[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
European journal of human genetics: EJHG 04/2010; 18(8):902-8. · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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).
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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)).
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.
New England Journal of Medicine 05/2008; 358(16):1682-91. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide linkage scans to identify asthma susceptibility loci have revealed many linked regions, including a broad region on chromosome 5p.
To identify a 5p-linked asthma or bronchial hyperresponsiveness (BHR) locus.
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.
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.
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.
Identifying asthma or BHR genes could lead to novel therapeutic approaches.
Journal of Allergy and Clinical Immunology 09/2006; 118(2):396-402. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-15 is an important mediator in chronic inflammatory diseases. Recently, we have described the association of IL-15 haplotypes with bronchial asthma. Asthma genetics is highly complex - about every second candidate gene is not confirmed in consecutive studies. We were interested in whether association of asthma with IL-15 holds in a second population. Furthermore, we sought to investigate the effect of different controls.
Five IL-15 polymorphisms were genotyped on the German Multicenter Allergy Study (MAS) cohort consisting of 886 children who were followed up from birth to 10 years of age. At 10 years of age, 96 were found to be asthmatic. MAS children who never had any wheezing symptoms (n = 576), who were never diagnosed with asthma (n = 790) and 129 super controls who had never had any atopic disorder were used as controls. Finally, 270 randomly chosen adults served as controls.
Association was confirmed with single polymorphism and haplotypes. The super controls showed the highest difference to the asthmatics regarding haplotype frequencies. However, the effect escaped statistical significance, most likely because of the small sample size.
Association of IL-15 with asthma was confirmed. Although super controls might be the most suitable, more numbers are needed. This might hamper the value of these controls especially when investigating common diseases.
[Show abstract][Hide abstract] ABSTRACT: Bronchial asthma and juvenile idiopathic arthritis (JIA) are complex genetic diseases. As both represent chronic inflammatory diseases it is likely that they are at least partially influenced by the same genetic variants. One goal in dissecting the genetics of complex diseases is to identify a genetic risk profile. Therefore it is necessary to genotype polymorphisms in many different pathways. Thus we investigated 48 polymorphisms in 24 genes for association with asthma and/or JIA. Genotpying was performed on 231 asthmatic children, 86 children with JIA and 270 controls. Association analysis was performed by the Armitage's trend test. Furthermore haplotypes were calculated by FAMHAP. We found association of polymorphisms within IL-4, CTLA4 and TNFalpha with asthma and/or JIA. Furthermore, the polymorphisms showed an inverse distribution between children with asthma and JIA. However, we were not able to confirm association of most of the previously described candidate genes. We conclude from our data that it might be very difficult to identify genetic risk profiles for the development of asthma and/or JIA that would be valid across different populations. However, this study adds further evidence that the common genetic background of asthma and JIA is mainly based on polymorphisms in important TH1 and TH2 cytokines.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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)).
This newly described association between AMCase polymorphisms and asthma adds further evidence supporting the involvement of AMCase in the development of asthma.
American Journal of Respiratory and Critical Care Medicine 12/2005; 172(12):1505-9. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Pediatric Allergy and Immunology 10/2005; 16(6):539-41. · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Matrix metalloproteinase 9 plays an important role in the development of bronchial asthma. We were interested in whether the polymorphisms -T1702A, -C1562T, R279Q and +C6T within the matrix metalloproteinase 9 (MMP-9) gene were associated with asthma in a population of 231 asthmatic children. However, we found no association. Thus MMP-9 might not be a major gene for asthma.
International Journal of Immunogenetics 09/2005; 32(4):233-6. · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Pediatric Allergy and Immunology 07/2005; 16(4):310-4. · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Pediatric Allergy and Immunology 03/2005; 16(1):40-2. · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dissecting complex diseases in underlying distinct traits and studying these for their genetic basis might enhance the power as well as the specificity, of detection of disease genes. These phenotypes are known as intermediate phenotypes.
We were interested in the atopic basis of asthma, and used the sensitization to mite (Dermatophagoides pteronyssinus) allergens as a pathophysiologically important intermediate phenotype.
This time we performed a genome-wide scan based on the same already used multiethnic European population consisting of 82 nuclear families with at least two affected siblings. We carried out nonparametric as well as parametric MOD-score analyses based on the genotypes of 603 microsatellite markers.
In comparison with our first genome-wide candidate region search three novel regions additionally appeared to be significant. We obtained significant results for the region 2p12 with a MOD score of 3.35 and for the region 16q21 with a MOD score of 4.18. The most significant result was found for the region 3q21.3 with the same microsatellite marker, which showed significant linkage to atopic dermatitis (AD) in another study with a MOD score of 4.51 and an nonparametric linkage analysis (NPL) of 4.00.
Our findings indicate that atopy, allergic asthma, allergic rhinitis and AD on the one hand are distinct traits on both the clinical and genetic basis, but on the other hand, our results also underline that these traits are closely related diseases concerning the atopic basis of the traits.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
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.
Journal of Allergy and Clinical Immunology 10/2004; 114(3):671-6. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin-18 (IL-18) plays an important role in the regulation of TH1 as well as TH2 immunologic responses and thus in the development of chronic inflammatory diseases. Positive association studies of polymorphisms in IL-18 with different diseases have underlined the involvement of IL-18 in the pathogenetics processes. Our interest was to test polymorphisms of IL-18 for association with a typical TH1-mediated disease--juvenile idiopathic arthritis--and the TH2-mediated disease bronchial asthma in Caucasian children.
We genotyped five polymorphisms that were in association with chronic inflammatory diseases (-607C, -137C, 113G, 127T, and -133G). This was performed by restriction fragment length polymorphism in populations of asthmatic children, control individuals, and children with antinuclear antibodies (ANA)-positive juvenile idiopathic arthritis. Statistical analysis was performed by the Armitage trend test; haplotypes were calculated by the Arlequine program.
No significant association was found between any single nucleotide polymorphism or any haplotype and bronchial asthma or ANA-positive juvenile idiopathic arthritis.
We conclude that the effect of IL-18 in the immunologic context of diseases like bronchial asthma or juvenile arthritis might be too complex to be reflected in a simple one-way association study. Furthermore, the polymorphisms under investigation might be nonfunctional.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
These results strongly underscore previous findings that suggest a potential role of this cytokine in allergic diseases.
Journal of Allergy and Clinical Immunology 06/2004; 113(5):896-901. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several studies have investigated the association of a promoter polymorphism in CD14 with atopic phenotypes. We screened this and another polymorphism in 182 asthmatic children and found no association with asthma. Furthermore, there was substantial linkage disequilibrium of the polymorphisms. Thus CD14 does not play a major role in the development of asthma in our population of Caucasian children.
European Journal of Immunogenetics 11/2003; 30(5):345-8.
[Show abstract][Hide abstract] ABSTRACT: It has previously been shown that various inflammatory diseases, such as diabetes mellitus, bronchial asthma, chronic inflammatory bowel diseases, and rheumatoid arthritis, are in some circumstances genetically linked to the same chromosomal regions. Consequently, common genes underlying the pathogenetics of these diseases have been proposed. Chronic inflammatory disorders can be subdivided by their predominant immune response, either TH1 or TH2. For example, juvenile idiopathic arthritis (JIA) is a TH1 disease, and bronchial asthma is a TH2 disease.
The present study investigated the polymorphism Arg110Gln within the IL13 gene, a strong TH2 cytokine. We attempted to determine whether it is associated with these 2 diseases and whether this would reflect the TH1/TH2 paradigm.
Arg110Gln was typed in 4 different populations: asthmatic children, atopic children, children with JIA, and a control population. Statistical analysis was performed by using logistic and linear regression analysis of serum IgE levels and the Armitage trend test.
The variant Gln110 was shown to be associated with increased total serum IgE levels in our atopic population (P =.006) and was weakly associated with bronchial asthma (P =.04). There was no association of the variant with JIA when compared with the control population. However, the variant Gln110 was significantly less frequent in children with JIA compared with its presence in children with bronchial asthma (P =.007).
This is the first study to compare the same gene variant in TH1 and TH2 chronic inflammatory diseases. The results suggest that the same gene variant might protect from one disease and make an individual susceptible to the other.
Journal of Allergy and Clinical Immunology 11/2003; 112(4):735-9. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
We conclude from our data that UGRP1 does not play a major role in the development of bronchial asthma in our Caucasian population.
International Archives of Allergy and Immunology 09/2003; 131(4):291-5. · 2.25 Impact Factor