Jussi Karjalainen

Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and circulating immunoglobulin E in adult asthma.

Background IL‐10 has several functional effects relevant to asthma. It can modulate IgE production and induce apoptosis in eosinophils. Polymorphisms of IL‐10 gene have been shown to affect IL‐10 production.

Association of interferon-gamma +874(T/A) single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals.

Mechanisms induced by tryptophan (trp) catabolism are important in the regulation of both normal and pathogenetic immune responses. The key enzyme is indoleamine‐pyrrole 2,3‐dioxygenase (EC 1.13.11.42) (IDO) which converts trp to kynurenine (kyn), the main toxic metabolite. It is known that interferon‐gamma (IFN‐γ) is able to activate IDO. We wanted to analyse whether the strength of this mechanism would be under genetic control. To this end, we analysed the IFN‐γ+874(T/A) genotypes, which are known to have an effect on IFN‐γ production, of 309 healthy blood donors and correlated these to the levels of trp and kyn in their blood. The data obtained demonstrate that the presence of the high producer T allele was associated with increased IDO activity (i.e. elevated kyn and kyn/trp levels), but this effect was observed only in females. These data show that trp catabolism is genetically controlled by the IFN‐γ gene and may thus be operative in those disease conditions associated with the polymorphisms of the IFN‐γ gene.

Epistatic Effect of TLR4 and IL4 Genes on the Risk of Asthma in Females

Background: Many studies have demonstrated a connection between asthma and T-cell cytokine genes, such as genes coding for interleukin-4 (IL4) and IL-13, which are involved in the regulation of the TH1/TH2 balance. The toll-like receptor 4 (TLR4), the principal receptor for bacterial endotoxin, has attracted attention as a potential risk factor for asthma. We examined whether the polymorphisms of the TLR4 (A/G at +896) and IL4 (C/T at –590) showed an epistatic effect on the risk of asthma or atopy. Methods: Gene polymorphism analyses and skin prick tests were performed on asthmatic and nonasthmatic adult subjects of a Finnish population-based case-control study. The phenotype studied was persistent asthma. Results: The results showed that genotypes of neither the TLR4 SNP at +896 nor IL4 SNP at –590 were separately found to be associated with asthma. However, the female carriers of allele G (i.e. genotype AG or GG) of TLR4 and allele T (genotype CT or TT) of IL4 had a significantly increased risk for asthma. No association of these genes and atopy was found. Conclusions: Our results indicate that in females the TLR4 and IL4 genes show an epistatic effect on the risk of asthma. The low LPS-responsive allele G of TLR4 and high IgE production allele T of IL4 were found to be the predisposing combination. However, there was no epistatic effect on the risk of atopy.

The IL1A genotype is associated with nasal polyposis in asthmatic adults

Background: Nasal polyposis (NP) is a chronic inflammatory disease often found coexisting with asthma. As this disorder tends to cluster in families, a genetic predisposition has been suggested. Interleukin‐1 (IL‐1) has been proposed to play a role in the pathogenesis of NP.

Genetic and Environmental Factors in the Immunopathogenesis of Atopy: Interaction of Helicobacter pylori Infection and IL4 Genetics

Background: Both genetic and environmental factors, e.g. early childhood infections, have a role in the pathogenesis of atopic diseases. Objective: To examine simultaneously the strength and possible interactions of two known such factors, IL4 genetics and Helicobacter pylori infection, on the risk of atopy and asthma. Methods: Gene polymorphism analyses and skin prick tests (SPT) were determinedin 245 adult asthmatics and 405 nonasthmatic controls of population-based case-control study. SPTs were used as an indicator of atopy. H. pylori infection was verified by detecting anti-H. pylori IgG antibodies in sera. Results: A significant negative association was seen between the presence H. pylori antibodies and SPT positivity (≧1 positive reactions) in both asthmatics and controls (p = 0.002 and p = 0.025, respectively) but the effect of IL-4 polymorphism (SNP –590C/T) was nonsignificant in both groups (p = 0.071 and p = 0.072, respectively). However, IL4 genetics had an effect on susceptibility to H. pylori: asthmatics carrying the IL4 –590 allele T had a diminished risk to be H. pylori infected (OR 0.485 95%CI 0.287–0.819). This effect was not seen in controls. Logistic regression analysis indicated that H. pylori and IL4 effects on atopy risk are not interdependent. Conclusions: This study showed that the effect of H. pylori infection on atopy risk is stronger than that of IL4 genetics. There is no interaction between these factors on the pathogenesis of atopy suggesting that these factors have distinct immunopathogenetic mechanisms. However, the genetic effect may modify the role of infective agents by effecting on susceptibility to disease.

Mannose-binding lectin 2 (MBL2) gene polymorphism in asthma and atopy among adults.

Mannose‐binding lectin (MBL) insufficiency due to polymorphisms in the MBL2 gene causes an opsonization defect, which has been connected to infections and atopy. We investigated the significance of MBL2 genotypes with regard to persistent asthma and atopy among adults. The genotypes were determined in 243 adults with persistent asthma and 400 controls. Atopy was determined by skin‐prick test. As a result, the carriage of −221 base pairs (bp) promoter region variant allele X (nucleotide change G→C; alleles Y→X, respectively) causing low MBL expression proved to be a significant risk factor for asthma in non‐atopic males [odds ratio (OR) = 2·52, 95% confidence interval (CI) = 1·23–5·15; P = 0·01]. Furthermore, the X‐allele carriage was associated with the decrease in lung function (forced expiratory volume at 1 s, FEV1) during follow‐up in the patients with asthma (P = 0·033), the effect being strongest for non‐atopic asthmatics (P = 0·042). The MBL2 genotype had no clear effect on the occurrence of atopy in adults. In conclusion, our results abrogate the previously suggested predisposing effect of MBL insufficiency on atopy at least in adults. However, as MBL is a complement component participating in immune defence against microbes, and as in the pathogenesis of non‐atopic asthma infectious agents are probably involved, the gene–environment interactions between MBL and infections should be assessed further with regard to asthma.

Allergic rhinitis and polymorphisms of the interleukin 1 gene complex.

BACKGROUND Allergic rhinitis is a chronic inflammatory disease with a genetic background. Inflammatory reactions are regulated by cytokines. Cytokine genes are polymorphic and have been implicated as candidate genes in allergy. OBJECTIVES To study the significance of the interleukin 1 (IL-1) gene complex in allergic rhinitis. METHODS Population-based, cross-sectional study. We studied the polymorphisms of 3 IL-1 gene complex genes, IL1A (+4845G>T), IL1B (-511 degrees C>T), and IL1RN (variable number of tandem repeats; IVS2, 86 bp, duplicates 2 to 5), in patients with allergic rhinitis. The study group consisted of 405 nonasthmatic individuals of whom 56 had allergic rhinitis. RESULTS The genotype distribution differed significantly in all cytokine genes studied between subjects with and without allergic rhinitis. The difference was mainly due to an increased number of IL1A allele G homozygotes (67.9% vs 43.2%; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.5-5.1), IL1B heterozygotes (72.2% vs 47.4%; OR, 2.8; 95% CI, 1.5-5.3), and IL1RN allele 2 homozygotes (18.5% vs 7.5%; OR, 2.8; 95% CI, 1.3-6.2) in allergic rhinitis. Haplotype analysis revealed a significant difference in the distribution of IL-1 gene complex haplotypes between subjects with and without allergic rhinitis (P = 0.005, 10 df). CONCLUSIONS The IL-1 gene complex polymorphism is strongly associated with allergic rhinitis in nonasthmatic individuals.

Sensitization pattern affects the asthma risk in Finnish adult population

There is a large global variation in the sensitization pattern and its association with allergic diseases. In temperate and tropical urban environments, mite monosensitization can be the predominant cause of allergic airway diseases, whereas in other environments, polysensitization is more typical. Sensitization to mite allergens associates with asthma. However, it is suggested that mite sensitization might play a minor role in Northern Europe. The aim of the study was to analyze how sensitization pattern affects the asthma risk in Finnish adults, with a special focus on mites.

Hospitalizations due to allergic reactions in Finnish and Swedish children during 1999–2011

Several authors have reported on allergic reactions that resulted in presentation to the emergency department. However, studies of the secular trend of hospitalizations for paediatric allergic reactions, including anaphylaxis, are scarce. The aim of this study was to describe the secular trends of hospitalizations for allergic reactions, including anaphylaxis, among children aged 0–19 years in Finland and Sweden, and to establish the trend of prescribed epinephrine auto‐injectors (EAI) among paediatric populations.

Indoleamine 2,3-dioxygenase expression is associated with chronic rhinosinusitis with nasal polyps and antrochoanal polyps.

Chronic rhinosinusitis without and with nasal polyps (CRSwNP and CRSsNP), and antrochoanal polyps are different phenotypes with different pathomechanisms. Indoleamine 2,3-dioxygenase (IDO) is an enzyme expressed in many cells involved in the catabolism of the essential amino acid tryptophan to kynurenine. IDO might have a role in allergic airway inflammation. The aim was to evaluate if IDO expression is associated with CRSsNP, CRSwNP, or ACP. One hundred fifty specimens from the nasal cavity and sinus mucosa were immunohistochemically stained with mAb anti-IDO. The expression of epithelial and leukocyte IDO was associated with CRSwNP and ACP. The presence of ASA intolerance, asthma, atopy, smoking and use of medication did not significantly change the results. The different expression of IDO could putatively indicate the differences in the pathomechanisms of CRSsNP, CRSwNP and ACP. Further studies on the role of IDO in upper airways pathologies are required.