Association of defensin beta-1 gene polymorphisms with asthma

BACKGROUND: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. OBJECTIVE: We characterized the genetic diversity in the defensin beta-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. METHODS: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. RESULTS: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5' genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma ( P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion ( P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted ( P = .04) and was more prominent in female subjects ( P = .007). CONCLUSION: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.     

Smoke exposure interacts with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness

Introduction:  ADAM33 is the first identified asthma gene by positional cloning, especially asthma combined with bronchial hyperresponsiveness (BHR). Moreover, ADAM33 is associated with early-life lung function and decline of forced expiratory volume in 1 s (FEV₁) in the general population. In utero and postnatal cigarette smoke exposure (CSE) are associated with reduced lung function, and development of BHR and asthma. We hypothesized that this may occur via interaction with ADAM33.
Aim:  To replicate the role of ADAM33 in childhood lung function and development of BHR and asthma. Furthermore, we investigated gene–environment interaction of ADAM33 with in utero and postnatal CSE in the Dutch PIAMA cohort.
Methods:  Six ADAM33 single-nucleotide polymorphisms (SNPs) were genotyped. Rint was measured at age 4 and 8 years, FEV₁ and BHR at age 8 years; asthma was based on questionnaire data at age 8.
Results:  In the total cohort, the rs511898 A, rs528557 C, and rs2280090 A alleles increased the risk to develop asthma (+BHR). There existed interaction between in utero but not postnatal CSE and the rs528557 and rs3918396 SNPs with respect to development of BHR, the rs3918396 SNP with Rint at age 8 and the rs528557 SNP with FEV₁% predicted.
Conclusions:  We confirm associations between ADAM33 and the development of asthma (+BHR). This is the first study suggesting that interaction of in utero CSE with ADAM33 results in reduced lung function and the development of BHR, which needs further confirmation.     

Fine mapping of an IgE-controlling gene on chromosome 2q: Analysis of CTLA4 and CD28

BACKGROUND: Several genomic regions have been identified that might contain genes contributing to the development of asthma and atopy. These include chromosome 2q33, where we have observed evidence for linkage for variation in total serum IgE levels in a Dutch asthma population. Two candidate genes, CTLA4 and CD28, important homeostatic regulators of T-cell activation and subsequent IgE production, map within this candidate region. OBJECTIVE: We sought to fine-map the chromosome 2q33 region and evaluate CTLA4 and CD28 as candidate genes for the regulation of total serum IgE levels and related phenotypes. METHODS: The coding regions of CTLA4 and CD28 were resequenced in 96 individuals; 4 novel SNPs in CTLA4 and 10 in CD28 were identified. Polymorphisms in both genes were analyzed in 200 asthmatic probands and their spouses (n = 201). RESULTS: Subsequent fine- mapping in this region has resulted in an increased log of the odds (lod) score (1.96 to 3.16) for total serum IgE levels. For CTLA4, the +49 A/G single nucleotide polymorphism (SNP) in exon 1 and the 3 ' untranslated region microsatellite were significantly associated with total serum IgE levels (P =.0005 and.006, respectively). For the combined +49 A/G and 3 'untranslated region genotypes, individuals homozygous for the risk allele for both polymorphisms (AA and 86/86) had the highest total serum IgE values (87.1 IU/mL), whereas those individuals with the GG and XX/XX genotypes (anything but the 86-bp allele) had the lowest IgE values (29.3 IU/mL). Significant association was also observed for the CTLA4 -1147 C/T SNP with bronchial hyperresponsiveness (BHR) and asthma (P =.008 and.012, respectively), but not for allergy-related phenotypes. Promoter luciferase assays examining the -1147 polymorphism suggested that the T allele, which was associated with increased BHR susceptibility, was expressed at half the level of the C allele. Individuals with the risk genotypes for both BHR (-1147 CT or TT) and elevated IgE levels (+49 AA) were 4.5 times more likely to have asthma than individuals with both nonrisk genotypes (P =.0009). No significant associations were observed for SNPs in CD28. CONCLUSION: These data suggest that the costimulatory pathway, specifically CTLA4, is important in the development of atopy and asthma.     

Interleukin 18 receptor 1 gene polymorphisms are associated with asthma

The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined by genotyping seven SNPs in 294, 342 and 100 families from Denmark, United Kingdom and Norway and conducting family-based association analyses for asthma, atopic asthma and bronchial hyper-reactivity (BHR) phenotypes. Three SNPs in IL18R1 were associated with asthma (0.01131相似文献   

Factors influencing symptom expression in children with bronchial hyperresponsiveness at 10 years of age

OBJECTIVES: We sought to identify factors associated with wheezing symptoms in children found to have bronchial hyperresponsiveness (BHR) at 10 years of age. METHODS: Children were seen at birth, 1, 2, 4 and 10 years of age in an entire population birth cohort study (n = 1456). At each stage information was collected prospectively on genetic and environmental risk factors for BHR. Skin prick testing was performed at 4 and 10 years of age. Spirometry and methacholine bronchial challenge were conducted at 10 years of age when BHR was considered present if PC(20) FEV(1) was < 4.0 mg/mL. In children with BHR at 10 years of age, factors independently associated with current wheezing were determined by logistic regression. RESULTS: BHR was identified in 169 10-year-olds at bronchial challenge, 55.6% of whom manifested current wheeze. In children with BHR, current wheezers had higher Log(10) total IgE and greater BHR than those who had never wheezed. Symptomatic BHR was independently associated with atopic sensitization (P <.001) and maternal asthma (P =.011) at 10 years of age. If only factors present in the first 4 years of life were considered, parental smoking at 4 years of age (P =.021), maternal asthma (P =.017), and atopic sensitization at 4 years of age (P =.004) were independently associated with symptomatic BHR at 10 years of age. CONCLUSIONS: Symptomatic BHR is associated with greater degrees of BHR and higher total IgE. Heredity, atopy, and environmental exposure might influence symptom expression in children with BHR.     

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.     

CTLA-4 polymorphisms in allergy and asthma and the TH1/ TH2 paradigm

BACKGROUND: Several genomic regions are reported to be associated with the development of asthma and allergy, including chromosome 2q33. This region harbors the candidate gene cytotoxic T-lymphocyte antigen 4 (CTLA-4), an important regulator of T-cell activation and differentiation. OBJECTIVE: We sought to explore possible associations between CTLA-4 polymorphisms and allergy and asthma. METHODS: Seven single nucleotide polymorphisms (SNPs; MH30, -1147CT, +49AG, CT60, JO31, JO30, JO27_1) in CTLA-4 were analyzed for associations with total serum IgE, allergic sensitization (positive skin prick test to common allergens), bronchial hyperresponsiveness (BHR) to methacholine, asthma, and lung function (FEV1 % of predicted) in 364 asthmatic families from 3 European countries. RESULTS: Transmission disequilibrium test analysis showed that several SNPs were significantly associated with serum IgE levels, allergy, asthma, and FEV1 % predicted below 80%, but not with BHR, and CTLA-4 polymorphisms of potentially direct pathogenic significance in atopic disorders were identified. CONCLUSION: We identified associations between 4 newly discovered SNPs in the CTLA-4 gene and serum IgE levels, allergy, asthma, and reduced lung function, but not BHR, suggesting an important role for CTLA-4 in atopy and reduced lung function in asthmatic subjects rather than asthma per se. The particular SNP alleles found positively associated with our phenotypes were recently shown to be associated negatively with autoimmune disorders. Although a skewing toward a TH1 reactivity pattern is believed to characterize autoimmune diseases, atopic diseases are considered TH2-mediated. Hence, our data suggest a role for CTLA-4 polymorphisms in determining the TH1/TH2 balance and identify CTLA-4 signaling as a potential therapeutic target in atopic disease.     

TNF-alpha (-308 G/A) and CD14 (-159T/C) polymorphisms in the bronchial responsiveness of Korean children with asthma

BACKGROUND: TNF-alpha is a pivotal proinflammatory cytokine increased in asthmatic airways. The TNF-alpha gene family might be linked to asthma or bronchial hyperresponsiveness (BHR), and TNF-alpha production might be modulated by CD14(+) cells. OBJECTIVE: We investigated the association between asthma susceptibility or asthma-related phenotypes and TNF-alpha (-308G/A) polymorphism and examined the combined effect with CD14 (-159T/C) polymorphism in Korean children. METHODS: Asthmatic (n = 788) and control (n = 153) children were evaluated for asthma phenotypes. Genotypes were determined by using the single-base extension method and PCR-restriction fragment length polymorphism. RESULTS: There was no difference between asthmatic children and control subjects in terms of the allele frequencies of TNF-alpha (-308G/A) and CD14 (-159T/C). Significantly lower PC(20) values were seen in asthmatic (P = .016) children with the TNF-alpha risk allele (-308A). Higher frequencies of 1 or 2 copies of the risk allele were found in asthmatic children with moderate-to-severe BHR to methacholine and exercise compared with control children (adjusted odds ratio of 2.57 [95% CI, 1.30-5.08] and adjusted odds ratio of 2.04 [95% CI 0.99-4.20], respectively). In addition, asthmatic children with risk alleles at both loci had significantly greater BHR than those homozygous for the common alleles (P = .018). CONCLUSION: The TNF-alpha promoter polymorphism (-308G/A) might be associated with severe BHR in Korean children with asthma. In addition, these children show a synergistic effect between the TNF-alpha promoter (-308A) and CD14 promoter (-159C) polymorphisms in terms of BHR. CLINICAL IMPLICATIONS: The TNF-alpha polymorphism might be a disease-modifying gene in asthma and modulated by the CD14 gene.     

Estrogen receptor beta gene variants are associated with increased risk of Alzheimer's disease in women

We investigated the association of five intronic single-nucleotide polymorphism (SNP) at the estrogen receptor beta (ESR2) gene locus and the susceptibility of developing Alzheimer's disease (AD) in 387 subjects with clinically diagnosed probable AD and 467 cognitively normal individuals derived from eastern Finland. According to our results, variation in the ESR2 gene is associated with an increased risk of AD in women, whereas it does not contribute to the disease susceptibility in men. More specifically, in women, the allele T and the genotype T/T of two of the studied ESR2 gene SNPs (SNP2 and SNP3) were more frequent in AD women than in cognitively normal control women (P=0.012 and P=0.016, respectively). The ESR2 SNP2 T/T genotype and the SNP3 T/T genotype were associated with a significant, nearly two-fold increase in the risk of AD in women (OR=1.87, 95% CI=1.21-2.90), and remained significant after adjustment with the APOE genotype and age (OR=1.63, 95% CI, 1.00-1.68). The combined effect of the ESR2 SNP2 T/T or SNP3 T/T genotype and female gender increases the risk of the disease (OR=3.2, 95% CI=1.3-7.7). Consistent with these results, also the frequency of the haplotype containing the two above ESR2 gene risk alleles was elevated in AD women (P=0.027, OR=1.3, 95% CI=1.02-1.65). Results show that variation in ESR2 gene may be linked with increased AD susceptibility and furthermore, this association is gender specific.     

Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population

Asthma and atopy are related conditions that may share similar genetic susceptibility. Linkage studies have identified a region on chromosome 5q that contains biologic candidates for both asthma and atopy phenotypes, including several proinflammatory cytokines. Interleukin (IL)-13, one of the candidate genes in the region, is directly involved in the regulation of immunoglobulin E and has been associated with both asthma and atopy. We sought to identify new polymorphisms in the IL-13 gene, and evaluated the involvement of a subset of these variants in asthma and atopy in a case-control study using probands and spouses from a Dutch asthma family study. IL-13 was sequenced in 20 probands and 20 unaffected spouses, and 10 polymorphisms were identified, four novel and six previously reported. Three single nucleotide (nt) polymorphisms (SNPs) were detected in the 5'-promoter region, two in intron 1, and five in exon 4. Only one of the exon 4 SNPs resulted in an amino-acid change (Arg130Gln). We analyzed three SNPs in IL-13 in an extended group of 184 probands and their spouses: one in the promoter region (-1111), the Arg130Gln (nt position 4257), and a 3' untranslated region SNP (nt position 4738). The most significant associations were observed to asthma (P = 0.005), bronchial hyperresponsiveness (P = 0.003), and skin-test responsiveness (P = 0.03) with the -1111 promoter. These results provide evidence that variation in the IL-13 gene is involved in the pathogenesis of asthma and atopy. Further investigation is required to determine which specific alleles or combination of alleles contribute to these phenotypes, and the possible downstream effects of the resulting change in IL-13 levels or activity.     

Elevated serum melatonin is associated with the nocturnal worsening of asthma

BACKGROUND: Increased airway inflammation at night contributes to the nocturnal worsening of asthma. In vitro studies have shown exogenous melatonin to be pro-inflammatory in asthma, but it is unknown whether endogenous melatonin levels are a controller of airway inflammation in nocturnal asthma. OBJECTIVE: Our aim was to determine 24-hour patterns of serum melatonin and their relationship to overnight decline in physiology in subjects with nocturnal asthma, non-nocturnal asthma, and in healthy controls. METHODS: Observational study of pulmonary physiology and melatonin levels in patients with nocturnal asthma (n = 7), non-nocturnal asthma (n = 13), and healthy controls (n = 11). Subjects maintained a constant sleep-wake regimen for 7 days. On day 8, serum melatonin was measured every 2 hours by radioimmunoassay and analyzed by cosinor modeling. The correlation between serum melatonin levels and overnight change in spirometry was evaluated by Spearman's rank correlation analysis. RESULTS: In subjects with nocturnal asthma, peak melatonin levels were significantly elevated compared with healthy controls (67.6 +/- 5.0 pg/mL versus 53.5 +/- 4.0 pg/mL, P =.03). Melatonin acrophase was delayed in nocturnal asthma (02:54 versus 01:58 in healthy controls, P =.003, and 02:15 in non-nocturnal asthma, P =.01). In subjects with nocturnal asthma, increasing melatonin levels were significantly and inversely correlated with overnight change in FEV(1) (r = -.79, P =.04), a relationship that was not observed in non-nocturnal asthma or healthy controls. CONCLUSIONS: Nocturnal asthma is associated with elevation and phase delay of peak serum melatonin levels. Elevated melatonin levels might contribute to the pathogenesis of nocturnal asthma.     

Association of PTGDR gene polymorphisms with asthma in two Caucasian populations

The prostanoid DP receptor (PTGDR) is shown to be involved in the asthma patho-physiology and the results from the published genetic association studies are inconsistent. Four single nucleotide polymorphisms (SNPs) in PTGDR were genotyped in 342 and 294 families from UK and Denmark respectively. Asthma and asthma-related phenotypes were analyzed using family-based association analyses. In the UK families, a promoter polymorphism (-731A/G) showed significant associations with asthma (P=0.0022), atopic asthma (P=0.0044), bronchial hyperreactivity or BHR (P=0.00120) and strict asthma (P=0.0008). The P-values for asthma, BHR and strict asthma were significant even after the most stringent correction for the number of markers and the number of phenotypes analyzed (<0.0031). An intronic polymorphism (+6651C/T) also showed significant associations with asthma (P=0.0302), atopic asthma (P=0.0131), BHR (P=0.0249) and strict asthma (P=0.0261). In the Danish families, an intronic polymorphism (+6541C/T) showed significant associations with asthma (P=0.0071), atopic asthma (P=0.0348), BHR (P=0.0033) and strict asthma (P=0.0381). The results of haplotype analyses supported the ones of the single SNP analyses. Thus, we demonstrated significant evidence of association between polymorphisms in PTGDR with asthma phenotypes in the two Caucasian populations.     

A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects

BACKGROUND: The role of variation in the IL4 gene in asthma and allergy susceptibility is controversial. This cytokine is important in IgE isotype switching and the regulation of allergic inflammation; however, published studies have not delineated the specific role of variation in this gene in allergic disorders. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) in IL4 and to evaluate the association of SNPs and haplotypes with asthma and allergic phenotypes (total serum IgE) in white, African American, and Hispanic asthmatic populations. METHODS: Sixteen individuals were resequenced, and 19 SNPs were identified; 2 novel and 17 SNPs were previously reported. Eleven of the SNPs were used to evaluate association in the 3 groups. RESULTS: Nine polymorphisms were associated with total serum IgE levels in white subjects (.0012 < or = P < or =.034), and 5 of these were also associated with asthma in this population (.010 < or = P < or =.031). Three common haplotypes were observed, and all were associated with either high or low serum IgE levels in white subjects (.00008 < or = P < or =.004). Inspection of the haplotypes revealed that 3017 G/T in intron 2 was the only SNP concordant with serum IgE levels (G allele with lower levels and T allele with higher levels). CONCLUSIONS: After a comprehensive genetic evaluation, our data suggest that the 3017 G/T variant or the haplotype it identifies influences IL4's ability to modulate total serum IgE levels. Inconsistencies with previously reported IL4 associations might be due to population differences in allele frequencies, the extent of linkage disequilibrium with this SNP or haplotype, or both.     

G protein-coupled receptor 154 gene polymorphism is associated with airway hyperresponsiveness to methacholine in a Chinese population

BACKGROUND: A new asthma susceptibility gene, the G protein-coupled receptor for asthma susceptibility (GPRA, GPR154), has recently been identified and the association was replicated in 2 white populations, but not in a Korean population. OBJECTIVE: To test the association between GPR154 gene polymorphisms and airway responsiveness to methacholine in a Chinese population. METHODS: Eight single nucleotide polymorphisms (SNPs) in the GPR154 gene were genotyped in 451 cases and 232 controls in stage I. The association of 1 SNP, rs324981, was tested in an additional 264 case and 241 control subjects in stage II. Both single marker and haplotype associations were tested. RESULTS: In stage I, we found that airway hyperresponsiveness to methacholine was associated with 2 single SNPs, rs324981 and rs324987, but not with the haplotypes of GPR154. The minor allele homozygotes of rs324981 (AA) and rs324987 (TT) were at a significantly lower risk of hyperresponsiveness to methacholine with odds ratios of 0.59 (P=.02) and 0.56 (P=.01), respectively. In stage II, we found a similar trend of association between rs324981 and airway hyperresponsiveness (P=.09). In the pooled analysis, the odds ratio of the AA homozygote of rs324981 was 0.61 (P=.004). The permutation test resulted in a study-wide empirical P value of .023, which meant that the association remained significant after adjustment for multiple tests. CONCLUSIONS: Our study supports a role of the GPR154 gene in asthma susceptibility and suggests that the AA homozygote of rs324981 is a protective factor for airway hyperresponsiveness to methacholine in a Chinese population. CLINICAL IMPLICATIONS: Our findings confirmed a role of GPR154 in the genetic susceptibility of asthma and suggest that GPR154 polymorphism should be taken into consideration to improve the assessment of an individual's risk of asthma.     

New polymorphisms of haematopoietic prostaglandin D synthase and human prostanoid DP receptor genes

BACKGROUND: Prostaglandin D2 (PGD2), a major cyclo-oxygenase metabolite of arachidonic acid in mast cells, induces bronchoconstriction in the human lung. It has been reported that mice lacking PGD receptor fail to develop the bronchial hyper-responsiveness upon ovalbumin challenge, suggesting that PGD2 functions as a mediator of allergic asthma. OBJECTIVE: To determine if there are any mutations associated with the development of asthma in the haematopoietic prostaglandin D synthase (H-PGDS) gene and the human prostanoid DP receptor (PTGDR) gene. METHODS AND RESULTS: We screened the 5'flanking and coding regions of the H-PGDS gene and the PTGDR gene by direct sequence. We identified one variant in intron 2 (IVS2 + 11 A > C) and one variant in intron 3 (IVS3 + 13T > C) of the H-PGDS gene, and two variants in the 5'flanking region of the PTGDR gene (-197T > C and -2C > T). The IVS3 + 13T > C and -197T > C variants were rare, appearing only once in 48 subjects. transmission disequilibrium test (TDT) analysis of 144 asthmatic families revealed that the IVS2 + 11 A allele of the H-PGDS gene was significantly transmitted preferentially to asthma-affected children (P = 0.0056), but no association was observed between -2C/T polymorphism of the PTGDR gene and asthma (P > 0.05). CONCLUSION: Our results suggest that the IVS2 + 11A/C allele may be involved in the development of asthma in the Japanese population.     

Leptin: does it have any role in childhood asthma?

BACKGROUND: Although there is evidence of a positive association between asthma and obesity in adults and children, very little is known about the role of leptin in asthmatic children. OBJECTIVES: The aims of this study were to evaluate the relation between leptin and parameters of atopy and asthma in children. METHODS: Body mass index (BMI) and serum leptin levels were measured in 102 (37 female, 65 male; mean age, 5.9 +/- 3.4 years) asthmatic and 33 (14 female, 19 male; mean age, 6.1 +/- 3.4 years) healthy children. Skin prick tests, total serum IgE, and pulmonary function tests were performed and were completed. RESULTS: A significant difference was observed in serum leptin levels between asthmatic and healthy children. Median (interquartile range) levels were 3.53 (2.06-7.24) ng/mL and 2.26 (1.26-4.71) ng/mL, respectively (P=.008). Subgroup analysis revealed that this difference in leptin levels was confined entirely to boys: 3.09 (1.99-7.51) ng/mL in boys with asthma versus 1.52 (1.06-3.17) ng/mL in boys without asthma (P=.003). By logistic regression analysis, we found that leptin was a predictive factor for having asthma (odds ratio, 1.98; CI, 1.10-3.55; P=.021), whereas sex, age, or BMI were not. In a stepwise multiple regression analysis including sex (P=.001), age (P=.016), BMI (P <.001), and asthma (P=.022), all of these variables were found to affect log leptin levels (R2=0.404). There was no significant sex difference in serum leptin levels among asthmatic children, whereas healthy boys had significantly lower leptin levels than healthy girls (P=.019). Atopic asthmatic subjects had significantly higher leptin levels than nonatopic asthmatic subjects (P=.038) with similar BMI. A significant, but weak, correlation was observed between leptin levels and IgE in the overall group of asthmatic children (r=0.231; P=.019). Again, this correlation was confined entirely to boys (r=0.319; P=.010). There was no relation between leptin levels and skin prick tests, pulmonary function tests, passive smoking, birth weight, and duration of breast-feeding. CONCLUSION: Our findings suggest that leptin may play a role in atopic asthma. High serum leptin levels in asthmatic boys may partly explain the higher prevalence of childhood asthma in male sex.     

Analysis of Ig subclass deficiency: First reported case of IgG2, IgG4, and IgA deficiency caused by deletion of C alpha 1, psi C gamma, C gamma 2, C gamma 4, and C epsilon in a Mongoloid patient

BACKGROUND: IL-4 and IL-13 have been shown to be critical for expression of the asthma phenotype in a murine model and may modulate human fibroblast function. OBJECTIVE: We hypothesized that IL-4 and IL-13 would increase airway fibroblast proliferation and reduce the ability of dexamethasone to decrease this proliferation. METHODS: Six subjects with severe asthma, 5 subjects with mild asthma, and 5 healthy subjects underwent bronchoscopy with endobronchial biopsy. Biopsy specimens were placed in Dulbecco modified Eagle medium and cultured, and only fibro-blasts from the first and second passages were evaluated. Cells were incubated with IL-4 (50 ng/mL), IL-13 (10 ng/mL), and the combination for 48 hours in the presence and absence of dexamethasone, 10(-7) mol/L, and 10(-8) mol/L. Fibroblasts were also incubated with IFN-gamma at 50 ng/mL to assess the response of a T(H)1 cytokine on proliferation. RESULTS: Fibroblast proliferation, determined by (3)H-thymidine incorporation, was significantly increased by IL-4 in subjects with mild asthma as compared with IL-4 in subjects with severe asthma and healthy subjects (P =.003), IL-13 (P =.011), and the combination (P =.004). Dexamethasone also increased proliferation in the group with mild asthma as compared with the group with severe asthma and the healthy group (10(-7) mol/L, P =.02; 10(-8) mol/L, P =.02). IFN-gamma did not significantly alter airway fibroblast proliferation. CONCLUSION: IL-4, IL-13, and dexamethasone all significantly increased fibroblast proliferation in subjects with mild asthma.     

Fifteen-year follow-up of pulmonary function in individuals heterozygous for the cystic fibrosis phenylalanine-508 deletion

BACKGROUND: In a cross-sectional study, we previously showed that cystic fibrosis phenylalanine-508 deletion (DeltaF508) heterozygosity may be overrepresented among individuals with asthma. OBJECTIVE: Using 15-year follow-up data from the Copenhagen City Heart Study, we now further explore this relationship. METHODS: As part of 3 surveys in 1976 to 1978, 1981 to 1983, and 1991 to 1994, we measured pulmonary function and asked all participants about asthma and pulmonary risk factors. RESULTS: There was no difference in annual decline in lung function between DeltaF508 heterozygotes and noncarriers overall; however, among individuals with familial asthma, the annual declines in FEV(1) and forced vital capacity (FVC) were 49 and 36 mL in DeltaF508 heterozygotes versus 24 and 17 mL in noncarriers (P =.01 and P =.12, respectively). Cross-sectionally based on triple measurements, FEV(1) and FVC in individuals aged 20 to 70 years were lower in heterozygous participants versus noncarriers (P =.02 and P =.004, respectively). The average reduction of FEV(1) and FVC in DeltaF508 heterozygotes versus noncarriers was 70 mL (P =.06) and 136 mL (P =.008). Finally, 10% of carriers reported asthma versus 7% of noncarriers (P =.02), resulting in an odds ratio of 2.0 (1.3-3.2) for asthma in DeltaF508 heterozygotes. CONCLUSION: Cystic fibrosis DeltaF508 heterozygotes may be overrepresented among individuals with asthma and may have poorer lung function than noncarriers. Furthermore, DeltaF508 heterozygosity in context with familial predisposition to asthma may be associated with a greater annual FEV(1) decline.     

Comprehensive association analyses of IGF1, ESR2, and CYP17 genes with adult height in Caucasians

Human adult height is closely related to body growth that is regulated by multiple cytokines or hormones like growth hormone (GH) and estrogen. Our study focused on three potential candidate genes to human height, namely IGF1 (insulin-like growth factor 1), ESR2, and CYP17. We genotyped 43 single nucleotide polymorphisms (SNPs) and tested their associations in 1873 subjects from 405 nuclear families, using both the family-based quantitative transmission disequilibrium test (QTDT) and population-based ANOVA methods. Both analyses consistently detected that two novel SNPs of IGF1, rs5742694 and rs2033178, were significantly associated with human height, with the P-values of 0.0097 and 0.0057 in QTDT analyses, 0.0002/0.004 (sample 1/sample 2) and 8.46 x 10(-5)/1.92 x 10(-5) in ANOVA analyses. For ESR2, significant associations were only detected in women (rs1256061: QTDT P=0.002, ANOVA P=0.002/0.012; rs17766755: QTDT P=0.019, ANOVA P=0.023/0.006; rs1256044: QTDT P=0.022, ANOVA P=0.002/0.034). Haplotype analyses corroborated our single-SNP results. However, no association was detected between CYP17 and human height. In conclusion, we identified the important effects of IGF1 and ESR2 on adult height variation in Caucasians, and first suggested the potential sex-specific effect of ESR2 on height variation in Caucasian women. It will be valuable for other independent studies to replicate and confirm these findings.