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IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Background: The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity, thickening of the subepithelial basement membrane, and pulmonary function. We hypothesized that single-nucleotide polymorphisms (SNPs) that affect YKL-40 levels also influence asthma status and lung function., Methods: We carried out a genomewide association study of serum YKL-40 levels in a founder population of European descent, the Hutterites, and then tested for an association between an implicated SNP and asthma and lung function. One associated variant was genotyped in a birth cohort at high risk for asthma, in which YKL-40 levels were measured from birth through 5 years of age, and in two populations of unrelated case patients of European descent with asthma and controls., Results: A promoter SNP (-131C-->G) in CHI3L1, the chitinase 3-like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P=1.1 x 10(-13)), asthma (P=0.047), bronchial hyperresponsiveness (P=0.002), and measures of pulmonary function (P=0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case-control populations (combined P=1.2 x 10(-5)) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9 x 10(-3) to 2.5 x 10(-4))., Conclusions: CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function., (Copyright 2008 Massachusetts Medical Society.)

Background: Genome-wide linkage scans to identify asthma susceptibility loci have revealed many linked regions, including a broad region on chromosome 5p., Objective: To identify a 5p-linked asthma or bronchial hyperresponsiveness (BHR) locus., Methods: We performed fine mapping and positional candidate studies of this region in the Hutterites and an outbred case-control sample from Germany by genotyping 89 single nucleotide polymorphisms (SNPs) in 22 genes. SNP and haplotype analyses were performed., Results: Three genes in a distal region (zinc finger RNA binding protein [ZFR], natriuretic peptide receptor C, and a disintegrin and metalloproteinase domain with thrombospondin type 1 motif [ADAMTS12]) were associated with BHR, whereas 4 genes in a proximal region (prolactin receptor, IL-7 receptor [IL7R], leukemia inhibitory factor receptor [LIFR], and prostaglandin E4 receptor [PTGER4]) were associated with asthma symptoms in the Hutterites. Furthermore, nearly the entire original linkage signal in the Hutterites was generated by individuals who had the risk-associated alleles in ZFR3, natriuretic peptide receptor C, ADAMTS12, LIFR, and PTGER4. Variation in ADAMTS12, IL7R, and PTGER4 were also associated with asthma in the outbred Germans, and the frequencies of long-range haplotypes composed of SNPs at ZFR, ADAMTS12, IL7R, LIFR, and PTGER4 were significantly different between both the German and Hutterite cases and controls. There is little linkage disequilbrium between alleles in these 2 regions in either population., Conclusion: These results suggest that a broad region on 5p, separated by >9 Mb, harbors at least 2 and possibly 5 asthma or BHR susceptibility loci. These findings are consistent with the hypothesis that regions providing evidence for linkage in multiple populations may, in fact, house more than 1 susceptibility locus, as appears to be the case for the linked region on 5p., Clinical Implications: Identifying asthma or BHR genes could lead to novel therapeutic approaches.

Rationale: Chitinases are enzymes that cleave chitin, a polysaccharide contained in many parasites of humans. Recent studies in mouse models of bronchial asthma have shown that acid mammalian chitinase (AMCase) is involved in the pathophysiology of asthma. It acts downstream of interleukin-13; inhibition of AMCase leads to an abrogated T-helper cell 2 inflammation, less bronchial hyperreactivity, and fewer eosinophils., Objectives: The aim of this study was to identify common genetic variants in human AMCase and to use them to test for association of AMCase with pediatric asthma., Methods: By sequencing the promotor region and all 11 exons on 30 individuals, 12 high-frequency polymorphisms were identified. Genotyping of six variants in exons and one promotor polymorphism was performed on the following populations by means of restriction fragment length polymorphisms: 322 children with asthma, 270 randomly chosen adult controls, and a pediatric control population consisting of 565 children who, at age 10 yr, had never wheezed and never been diagnosed having asthma., Measurements and Main Results: We identified three known and two new amino acid variants. Analyses by the Armitage's trend test using both control populations showed association of the newly identified variant K17R and the nearby noncoding polymorphism rs3818822 with asthma (p = 0.0031 and p = 0.0003, respectively). In addition, haplotype analyses revealed strong association of haplotypes with the disease (asthma population vs. pediatric control subjects, p < 10(-10))., Conclusions: This newly described association between AMCase polymorphisms and asthma adds further evidence supporting the involvement of AMCase in the development of asthma.

Glutathione S-Transferase P1 (GSTP1) is an important enzyme in the detoxification of products of oxidative stress. Several studies have shown an association of the amino acid variant Ile105Val with bronchial asthma and the reaction of the lung to inhalant pollutants. The aim of this study was to test the two known amino acid variants in GSTP1 for association with bronchial asthma and airway hyper-responsiveness in two German pediatric populations. We genotyped Ile105Val and Ala114Val in the Multicenter Allergy Study cohort (85 children with asthma, 123 controls) and asthmatic children from Freiburg (n = 178). We did not find association of either polymorphisms with bronchial asthma or airway hyper-responsiveness. We conclude from our data that polymorphisms within GSTP1 do not play a major role in the development of bronchial asthma in German children.

The chromosomal region 19q13 has been found in linkage to allergic diseases in several genome-wide linkage screens. One candidate gene within this region is the gene coding for TGF-beta1. Transforming growth factor (TGF)-beta acts as an anti-inflammatory cytokine suppressing allergic inflammation and hyper-reactivity. However, in ongoing inflammation of the lungs it can induce fibrosis and airway remodelling as seen in chronic asthma. Several polymorphisms within TGF-beta1 have been identified and one, -C509T, has been shown to be in association with elevated immunoglobulin E levels and severe bronchial asthma in different populations. However, other studies failed to confirm the association. The present study investigated two polymorphisms within the gene coding for TGF-beta1, -C509T and G915C, and for their potential association with bronchial asthma in Caucasian children. Genotyping of these polymorphisms was performed by means of restriction fragment length polymorphisms in a population of 231 asthmatic children and a control population of 269 individuals. Statistical analyses made use of the Armitage's trend test. In addition haplotypes were calculated by arlequin. None of the two polymorphisms showed association with bronchial asthma. They were found to be in linkage disequilibrium. We conclude from our data that TGF-beta1 is unlikely to represent a major gene in the development of bronchial asthma in the Caucasian population.

Histamine plays an important role in the allergic inflammation. Histamin N-Methyltransferase (HNMT) catalyses the major pathway of histamine metabolism in the human lung. A common functional single nucleotide polymorphism (SNP) within the HNMT gene (C314T) was recently related to asthma. We tested this SNP for associations with asthma and asthma associated traits in two German pediatric populations (1. MAS-cohort, n=888, 85 children with asthma; 2. asthmatic children from Freiburg, n=176). Non-asthmatic (n=515) and non-atopic (n=211) children from the MAS-cohort were used as controls. For genotyping melting curve analyses (Light Cycler System) were applied. In contrast to a previous study, no association of the HNMT 314T allele with asthma, bronchial hyperresponsiveness (BHR) or other asthma related phenotypes could be observed in either study population. We conclude that this SNP might not play a major role in the pathogenesis of asthma or BHR in German children.

Background: IL-8 is a strong inductor of inflammation. Accordingly, it plays a pivotal role in acute inflammatory responses during respiratory syncytial virus (RSV) infections and in chronic inflammatory diseases such as bronchial asthma and juvenile idiopathic arthritis. Recently, 2 studies have found association of the polymorphism -251A of IL8 with RSV bronchiolitis. Furthermore, epidemiologic studies have demonstrated an increased risk for the development of asthma after RSV bronchiolitis, and a common genetic background for the 2 diseases is currently being discussed., Objective: This study investigated whether IL-8 is in association with asthma and/or arthritis and whether the results can confirm a common genetic background of RSV bronchiolitis and asthma., Methods: The polymorphisms -A251T, C781T, C1633T, and A2767T within IL8 were genotyped in the following 4 populations: children with asthma, atopic children, children with juvenile idiopathic arthritis, and control subjects. Statistical analysis made use of the Armitage trend test and the software program Arlequine., Results: Association of all polymorphisms was found with asthma ( P =.008 to P =.03). Surprisingly -251T was associated with asthma, which is the opposite allele as described in association with RSV bronchiolitis. Furthermore, all polymorphisms were significantly more common in children with arthritis than in asthmatic children ( P =.006 to P =.02). No association was seen with the diagnosis of arthritis per se or with atopy., Conclusion: This is the first study to describe association of IL-8 with asthma and a significant inverse distribution of the polymorphisms in juvenile idiopathic arthritis. In addition, the results of this study might suggest that RSV bronchiolitis and bronchial asthma have at least some different genetic factors.

Background: IL-15 is a T(H)1-related cytokine that is involved in the inflammatory response in various infectious and autoimmune diseases. IL-15 has recently been shown to be upregulated in T-cell-mediated inflammatory disorders. The observations suggest a potential role for this cytokine in a variety of pathologic conditions, including T(H)1-mediated and T(H)2-mediated inflammatory diseases., Objective: In this study, we searched for single nucleotide polymorphisms in the whole IL-15 gene and investigated their association with inflammatory and/or atopic phenotypes., Methods: The screening for single nucleotide polymorphisms was performed by single-strand conformation polymorphism analysis. Genotyping of the identified polymorphisms was performed by restriction fragment length polymorphism. Genotypic association analysis used the Armitage trend test. Haplotype frequency estimation and subsequent testing for differences between cases and controls were performed by using the programs FASTEHPLUS and FAMHAP., Results: We identified 5 novel noncoding nucleotide sequence variants, all of which were typed in our asthmatic, our atopic, and our control population. According to the Armitage trend test, none of the 5 polymorphisms is associated with the phenotype bronchial asthma or atopy. However, multilocus haplotype analysis based on simulations to find out whether the haplotype frequencies differed between cases and controls by using the program FAMHAP yielded a P value of 6.1 x 10(-5) in the asthmatic versus the control population, which is highly significant. Furthermore, we obtained a nominally significant result of P=.0232 for the atopic versus the control population by using FAMHAP., Conclusion: These results strongly underscore previous findings that suggest a potential role of this cytokine in allergic diseases.

Background: Chromosomal region 5q31 harbours a number of genes associated with atopic phenotypes, for example the genes coding for interleukin (IL) 4, IL13 and the beta(2)-adrenoreceptor. A new gene within this region was identified only very recently. The encoded protein - uteroglobin-related protein 1 (UGRP1) - is thought to act as an anti-inflammatory agent and is mainly expressed in the lung and trachea. The functional promoter polymorphism A-112G in UGRP1 was shown to be associated with bronchial asthma in a Japanese population. We were thus interested in finding out whether the polymorphism so far identified or others within UGRP1 were associated with bronchial asthma in a German Caucasian population., Methods: We performed direct genomic sequencing of the promoter and coding region of UGRP1 in 15 asthmatic children and 15 controls. The identified polymorphisms were genotyped by means of RFLP. Statistical analysis was performed with the Armitage trend test., Results: We identified 5 non-coding variants, 4 of which being described for the first time. Three polymorphisms were common and typed in 182 asthmatic children and 270 controls. None of the polymorphisms were associated with bronchial asthma in our population., Conclusions: We conclude from our data that UGRP1 does not play a major role in the development of bronchial asthma in our Caucasian population., (Copyright 2003 S. Karger AG, Basel)

The association of a tumor necrosis factor -308 allele (TNF2) to asthma has been reported in some studies but not in others. The aim of this study was to test this association in a population recruited on the basis of allergy to Parietaria. In the study population, asthma was positively associated to HLA-DRB1*03 (p = 0.01) and to the haplotype TNF2/DRB1*03 (p = 0.02). In the parent subgroup, the proportion of asthmatics was increased in patients with TNF2 (p = 0.01), but the primary association of asthma was to the haplotype TNF2/DRB1*1104 (p = 0.005). The study population was subdivided according to prick skin test (ST) positivity to Lolium, Parietaria, and D. pteronyssinus. Asthma was associated to HLA-DRB1*03 and to the haplotype TNF2/DRB1*03 (p = 0.0015 and 0.0001, respectively) in patients ST positive to Lolium, and to the haplotype TNF2/DRB1*1104 (p = 0.025) in patients ST positive to Parietaria. The transmission disequilibrium test detected excess transmission of HLA-DRB1*03 and of the haplotype TNF2/DRB1*03 (p = 0.03 and 0.04, respectively) to siblings with asthma and ST positivity to Lolium and of HLA-DRB1*1104 and of the haplotype TNF2/DRB1*1104 (p = 0.04 and 0.015, respectively) to siblings with asthma and ST positivity to Parietaria. Taken together, these observations indicate that the haplotypes TNF2/DRB1*03 and TNF2/*B1*1104 contain alleles controlling atopic asthma in patients with sensitization to Lolium and Parietaria, respectively. This suggests that the association of asthma to TNF2 reflects linkage disequilibrium with genes influencing specific immune response.

Background: Several studies have indicated linkage of chromosome 11q12-13 to asthma and associated traits. Among other candidate genes, the Clara cell protein 16 (CC16) gene maps to this region. CC16 is expressed in the bronchial epithelium and exhibits potent anti-inflammatory properties. A single-nucleotide polymorphism (SNP) in the CC16 gene (A38G) was previously associated with asthma., Objective: We evaluated the role of the CC16 SNP in pediatric asthma and asthma severity in 2 German study populations., Methods: The German Multicenter Allergy Study (MAS) cohort (n = 872, 94 asthmatic patients) and 112 allergic asthmatic children recruited in Freiburg, Germany, were included in the present study. Histamine provocations were performed at the age of 7 years in the MAS cohort to determine bronchial hyperreactivity; in the Freiburg study population a standardized exercise-induced decrease in FEV1 was evaluated. For genotyping, melting-curve analysis and restriction enzyme digestion were applied., Results: No association of the CC16*38A allele with asthma could be observed in either study population. However, in asthmatic subjects (MAS cohort) PC(20)FEV(1) values were significantly lower in individuals homozygous or heterozygous for the CC16*38A allele compared with those in subjects with the CC16*38GG genotype (P <.05 and P <.03, respectively). Similarly, allergic asthmatic patients in the Freiburg cohort showed a significantly greater decrease in FEV1 after exercise when homozygous for the CC16*38A allele compared with that seen in asthmatic patients with the *38AG or *38GG genotype (P <.04 and P =.006, respectively)., Conclusion: We conclude that the CC16*A38G SNP influences bronchial hyperreactivity and might be a genetic determinant of asthma severity in German children.

Heinzmann A, Bauer E, Ganter K, Kurz T, Deichmann KA. Polymorphisms of theTGF-β1gene are not associated with bronchial asthma in Caucasian children.Pediatr Allergy Immunol 2005: 16: 310–314.© 2005 Blackwell MunksgaardThe chromosomal region 19q13 has been found in linkage to allergic diseases in several genome-wide linkage screens. One candidate gene within this region is the gene coding forTGF-β 1. Transforming growth factor (TGF)-β acts as an anti-inflammatory cytokine suppressing allergic inflammation and hyper-reactivity. However, in ongoing inflammation of the lungs it can induce fibrosis and airway remodelling as seen in chronic asthma. Several polymorphisms withinTGF-β 1have been identified and one,−C509T, has been shown to be in association with elevated immunoglobulin E levels and severe bronchial asthma in different populations. However, other studies failed to confirm the association. The present study investigated two polymorphisms within the gene coding forTGF-β 1,−C509T and G915C, and for their potential association with bronchial asthma in Caucasian children. Genotyping of these polymorphisms was performed by means of restriction fragment length polymorphisms in a population of 231 asthmatic children and a control population of 269 individuals. Statistical analyses made use of the Armitage's trend test. In addition haplotypes were calculated byarlequin. None of the two polymorphisms showed association with bronchial asthma. They were found to be in linkage disequilibrium. We conclude from our data thatTGF-β 1is unlikely to represent a major gene in the development of bronchial asthma in the Caucasian population. [ABSTRACT FROM AUTHOR]

Examines the effect of the variants of plasmatic platelet-activating factor-aceytlhydrolase (PAFAH) on catalytical activities and asthma. Basis of immunoglobulin-E mediated responses; Use of mutations in a schizophrenia study; Elucidation of the influence of PAFAH variants.