Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma.

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 asthma associated phenotypes were compared among the ethnic groups. RESULTS: In comparison with the other groups, African American sibling pairs had a significantly lower baseline FEV(1) 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.

Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma.

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.

HLA-DRB1*01 alleles are associated with sensitization to cockroach allergens.

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.

Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations.

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.

Aerosolized recombinant human DNase in hospitalized cystic fibrosis patients with acute pulmonary exacerbations.

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.

Delta F508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population.

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.

Ethnic heterogeneity and cystic fibrosis transmembrane regulator (CFTR) mutation frequencies in Chicago-area CF families.

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.

Cardiac abnormalities in children with sickle cell anemia.

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.

Cardiovascular effects of hypertransfusion therapy in children with sickle cell anemia.

Thirteen children, age 1.9 to 14.8 years with documented sickle cell disease, underwent echocardiographic assessment of cardiac status while on and off periodic hypertransfusion therapy (HTX). Two to three units of washed packed red blood cells were transfused every 2-4 weeks in children with splenic sequestration crises, cerebrovascular accidents (CVA), aseptic necrosis of the femoral head, and miscellaneous complications of sickle cell disease to maintain hemoglobin (Hgb) concentrations of greater than or equal to 10 g/dl and % sickle hemoglobin (S Hgb) of less than or equal to 20%. This therapy administered over an average duration of 24 months resulted in normalization of left heart chamber enlargement and statistically significant decrease in heart rate, left ventricular mass, and cardiac output. Echocardiographically derived left ventricular function parameters remained normal on and off transfusion therapy. Changes in left ventricular diastolic dimension and cardiac output correlated with changes in % S Hgb (r = 0.59, p less than 0.001; and r = 0.54, p less than 0.001, respectively), and with changes in Hgb concentration (r = -0.78, r = -0.76, p less than 0.001). Expression of left heart abnormalities as a single composite function (Ydv), using multivariate regression analysis, allowed a comparison of cardiac status of 99 normal black controls, nontransfused sickle cell anemia (SCA) patients, and 13 study patients on and off HTX, and permitted serial assessment of cardiac status on and off treatment over 5 years in a single patient.(ABSTRACT TRUNCATED AT 250 WORDS)

M-mode echocardiography in normal children and adolescents: some new perspectives.

Normal M-mode echocardiography values were determined using computer-assisted measurements of echocardiograms (ECHO) in 202 children and young adults 25 days to 23 years of age: 77 were female, and 125 were male and, reflecting the population served by our Center, 99 were black and 103 were white children. The values for left and right heart wall thicknesses and chamber sizes were graphically displayed as a function of body surface area, and with an illustration of the regression line and 2 standard deviation (SD) range of normal for each parameter. In addition, normal ECHO predicting equations for dimension and function parameters were derived using multiple linear regression analysis with age, height, weight, sex, race, and heart rate as independent variables. A comparison was made between the observed data and the data derived from the normal predicting equations for each of the parameters. Also, values obtained from these equations were compared to data generated from other published normal predicting equations. A description of the digitizer measurements, computer interfacing, and a sample ECHO report form utilizing the predicted normal ranges for each of the parameters is presented. We propose that quantitative M-mode echocardiographic reporting should be easily accessible to all pediatric cardiology laboratories.

Intestinal lymphangiectasia and bilateral pleural effusions: effect of dietary therapy and surgical intervention on immunologic and pulmonary parameters.

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.

Supplemental parenteral nutrition in cystic fibrosis.

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.

Cystic fibrosis and gastroesophageal reflux in infancy.

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.

Diagnostic and therapeutic applications of bentiromide screening test for exocrine pancreatic insufficiency in patients with cystic fibrosis. Comparison with other tests of exocrine pancreatic disease.

The bentiromide test for exocrine pancreatic function was carried out in normal volunteers, patients with cystic fibrosis (CF) without clinical evidence of pancreatic dysfunction, and CF patients with clinically significant exocrine pancreatic insufficiency. The test was performed with and without the concomitant administration of a Lundh test meal. p-Aminobenzoic acid was given on a separate occasion to eliminate false positives due to factors unrelated to pancreatic disease. Correct classification of 25 CF patients with pancreatic insufficiency and 9 CF patients without clinical pancreatic dysfunction was possible by interpreting the results of the above three tests. Isoamylase determinations would have misclassified 20% of the CF patients with pancreatic insufficiency, but were able to detect the CF patients without clinical pancreatic dysfunction on the basis of an elevated pancreatic amylase isoenzyme. The bentiromide test results were normal in CF patients without clinical pancreatic dysfunction despite previous findings of decreased bicarbonate secretion in this group. However, the bentiromide test did appear to be useful in the evaluation of therapeutic intervention with exogenous pancreatic enzymes and other adjunctive therapy.

Aspiration and lung abscess in cystic fibrosis.

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.

Cardiac abnormalities in children with hyperthyroidism.

The cardiac status of 18 hyperthyroid (HT) children (9 black and 9 white) was evaluated by echocardiography. Mitral regurgitation (MR) was diagnosed clinically in 33% (6 of the 9 blacks). None of the 9 white children had MR. Left ventricular end-diastolic diameter (LVEDD) and volume (LVEDV) did not differ from the predicted normal (PN) based on body surface area and heart rate, except in those with MR where increased LVEDD and LVEDV were noted (p less than 0.02). LV mass was +1.75 standard deviations (sigma) of the PN (p less than 0.01), due to increased wall thickness of LVEDV. Left ventricular output (LVO) was +0.35 sigma PN (p = ns); however, when compared to that of normal children, LVO of HT was higher (p less than 0.001) due to the increased heart rate. Enhanced left ventricular contractility was suggested by increased rate of dimensional change during ejection (peak dD/dt-syst), with a mean value of -11.39 cm/sec as compared to the normal of -9.54 cm/sec (p less than 0.01). A linear multivariate regression equation differentiated the cardiac status of HT from that of normal children. Following treatment to euthyroid state, MR disappeared in 2 and became less in 4 patients. LVO, LV mass, and peak dD/dt-syst also became less. Significant cardiac changes occur in children with hyperthyroidism, which may be reversible in part after euthyroidism is restored.

Echocardiography in cystic fibrosis: A proposed scoring system.

An echocardiographic scoring system was developed on the basis of an observed sequence of echo abnormalities, beginning with RV hypertrophy, through RV dilation, to abnormal RV systolic time intervals, noted to be associated with the progressive pulmonary disease of cystic fibrosis. This score correlated significantly with both the Shwachman-Kulczycki (r = 0.87, P < 0.001) and Taussig-NIH (r = 0.86, P < 0.001) clinical scoring systems, the Brasfield chest roentgenogram score (r = 0.86, P < 0.001), and pulmonary function test results. The scoring of echos appears to be useful for the early detection and systematic quantitation of the cardiac effects of the progressive pulmonary disease. Preliminary sequential echo studies suggest that this system provides a method for assessing the progression of cardiac disease and evaluating prognosis in individual patients, and may prove to be useful in monitoring therapeutic interventions for cor pulmonale.

Effectiveness of cimetidine as an adjunct to supplemental pancreatic enzymes in patients with cystic fibrosis.

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.