their functional correlates. To date, a single-nucleotide polymorphism was found in the RANTES proximal promoter region, and a high degree of sequence variation was identified in the 3'-untranslated region -of the eotaxin gene. Also, we are pursuing a series of functional genomics' studies designed to identify differentially expressed genes in a panel of allergen-specific human Th2 cells and in antigen-induced hyperreactive murine airways. This is performed using a combination of protocols including suppression-subtractive hybridization and cDNA array hybridizations with 18,363 nonredundant sequences. A data base is being generated from a list of subtracted cDNA sequences and array-positive clones to categorize differentially expressed genes. Sequences are being placed in biologically relevant categories on the basis of function (i.e., receptor, signal transduction pathways, transcription, and translation). With the increasing amount of sequence information compiled by the Human Genome Project, it will be particularly challenging to integrate functional gene-mapping efforts to define and compare aberrant genotypes/phenotypes in atopic diseases.

Linkage analysis of Dermatophagoides pteronyssinus-specific IgE responsiveness with polymorphic markers on chromosome 6p21 (HLA-D region) in Caucasian families by the transmission/disequilibrium test. Collaborative Study on the Genetics of Asthma (CSGA).

BACKGROUND: Recently, we have obtained evidence for linkage between Der p 1-specific IgE antibodies and markers on chromosome 6p21 (HLA-D region) in a genome-wide screening in Caucasian families recruited as a part of the Collaborative Study on the Genetics of Asthma (CSGA). OBJECTIVE: Specific IgE antibodies toward different Dermatophagoides pteronyssinus (Der p) polypeptides were detected by immunoblotting analysis, and the transmission/disequilibrium test (TDT) was performed between specific IgE responsiveness toward each different Der p polypeptide and markers on chromosome 6p21 to better clarify the genetic contribution of HLA-D genes. METHODS: We studied 299 individuals in 45 Caucasian families participating in the CSGA. Serum samples from 137 individuals that showed elevated specific IgE antibodies toward the Der p crude allergen (> -0.5 log IU/mL) by ACCESS immunoassay were subjected to immunoblotting analysis. TDT was conducted between the presence of specific IgE antibodies toward each of 12 different Der p polypeptides and 4 polymorphic markers on chromosome 6p21. RESULTS: The 196-bp allele of D6S1281 and the 104-bp allele of DQCAR showed significant excess transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 55 kd, 45 kd, or 37 kd). In contrast, the 200-bp allele of D6S1281 and the 204-bp allele of D6S291 showed significantly decreased transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 90 kd, 52 kd, or 45 kd). Deviation from the expected 50% transmission in heterozygous parents was statistically significant after correcting for multiple comparisons. CONCLUSION: This study supported our previous findings that genes on chromosome 6p21 (HLA-D region) may influence the expression of Der p-specific IgE responsiveness in this Caucasian population. Our results, however, reveal the complexity of genetic regulations of Der p-specific IgE responsiveness by HLA-D genes, suggesting the strong influence of non-HLA loci and perhaps environmental factors for the development of Der p-specific IgE responsiveness.

Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: a genome-wide multipoint linkage analysis in families recruited through 2 asthmatic sibs. Collaborative Study on the Genetics of Asthma (CSGA).

BACKGROUND: Dermatophagoides pteronyssinus (Der p) is one of the most frequently implicated allergens in atopic diseases. Although HLA could play an important role in the development of the IgE response to the Der p allergens, genetic regulation by non-HLA genes influences certain HLA-associated IgE responses to complex allergens. OBJECTIVE: To clarify genetic control for the expression of Der p-specific IgE responsiveness, we conducted a genome-wide search for genes influencing Der p-specific IgE antibody levels by using 45 Caucasian and 53 African American families ascertained as part of the Collaborative Study on the Genetics of Asthma (CSGA). METHODS: Specific IgE antibody levels to the Der p crude allergen and to the purified allergens Der p 1 and Der p 2 were measured. Multipoint, nonparametric linkage analysis of 370 polymorphic markers was performed with the GENEHUNTER program. RESULTS: The best evidence of genes controlling specific IgE response to Der p was obtained in 2 novel regions: chromosomes 2q21-q23 (P = .0033 for Caucasian subjects) and 8p23-p21 (P = .0011 for African American subjects). Three regions previously proposed as candidate regions for atopy, total IgE, or asthma also showed evidence for linkage to Der p-specific IgE responsiveness: 6p21 (P = .0064) and 13q32-q34 (P = 0.0064) in Caucasian subjects and 5q23-q33 (P = 0.0071) in African American subjects. CONCLUSIONS: No single locus generated overwhelming evidence for linkage in terms of established criteria and guidelines for a genome-wide screening, which supports previous assertions of a heterogeneous etiology for Der p-specific IgE responsiveness. Two novel regions, 2q21-q23 and 8p23-p21, that were identified in this study merit additional study.

Genetic influences of chromosomes 5q31-q33 and 11q13 on specific IgE responsiveness to common inhaled allergens among African American families. Collaborative Study on the Genetics of Asthma (CSGA).

BACKGROUND: We have recently conducted a genome-wide screening for genes influencing Dermatophagoides pteronyssinus-specific IgE responsiveness as a part of the Collaborative Study on the Genetics of Asthma (CSGA), which showed evidence for linkage in some regions, including chromosomes 5131-q33 and 11q13 in African American families. OBJECTIVES: To clarify relative contributions of these regions to atopy in the same African American population, we have conducted further genetic linkage studies of specific IgE responses toward common inhaled allergens. METHODS: We studied 328 individuals in 58 African American families participating in the CSGA. Specific IgE responses toward Dermatophagoides farinae, cat, dog, American cockroach, rye grass, and Bermuda grass, as measured by skin tests, were used for multipoint linkage analysis with polymorphic markers on chromosomes 5q31-q33 and 11q13. RESULTS: Specific IgE response toward American cockroach showed evidence for linkage to chromosomes 5q31-q33 (P = .0050) and 11q13 (P = .017). Specific IgE response toward dog showed evidence for linkage with chromosome 5q31-q33 (P = .0043). Evidence for linkage with chromosome 11q13 was obtained for specific IgE responses toward Dermatophagoides farinae (P = .012), cat (P = .035), and Bermuda grass (P = .017). The presence of a positive ST response for at least 1 of 30 common allergens showed evidence for linkage to chromosomes 5q31-q33 (P = .017) and 11q13 (P = .00058). CONCLUSIONS: These data support that genes on both chromosomes 5q31-q33 and 11q13 confer susceptibility to upregulated IgE-mediated immune responses in this African American population. The putative genes on chromosomes 5q31-q33 and 11q13, however, showed contrasting effects on atopy, which may result from strong gene-environmental interactions.

A double-blind study of the discontinuation of ragweed immunotherapy.

BACKGROUND: Immunotherapy effectively treats the symptoms of allergic rhinitis and improves its pathophysiology. We studied whether the effects of immunotherapy on the early response to nasal challenge with antigen and seasonal symptoms persist after discontinuation. METHODS: Twenty subjects with ragweed allergy who were receiving immunotherapy and who had nasal challenges performed before initiation of treatment were selected. The patients had been receiving maintenance therapy with aqueous ragweed extract at a dose of 12 microg of Amb a 1 equivalent for a minimum of 3 years, at which point they were randomized to receive either placebo injections or to continue with the maintenance dose. Nasal challenges were performed before and 1 year after randomization. Nasal challenges were monitored by counting the number of sneezes and measuring histamine, N-alpha-tosyl-L-arginine methyl ester-esterase activity, and kinins in recovered nasal lavages. In the same year symptom diaries were collected during the ragweed season. RESULTS: The initial immunotherapy significantly reduced responses to nasal challenge in both groups. The group continuing to receive active treatment showed no significant changes from the response before randomization. In contrast, the group randomized to placebo treatment showed a partial return of histamine, kinins, and N-alpha-tosyl-L-arginine methyl ester-esterase in nasal secretions and the numbers of sneezes. IgG antibodies to ragweed declined only in the group switched to placebo treatment. Seasonal rises of IgE antibodies to ragweed did not return during the first season after treatment was stopped. Symptoms reported during the ragweed season were not different between the groups. CONCLUSIONS: One year after discontinuation of ragweed immunotherapy, nasal challenges showed partial recrudescence of mediator responses even though reports during the season appeared to indicate continued suppression of symptoms.

Natural history of Hymenoptera venom sensitivity in adults.

BACKGROUND: Epidemiologic studies of Hymenoptera venom allergy in adults show a prevalence of positive venom skin test results, RASTs of 15% to 25%, or both, but most such individuals have had no systemic reactions to stings. The clinical significance and natural history of this apparently common sensitivity is uncertain. OBJECTIVE: We sought to determine the natural history of venom sensitization by observing the rate of decrease or increase in sensitivity in normal adults over 5 to 10 years. The clinical significance of these findings is related to the frequency of systemic reactions to stings during the period of observation. METHODS: Serial observations were planned in 520 volunteers and randomly selected subjects. Two follow-up visits were attempted, once after 2 to 3 years and again after 5 to 9 years, to perform repeat venom skin tests and RASTs and to review any history of interim stings and their outcomes. RESULTS: Follow-up visits were conducted with 398 subjects (375 early visits and 205 late visits). Overall, in the 398 subjects with one or more visits after a mean of 4 years, skin test responses changed from positive to negative in 44 of 98 (45%) and from negative to positive in 27 of 309 (8.7%) of the subjects. Skin test responses changed from positive to negative in 29 of 87 (33%) subjects after 2.5 years and in 43 of 54 (80%) after 6.8 years. Even when the skin test response became negative, venom-specific IgE remained positive in 11 of 29 (38%) subjects after 2.5 years and in 13 of 43 (30%) after 6.8 years. The rate of loss of sensitivity was 12% per year, similar to retrospective estimates. Skin test sensitivity to venoms disappears more rapidly in these subjects without symptoms (half-life, 4 years) than in patients receiving venom immunotherapy (half-life, 7 years). Skin test responses changed from negative to positive in 23 of 288 (8%) subjects after 2.5 years and in 9 of 151 (6%) after 6.8 years. Insect stings caused no reaction in 120 subjects with a negative skin test response, but 17% (11 of 65) of subjects with a positive skin test response (but with a negative history) had systemic reactions when stung. There was no difference between the early and late visits in the frequency of systemic reactions reported. The risk may be higher than 17% for the specific individuals (67% after 2.5 years and 20% after 6.8 years) whose positive skin test responses persist for years. This risk is lower than that of patients with a positive history (50%) but higher than that of "normal" adults or venom-treated patients (<2%). It is still not clear whether any subset of adults with a positive skin test response but a negative history can be identified, in whom the risk of systemic sting reaction would justify venom immunotherapy even before any reaction occurs. CONCLUSION: Asymptomatic venom sensitization in adults is common but transient, disappearing at the rate of 12% per year. However, the risk of a systemic reaction to a subsequent sting is significant in adults without symptoms but with positive venom skin test responses (17%) and may be higher when skin test sensitivity does persist for years.

Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations.

To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to this region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) controlling asthma and the associated "high total IgE" trait.

Inadequate outpatient medical therapy for patients with asthma admitted to two urban hospitals.

PURPOSE: To determine the patterns of chronic outpatient management in urban patients with moderate and severe asthma, and to assess medical practice adherence to the Guidelines for the Diagnosis and Management of Asthma from the National Asthma Education Program (NAEP). PATIENTS AND METHODS: This is a cross-sectional survey of adult patients with asthma admitted to the general medical services at the Johns Hopkins Medical Institutes (Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center) Baltimore, Maryland. Subjects were 101 adults admitted with an asthma exacerbation from February 1992 through January 1993. Using a validated questionnaire, these subjects were surveyed within 48 hours of admission concerning their chronic outpatient medical management and the measures patients or their physicians took to alleviate symptoms during the asthma exacerbation leading to hospitalization. RESULTS: The average asthma admission rate in the past year for this group of patients was 2.5, indicative of moderate to severe disease. Less than half of these patients had been prescribed inhaled anti-inflammatory therapy. Of the patients who had previously been shown the metered dose inhaler technique by a health care professional, 11% could perform all components of this technique correctly. Only 28% of patients had been given an action plan by their physician in the event of an acute exacerbation. Sixty percent of patients who contacted their physician during the exacerbation that preceded admission had no changes made in their treatment regimen. In those whose exacerbation lasted at least 24 hours, the average beta-agonist metered dose inhaler use during the 24 hour prior to admission was 44.8 +/- 7.8 puffs (mean +/- standard error of the mean). Older age, (current smoking, and race (black) were the most significant correlates of inhaled beta-agonist use during this period. CONCLUSIONS: This is the first documentation of multiple problems in conforming with the standards of care delineated by the NAEP as they relate to the outpatient management of inner-city patients with moderate to severe asthma in the United States. In this population of patients with asthma, management was characterized by underutilization of anti-inflammatory therapy, inability to use inhalation devices properly, inadequate communication between patient and physician of an action plan to be utilized in the event of an acute exacerbation and inadequate physician intervention during the acute stages of the exacerbation. There was also overutilization of inhaled beta-agonists during exacerbations. It is imperative that these aspects of management, for which the NAEP has set standards of care, are addressed as part of the effort to reduce asthma morbidity in the urban United States.

Association of responsiveness to the major pollen allergen of Parietaria officinalis with HLA-DRB1* alleles: a multicenter study.

Parietaria, a plant belonging to the family of Urticaceae, is a major source of allergenic pollen in Europe. In the context of a multinational study, we investigated whether in allergic subjects antibody response towards Par o 1, the major allergen from P. officinalis, was associated with defined HLA-DRB1* alleles. The study population consisted of 234 allergic patients: 65 from Bulgaria, 30 from Israel, 99 from Italy, and 40 from Spain. In the Italian study group, the prevalence of ST positivity to Parietaria was 77%. In Parietaria ST-positive subjects, the prevalences of IgG and IgE serum Ab towards Par o 1 were 91% and 75%, respectively. HLA-DRB1*1101 and/or 1104 were significantly positively associated with the presence of IgG Ab and with high levels of IgE Ab towards this allergen (p = 0.0007 and p = 0.012, respectively). In the Spanish study group, the positive association of DR1100 with responsiveness to Par o 1 was confirmed (p = 0.02, RR = 4, and p = 0.002, RR = 7, for IgG and IgE Ab, respectively). None of the Bulgarian patients had IgE Ab to Par o 1, whereas IgG Ab response was observed in 7 out of 65 subjects and was positively associated with DRB1*1101 and/or 1104 (p = 0.025). In the Israeli study group, responsiveness to Par o 1 was not associated with specific HLA-DRB1* alleles. In conclusion, this study shows that in allergic patients from three European populations antibody response to the major allergen from the pollen of Parietaria is associated with HLA-DRB1*1101 and/or 1104. Our data suggest that this association is stronger in subjects monosensitized to Parietaria.

Genetic basis of IgE responsiveness: relevance to the atopic diseases.

Genetic analysis of 170 subjects in 11 extended Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum IgE levels. No linkage was found between these markers and specific IgE antibody levels. Analysis of total IgE within a subset of 128 IgE-antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially IL4 (p = 4 x 10(-6)). These and other data suggest that IL4 or a nearby gene regulates IgE production in a non-antigen-specific (noncognate) fashion and provide evidence for a possible link between asthma and the IL4 gene.