Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.

Our objective was to study the effect of tobramycin solution for inhalation (TSI; TOBI(R), Chiron Corp.) on lung function decline rate in 400 young persons with cystic fibrosis (CF) and mild lung disease. Effects on hospitalization, antibiotic use, school days missed, and nutritional status also were determined. This was an open-label, randomized (stratified by sex and age group, i.e., 6-10 and 11-15 years), parallel-group, multicenter study. Routine subject management (control group) was compared to routine management plus 28 days of twice-daily TSI inhalation, followed by 28 days off the drug (TSI group) for 56 weeks. Primary efficacy endpoints included rate of lung function decline (as measured by forced expiratory volume in 1 sec; FEV1), hospitalization, and concomitant antibiotic use. Safety was assessed by analysis of treatment-emergent adverse events. Only 184 of 400 planned subjects were recruited and randomized (93 to the TSI group, and 91 to the control group). Enrollment was ended after 2 years because of difficult recruitment. An interim safety review showed a 2.42-fold risk of respiratory hospitalization for control group subjects (P=0.020), and the study was terminated. Sixty-three subjects (34.2%) completed the entire study (30 in the TSI group, or 32.3%; and 33 in the control group, or 36.3%). Significantly fewer TSI subjects were hospitalized for worsening of respiratory symptoms (11.0% vs. 25.6%; P=0.011), and fewer TSI subjects were hospitalized overall (16.5% vs. 27.8%; P=0.065). Fewer TSI subjects received antibiotics other than the study drug (78.0% vs. 95.6%), and significantly fewer received oral antibiotics (76.9% vs. 91.1%; P=0.009). No other safety or adverse event differences were observed. In conclusion, significant reductions in respiratory hospitalizations, concomitant antibiotic use, and a trend towards improvement in percent predicted forced expiratory flow (FEF25-75) provide evidence of a clinical benefit of TSI use in young persons with CF and mild lung disease. An effect on lung function decline rate could not be evaluated as planned, due to inadequate enrollment and early study termination. (C) 2004 Wiley-Liss, Inc.

The genomewide screen to search for asthma-susceptibility loci, in the Collaborative Study on the Genetics of Asthma (CSGA), has been conducted in two stages and includes 266 families (199 nuclear and 67 extended pedigrees) from three U.S. populations: African American, European American, and Hispanic. Evidence for linkage with the asthma phenotype was observed for multiple chromosomal regions, through use of several analytical approaches that facilitated the identification of multiple disease loci. Ethnicity-specific analyses, which allowed for different frequencies of asthma-susceptibility genes in each ethnic population, provided the strongest evidence for linkage at 6p21 in the European American population, at 11q21 in the African American population, and at 1p32 in the Hispanic population. Both the conditional analysis and the affected-sib-pair two-locus analysis provided further evidence for linkage, at 5q31, 8p23, 12q22, and 15q13. Several of these regions have been observed in other genomewide screens and linkage or association studies, for asthma and related phenotypes. These results were used to develop a conceptual model to delineate asthma-susceptibility loci and their genetic interactions, which provides a promising basis for initiation of fine-mapping studies and, ultimately, for gene identification.

Background: In the Collaborative Study on the Genetics of Asthma, 314 families with 2584 subjects were characterized for asthma and allergy. Objective: The purpose of this investigation was to examine clinical heterogeneity observed in asthma and allergic characteristics among 3 ethnic groups (African American, white, and Hispanic family members). Methods: Pulmonary function parameters and asthmaassociated phenotypes were compared among the ethnic groups. Results: In comparison with the other groups, African American sibling pairs had a significantly lower baseline FEV1 percent of predicted (P = .0001) and a higher rate of skin test reactivity to cockroach allergen (P = .0001); Hispanic sibling pairs had significantly more skin reactivity overall (P = .001); and white sibling pairs had significantly lower total serum IgE (P < .05). In addition, there were significantly more relatives with asthma among the African American families than among the white and the Hispanic families (P = .001). Conclusion: Although different environmental backgrounds should be considered, these clinical differences could be due to differences in genetic susceptibility among the ethnic groups, such as those suggested by our previous genome screen. (J Allergy Clin Immunol 2001;108:357-62.)

After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values .039-.0044 for atopy and .029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.

BACKGROUND:Sensitization to cockroach allergens is an important epidemiologic risk factor for asthma, particularly among African Americans living in urban environments. A recent genome screen in the Hutterites, a white founder population, identified a linkage between an HLA-linked marker and sensitization to cockroach allergens. OBJECTIVE:Our purpose was to determine whether alleles at one or more HLA loci are associated with sensitization to cockroach allergens in ethnically diverse populations. METHODS:Alleles at 14 HLA region loci were studied in the Hutterites. On the basis of these results, selected loci were examined in 54 African Americans with cockroach sensitization (cases) and 65 African Americans without cockroach sensitization (controls). Sensitivity to cockroach allergens was assessed in both samples by skin prick test to purified cockroach allergens (Periplaneta americana and Blatella germanica). RESULTS:Significant associations between cockroach allergies and DRB1*0101 (P(corrected) =.0066), DQA1*0101 (P(corrected) =.0012), and DQB1*0501 (P(corrected) =.00096) were detected in the Hutterites. In the African American sample, the most significant association was with the DRB1*0102 allele (P(corrected) =.0088, odds ratio 16.4, 95% confidence interval 2.0, 131). The DRB1*0101 allele was infrequent in the African American sample (frequency 0.06) and the DRB1*0102 allele was absent in the Hutterites. DRB1*0101 and DRB1*0102 are closely related alleles that differ from nearly all other DRB1 alleles at 3 amino acids in the 1 peptide binding domain of the HLA-DR molecule. CONCLUSIONS:The DRB1*0101 allele in the Hutterites and the DRB1*0102 allele in African Americans confer risk for cockroach sensitization. Elucidating this interaction at the molecular level may allow for more targeted treatment and prevention of atopic asthma in inner-city populations.

Asthma is an inflammatory airways disease associated with intermittent respiratory symptoms, bronchial hyperresponsiveness (BHR) and reversible airflow obstruction and is phenotypically heterogeneous(1,2). Patterns of clustering and segregation analyses in asthma families have suggested a genetic component to asthma(3-6). Previous studies reported linkage of BHR and atopy to chromosomes 5q (refs 7-9), 6p (refs 10-12), 11q (refs 13-15), 14q (ref. 16), and 12q (ref. 17) using candidate gene approaches. However, the relative roles of these genes in the pathogenesis of asthma or atopy are difficult to assess outside of the context of a genome-wide search. One genome-wide search in atopic sib pairs has been reported(18), however, only 12% of their subjects had asthma. We conducted a genome-wide search in 140 families with greater than or equal to 2 asthmatic sibs, from three racial groups and report evidence for linkage to six novel regions: 5p15 (P = 0.0008) and 17p11.1-q11.2 (P = 0.0015) in African Americans; 11p15 (P = 0.0089) and 19q13 (P = 0.0013) in Caucasians; 2q33 (P = 0.0005) and 21q21 (P = 0.0040) in Hispanics. Evidence for linkage was also detected in five regions previously reported to be linked to asthma-associated phenotypes: 5q23-31 (P = 0.0187), 6p21.3-23 (P = 0.0129), 12q14-24.2 (P = 0.0042), 13q21.3-qter (P = 0.0014), and 14q11.2-13 (P = 0.0062) in Caucasians and 12q14-24.2 (P = 0.0260) in Hispanics.

The goal of this study was to evaluate the safety and efficacy of recombinant human DNase (rhDNase) in hospitalized patients with cystic fibrosis (CF) experiencing acute pulmonary exacerbations. Eighty patients with documented CF were enrolled at 11 CF centers when admitted for antibiotic therapy. Patients were at least 5 yr old with a forced vital capacity (FVC) > or = 35% of predicted and an oxygen saturation > or = 90% on a fraction of inspired oxygen (FIO2) < 0.5. Patients were randomized to receive rhDNase 2.5 mg in 2.5 ml excipient twice a day (n = 43) or 2.5 ml excipient alone twice daily (n = 37) along with conventional treatment for exacerbations. Administration of rhDNase was not associated with acute adverse events or deaths, and no patients experienced allergic or anaphylactic reactions. Although forced expiratory volume in one second (FEV1) and FVC improved in both treatment groups during the double-blind period, there were no statistically significant differences in the mean change from baseline in FEV1 or FVC between the two groups. rhDNase therapy is safe and well tolerated in CF patients with acute exacerbations requiring hospitalization, but the study did not demonstrate a statistically significant therapeutic effect of rhDNase when added to a regimen of antibiotics and chest physical therapy.

"Prioritizing asthma research: the need to investigate childhood asthma.." American journal of respiratory and critical care medicine, 151(5), pp. 1294–1295

OBJECTIVE:As part of a study to determine population-based frequencies of CFTR mutations in an ethnically diverse, midwestern cystic fibrosis (CF) population, clinical histories were studied in 119 CF patients.METHODOLOGY:We sought to examine the association between genotype as characterized by the delta F508 and 11 other commonly occurring mutations and clinical parameters including age at diagnosis, clinical presentation, sweat chloride level, chest roentgenogram score, clinical scores, pulmonary function test results, percent weight for height, and presence of associated CF complications.RESULTS:Age at diagnosis of CF was significantly associated with homozygosity for delta F508 (mean age at diagnosis +/- SE: 1.7 +/- 0.3 years for delta F508/delta F508 vs 3.9 +/- 0.9 years for delta F508/other and other/other; P = .03). No other age-adjusted clinical parameter was significantly associated with delta F508 or any other genotype.CONCLUSION:These data suggest that in this sample of CF patients, delta F508 genotype is not predictive of disease severity. The lack of association between disease severity and genotype in this ethnically diverse sample may reflect the presence of more severe undetected mutations in our sample, or the effects of modifying genes at other, non-CF loci.

The identification of a common mutation, delta F508, in the CFTR gene allowed, for the first time, the detection of cystic fibrosis (CF) carriers in the general population. Further genetic studies revealed > 100 additional disease-causing mutations in this gene, few of which occur on > 1% of CF chromosomes in any ethnic group. Prior to establishing counseling guidelines and carrier risk assessments, we sought to establish the frequencies of the CFTR mutations that are present in CF families living in the Chicago area, a region notable for its ethnic heterogeneity. Our sample included 283 unrelated CF carriers, with the following ethnic composition: 78% non-Ashkenazi Caucasians, 5% Ashkenazi, 9% African-American, 3% Mexican, 0.3% Native American, and 5% mixed ancestry. When a panel of 10 mutations (delta F508, delta I507, G542X, G551D, R553X, S549N, R1162X, W1282X, N1303K, and 1717-1G-->A) was used, detection rates ranged from 75% in non-Ashkenazi Caucasians to 40% in African-Americans. These data suggest that the goal of screening for 90%-95% of CF mutations may be unrealistic in this and other, similar U.S. populations.

The cardiac status of 64 children (ages 0.2 to 18 yr) with sickle cell anemia documented by hemoglobin electrophoresis was evaluated by echocardiography. Left atrial, left ventricular and aortic root dimensions were significantly increased in over 60 percent of these children at all ages compared to values for 99 normal black (non-SCA) control subjects. Left ventricular wall thickness was increased in only 20 percent of older children with sickle cell anemia. Estimated LV mass/m2 and left ventricular cardiac index were increased compared to control subjects (p less than 0.001). Left heart abnormalities expressed as a single composite function, derived from multivariate regression analysis, correlated well with severity of anemia expressed as grams of hemoglobin (r = -0.52, p = less than 0.001) and with percentage of hemoglobin S (r = 0.51, p less than 0.001), but not to the same extent with age. Echocardiographically assessed left ventricular function at rest was comparable to that of control subjects. These data suggest that the major cardiac abnormalities in children are related to the volume overload effects of chronic anemia, and that in this age group, there is no evidence for a distinct "sickle cell cardiomyopathy" or cardiac dysfunction.

This article describes the immunologic and pulmonary abnormalities and the chemical composition of pleural effusion fluid in a patient with intestinal lymphangiectasia as they are effected by therapeutic measures during a 7-year period. Lymphedema was first noticed in the patient at 3 years of age, and pleural effusions developed 7 years later. Thoracentesis demonstrated that the right pleural fluid was yellow, clear, and had the composition of lymph. The left pleural fluid was milky and had a higher triglyceride and lymphocyte content than the right pleural fluid. Complete removal of pleural fluid transiently increased total lung capacity to a maximum of 52% predicted. Strict dietary management with a low-fat and high-protein diet resulted in a transient partial reversal of circulating lymphopenia and low T cell concentration. This was accompanied by a decrease in lymphocyte and T cell concentration in the pleural fluid. Unstimulated mononuclear cells from pleural fluid synthesized increased amounts of DNA, and added mitogens or antigens further increased DNA synthesis. Dietary therapy had a minimal effect on this DNA synthesis. Despite circulating hypogammaglobulinemia, normal antibody activity was detected. The proportion of B cells in pleural fluid was greater than that in the circulation, and dietary therapy did not alter this difference. Pulmonary physiology improved during the initial 9-month period of diet therapy, but then the rate of fluid accumulation increased, causing respiratory compromise. Stability was achieved by a right-sided pleurodesis, followed 18 months later by a left pleurodesis with the addition of a shunt to provide internal lymph drainage.

The efficacy and safety of short-term supplemental peripheral hyperalimentation (PH) was evaluated in 15 hospitalized cystic fibrosis (CF) patients who exhibited varying degrees of pulmonary disease severity and nutritional impairment. An average of 1000 supplemental calories/day were administered intravenously for a 2- to 3-week period to patients being treated with parenteral antibiotics for exacerbation of their pulmonary disease. Eleven of 15 patients responded with a weight gain of greater than 2.0 kg and showed continued weight gain and stabilized pulmonary status for the 6- to 12-month follow-up period; two patients showed dramatic reversal of poor weight gain and growth following PH. Total calorie intake (oral + PH) equaled 141 +/- 40% of the recommended dietary allowances (RDA) in responders, with 45 +/- 12% RDA contributed by PH, in contrast to 68 +/- 20% of the RDA for total calories with 31 +/- 13% supplied using PH achieved in the nonresponders. Linoleic acid deficiency was documented in these patients (linoleic acid level as a percent of total fatty acid = 21.9% +/- 1.41 SEM vs 31.8% +/- 1.16 SEM in normal controls), and all seven patients achieved normalization of linoleic acid level after PH. Prior assessment of nutritional status (anthropometric measurements) or of severity of pulmonary disease (NIH clinical score) did not allow prediction of response to PH. No complications resulted from administration of PH to these hospitalized CF patients.

Gastroesophageal reflux (GER) was initially diagnosed in two black infants, aged 5 and 9 months, as a cause of their chronic lung disease and failure to thrive. Both infants were treated with bethanechol chloride as part of the management of their GER, but respiratory failure developed in both patients and they required ventilatory support. Both infants had severe air trapping, CO2 retention, difficulty in being weaned from mechanical ventilation, and Staphylococcus aureus cultured from their respiratory tract secretions. These factors led to the suspicion of cystic fibrosis (CF), and this diagnosis was subsequently confirmed by sweat test. The condition of both infants improved substantially on withdrawal of bethanechol therapy and the institution of a regimen of CF care. The early diagnosis of GER in these infants may have led to a delay in diagnosis and treatment of CF.

Large abscess cavities are not commonly encountered in patients with cystic fibrosis (CF). One such patient is reported in whom an abscess developed secondary to aspiration of sand and salt water. Material obtained at bronchoscopy revealed anaerobes as well as the aerobic organisms previously cultured from her sputum. Rapid improvement occurred after institution of antibiotic therapy specifically directed against the anaerobic organisms.

Echocardiograms (E) were obtained from 44 children with SS and from 54 normal Blacks (Nl). Equations for predicting the normal values (PN) for 12 echo parameters were derived (PN = A . BSAb . HRc ± K), and the observed values from SS then expressed as standard deviation from normal (O PN). Increased cardiac output, LVEDD, LVESD, wall thickness, LAmax and Ao diameter were observed in SS (p < 0.001); however, the functional parameters %MAS, VCF and PEP/ET did not differ from Nl. Density function curves (DFC), derived by discriminant regression analysis using 7 echo parameters were obtained with equation: Ydv = K1 OPN1 + K2 OPN2 + Kn OPNn ± X, where Ydv = discriminating value and K, X = constants. There was clear separation of the DFC of SS and Nl. Eleven children with SS underwent hypertransfusion therapy (HT) for 3/12-3 yrs (packed RBC q 2-3 weeks) to achieve Hgb ≥ 10 gm %, % S Hgb < 20%. E were obtained periodically before/after, and during HT. Mean values during HT/off HT were: Hgb 9.7/7.2 (p < .001), % S Hgb 12.1/88.2 (p < .001). The DFC and Ydv before and after HT did not differ from those of 44 untreated SS (P = NS); during HT, there was significant shift (p < 0.001) of DFC and Ydv towards Nl. We conclude that cardiac size and function are abnormal in SS children, improve during HT, but revert back to abnormal state after discontinuing the HT.

The effectiveness and safety of the use of cimetidine as an adjunct to pancreatic enzymes was evaluated in eight patients with cystic fibrosis having pancreatic insufficiency. Cimetidine (300 mg, three times a day) was given for a 6-week period during which the patients demonstrated a significant weight gain (P < 0.05) and reduction of steatorrhea (P < 0.01). Data suggesting an early correction of the abnormal fatty acid composition of plasma lipids were observed. No side effects were apparent during the clinical trial. These results demonstrate the beneficial effects of the use of cimetidine in patients with cystic fibrosis and indicate the need for long-term clinical trials.