Relationship between the 17q21 locus and adult asthma in a Czech population

Several whole-genome association studies have shown a significant link between childhood asthma and the 17q12 chromosome region. We selected tagging single nucleotide polymorphisms (SNPs) in the ORMDL3 gene (17q12) to investigate gene variability in relation to adult allergic asthma and asthma/atopy traits in a Czech Caucasian population of adults. We conducted a case-control association study comprising 668 unrelated subjects (337 asthmatic and 331 control subjects). Four selected SNPs (rs17608925, rs12603332, rs8076131, and rs3169572) were genotyped using the TaqMan SNP Genotyping Assays. The single locus analysis showed only a borderline association between rs3169572 variant and asthma (p = 0.030, p(corr) > 0.05). However, seven different haplotypes were identified; among them, the TTAA haplotype was marginally associated with asthma (p = 0.045, p(corr) > 0.05) and TCAG haplotype was significantly associated with asthma in males (p = 0.009, p(corr) < 0.05, odds ratio = 1.48, 95% confidence interval = 1.10-2.00). In addition, associations between the ORMDL3 genotypes and the total IgE level (p = 0.05, p(corr) > 0.05) and hypersensitivity to the pollen (p = 0.007, p(corr) < 0.05) were established. However, no relationship between ORMDL3 SNPs and the pulmonary functions was found (p > 0.05). These findings suggest that the genetic variability in the 17q21 region may be one of the risk factors also for adult asthma, especially in male individuals.     

Asthma and atopy are associated with chromosome 17q21 markers in Chinese children

Background:  Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children.
Methods:  Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshot™, and their genotype associations with asthma traits analyzed using multivariate regression.
Results:  315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 ( P  =   0.019–0.034), whereas atopy was associated only with rs11650680 ( P  =   0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 ( P  =   0.008–0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09–0.52 ( P  =   0.0002) and 0.41 and 0.18–0.90 ( P  =   0.025).
Conclusion:  Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region.     

Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant

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A polymorphism in the promoter region of the human interleukin-16 gene is not associated with asthma or atopy in an Australian population

BACKGROUND: IL-16 is an immunomodulatory cytokine whose expression is increased in the bronchial mucosa, bronchoalveolar lavage fluid and induced sputum of asthmatic patients. It has been suggested that IL-16 has a regulatory role in the pathophysiology of asthma. A single-nucleotide polymorphism (T(-295)C) has been described in the promoter region of the gene and it has been hypothesized that this polymorphism may be associated with altered levels of IL-16 expression, and account for the increased levels of IL-16 seen in the asthmatic airway. OBJECTIVE: To determine the association between the T(-295)C promoter polymorphism and asthma, disease severity and atopy in a large Australian Caucasian population. METHODS: We used PCR and restriction fragment length polymorphism analysis to establish the allele frequency of the T(-295)C promoter polymorphism in a random Australian Caucasian population (n=176) and to characterize the polymorphism in a large Australian Caucasian population of mild (n=273), moderate (n=230) and severe (n=77) asthmatic patients, and non-asthmatic controls (n=455). Genotype association analyses were performed using chi(2) tests. RESULTS: The polymorphic C allele was present in 19% of the asthmatic population and 21% of the non-asthmatic population. There was no association between the polymorphism and asthma (P=0.153) nor with asthma severity (P=0.417) or atopy (P=0.157) in this population. CONCLUSION: Although it has been hypothesized that the T(-295)C promoter polymorphism may be associated with increased IL-16 gene expression, it is not associated with asthma, disease severity or atopy in this Australian population.     

A novel SNP at exon 17 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS

To investigate the association of single-nucleotide polymorphisms (SNPs) in exon 17 of the insulin receptor (INSR) gene with insulin resistance and INSR beta-subunit expression in polycystic ovary syndrome (PCOS) patients, a case-control study was carried out in an academic endocrinology clinic of China. One hundred and nine Chinese patients with PCOS and 107 healthy Chinese women as control were recruited. Their leukocytes and red blood cells were separated from blood samples, for SNP analysis with single-stranded conformation polymorphism and for the INSR beta-subunit expression detection by western blot analysis, respectively. A novel T/C SNP at codon Cys1008 (position 3128 of NM_000208) of INSR was found in two allele genotypes, i.e. the homozygous CC and the heterozygous TC. A higher frequency of the mutant homozygous CC was observed in the PCOS women with PCOS than that in the controls (21.1 versus 5.6%, P < 0.01). In contrast with the women with wild-type genotype, a significantly lower insulin sensitivity index in the women with each of the two mutant genotypes was revealed (CC: 0.335 +/- 0.026/TC: 0.346 +/- 0.027 versus TT: 0.367 +/- 0.029, P < 0.05). No relationship was found between the novel SNP and the INSR beta-subunit expression. We concluded that the novel T/C SNP at codon Cys1008 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS and that the association is not by the change of synthesis or secretion of INSR beta-subunit, but most possibly by the effects of this novel SNP on the function of INSR beta-subunit.     

A novel promoter polymorphism in the gene encoding complement component 5 receptor 1 on chromosome 19q13.3 is not associated with asthma and atopy in three independent populations

BACKGROUND: The inflammatory functions of complement component 5 (C5) are mediated by its receptor, C5R1, which is expressed on bronchial, epithelial, vascular endothelial and smooth muscle cells. A susceptibility locus for murine allergen-induced airway hyper-responsiveness was identified in a region syntenic to human chromosome 19q13, where linkage to asthma has been demonstrated and where the gene encoding C5R1 is localized. OBJECTIVE: The aim of this study was to screen for novel polymorphisms in the C5R1 gene and to determine whether any identified polymorphisms are associated with asthma and/or atopy and whether they are functional. METHODS: Single-nucleotide polymorphism (SNP) detection in the gene encoding C5R1 was performed by direct sequencing. Genotyping was performed in three populations characterized for asthma and/or atopy: (1) 823 German children from The Multicenter Allergy Study; (2) 146 individuals from Tangier Island, Virginia, a Caucasian isolate; and (3) asthma case-parent trios selected from 134 families (N=783) in Barbados. Functional studies were performed to evaluate differences between the wild-type and the variant alleles. RESULTS: We identified a novel SNP in the promoter region of C5R1 at position -245 (T/C). Frequency of the -245C allele was similar in the German (31.5%) and Tangier Island (36.3%) populations, but higher in the Afro-Caribbean population (53.0%; P=0.0039 to <0.0001). We observed no significant associations between the -245 polymorphism and asthma or atopy phenotypes. Upon examination of the functional consequences of the -245T/C polymorphism, we did not observe any change in promoter activity. CONCLUSION: This new marker may provide a valuable tool to assess the risk for C5a-associated disorders, but it does not appear to be associated with asthma and/or atopy.     

Association between asthma and an intragenic variant of CC16 on chromosome 11q13

The β subunit of high affinity immunoglobulin E (IgE) receptor (FcɛRIβ) and the Clara cell derived inflammatory molecule, CC16 have been cited as candidate genes for atopic asthma on chromosome 11q13. A genetic association study was performed with an intragenic microsatellite repeat of CC16 gene on chromosome 11q12–13 in relation to atopic and non-atopic asthma. Whereas variants of FcɛRIβ at chromosome 11q13 show association with atopy and asthma, no significant association was found between asthma and CC16 genotypes irrespective of atopic status. These data support the candidacy of FcɛRIβ rather than CC16 for the atopic asthma locus on chromosome 11q.     

The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma

BACKGROUND: The cysteinyl-leukotriene receptor type 1 (CysLT1) mediates the bronchoconstrictor and pro-inflammatory actions of cysteinyl-leukotrienes (LTC4, LTD4, LTE4) in asthma and is the molecular target of the lukast class of oral anti-leukotriene drugs. We screened the CYSLTR1 gene on chromosome Xq13-21 for coding region polymorphisms, and investigated their associations with allergy and asthma. METHODS: Solid-phase chemical cleavage was used to screen polymorphisms in the coding region of CYSLTR1. A TaqMan allelic discrimination assay was used to genotype a 927T/C SNP and oligonucleotide ligation assays were used to genotype the previously reported 617T/C and 898G/A SNPs of CYSLTR1 in 341 asthmatic families from the UK. Associations with asthma diagnosis, atopic status, serum-specific IgE and severity of allergy and asthma were examined. RESULTS: Family-based association tests showed that the 927 T allele was associated with atopy severity, especially in female subjects, but not with asthma diagnosis or severity, atopic status, bronchial hyper-responsiveness to methacholine or forced expiratory volume in 1 s. CONCLUSION: Mutation screening identified only one polymorphism, 927T/C, in the coding region of the CysLT1 receptor. This polymorphsim is predictive of atopy severity, but not associated with asthma.     

Cytomegalovirus DNA is highly prevalent in the blood of patients with asthma and is associated with age and asthma traits

Cytomegalovirus (CMV) IgG antibodies have been associated with inflammaging and immunosenescence. We aimed to assess the presence of CMV DNA in the blood of adult and elderly patients with bronchial asthma to establish potential association of CMV DNAemia with asthma and asthma characteristics. Eighty‐five elderly asthmatics, 74 younger asthma patients, and 114 age‐matched controls were recruited. The CMV DNA was detected using commercial artus assay in 10.7% of asthma patients, but was negative in all control individuals. The secondary assay identified CMV DNA in 41.5% of asthmatics and 13.3% of control subjects (P < .001). Presence of CMV DNA was associated with an increased risk of asthma and CMV DNA copy numbers correlated with some asthma traits, including respiratory parameters and exhaled breath nitric oxide. We conclude that CMV infection is associated with asthma and may contribute to the pathogenesis of asthmatic inflammation.     

Factors associated with severity of occupational asthma with a latency period at diagnosis

BACKGROUND: Severity of occupational asthma at diagnosis is an important prognostic factor. The aim of this study was to determine which factors affect the severity of occupational asthma with a latency period at diagnosis. METHODS: The study population consisted of 229 consecutive subjects with occupational asthma with a latency period recruited by four occupational health departments and divided into two groups according to the severity of the disease at diagnosis. The moderate-severe (FEV(1) <70% predicted, or PD(20) methacholine /=70% predicted and PD(20) methacholine >300 microg, n = 128) groups were compared in terms of clinical and demographic parameters. Multivariate analysis using logistic regressions was performed to examine factors associated with asthma severity. RESULTS: Duration of symptoms before diagnosis was significantly longer in the moderate-severe group (mean +/- SD: 6.3 +/- 6.8 years vs 3.4 +/- 4.4 years, P < 0.001). Sex ratio, age, atopy, smoking habits, duration of exposure before symptoms, and molecular weight of the causal agent were not significantly different between the two groups. On multivariate analysis, only duration of symptoms before diagnosis was associated with asthma severity (aOR = 1.12, 95% CI 1.05-1.18, P < 0.001). CONCLUSIONS: Severity of occupational asthma with a latency period at diagnosis was associated with duration of symptoms before diagnosis, but not with the type of causal agent. This finding emphasizes the need for early diagnosis and avoidance of exposure.     

Early exposure to dichlorodiphenyldichloroethylene, breastfeeding and asthma at age six

Our aims were to assess association of dichlorodiphenyldichloroethylene (DDE) with childhood asthma measured up to age 6 and the effect of DDE on the protective effect of breastfeeding on asthma. In addition, we attempted to assess the relevant time-window of DDE exposure (i.e. at birth or at 4 years). All women presenting for antenatal care in Menorca, Spain over a 12-month period beginning in mid-1997 were invited to take part in a longitudinal study that included a yearly visit. Four hundred eighty-two children were enrolled and 462 provided complete outcome data after 6.5 years of follow-up. Organochlorine compounds were measured in cord serum of 402 (83%) infants and in blood samples of 285 children aged 4. We defined asthma as the presence of wheezing at age 6 and during any preceding year or doctor-diagnosed asthma, and used skin prick test at age 6 to determine atopic status. Results At birth and 4 years of age, all children had detectable levels of DDE (median 1 ng/mL and 0.8 ng/mL, respectively). From birth to age 4, the mean DDE level among children with artificial feeding decreased by 72%, while among breastfed children it increased by 53%. Diagnosed asthma and persistent wheezing were associated with DDE at birth [odds ratio (OR) for an increase in 1 ng/mL, OR=1.18, 95% confidence interval (95% CI)=1.01-1.39 and OR=1.13, 95% CI=0.98-1.30, respectively], but not with DDE at 4 years. Neither breastfeeding nor atopy modified these associations (P>0.3). Breastfeeding protected against diagnosed asthma (OR=0.33, 95% CI=0.08-0.87) and wheezing (OR=0.53, 95% CI=0.34-0.82) in children with low and high DDE levels at birth. Conclusion In a community without known dichlorodiphenyltrichloroethane environmental releases, this study strengthens the evidence for an effect of DDE on asthma by measuring the disease at age 6 and does not support the hypothesis that DDE modifies the protective effect of breastfeeding on asthma.     

Associations between interleukin 17A and 17F polymorphisms and asthma susceptibility: A meta-analysis

Owing to their role in inflammatory reactions and immunological responses as well as their chromosomal location, interleukin (IL) 17A and 17F are regarded as candidate causal genes associated with asthma. The aim of this study was to determine whether IL17 polymorphisms are associated with susceptibility to asthma. We used the PubMed/Medline and Embase databases to search for studies reporting IL17 polymorphisms in patients with asthma and healthy controls. Meta-analyses were conducted to determine the associations between IL17A rs8193036 (−737C/T), rs2275913 (−197G/A), rs3819024 (A/G), rs3748067 (C/T), and rs4711998 (A/G) and IL17F rs763780 (7488A/G), rs2397084 (T/C), rs1889570 (C/T), rs11465553 (G/A), and rs1266828 (T/C) polymorphisms and asthma susceptibility. A total of 20 studies were included in this meta-analysis. Our results revealed the IL17A rs8193036 CC genotype was associated with asthma susceptibility (odds ratio [OR] = 1.490, 95% confidence interval [CI] = 1.027–2.161, p = .036). However, stratification by ethnicity indicated no association between this polymorphism and asthma in European and Asian subjects. Furthermore, no association was found between this polymorphism and asthma using the allele contrast, dominant or homozygous contrast models. No evidence of an association was found between any of the other IL17A and IL17F polymorphisms and asthma susceptibility in this meta-analysis. This meta-analysis showed that, among the studied polymorphisms, only the CC genotype of IL17A rs8193036 is associated with asthma susceptibility.