Study On The Polymorphisms Of Childhood Asthma Gene TIM Family And Relative Factors

Background:Asthma is the most common chronic respiratory allergic disease in childhood, and in recent years its prevalence has increased worldwide [1' 2]. Asthma is a complex disease of multifactorial etiologies including environmental factors and an obvious genetic element [3]. Prevalence of asthma reported in various countries and regions have great differences.Mclntire et al. [4] discovered a Tapr (T cell and airway phenotype regulator) on mouse chromosome 11, which can regulate the T cell and airway phenotype, and found a novel gene TIM (T cell immunoglobulin domain and mucin domain) family. TIM-1, TIM-2, and TIM-3 were found to be members of the TIM gene family located on chromosome 5q33.2 [5"7]. This is also one of the major genetic susceptibility sites for asthma. TIM protein is a type I transmembrane protein encoded by the TIM gene, including an N-terminal Ig V region (IgV) domain, a mucin-like domain, a transmembrane domain, and a cytoplasmic tail with a phosphorylation motif [8]. The TIM gene family plays a critical role in the development of allergic disorders such as asthma and autoimmune diseases [9]. TIM-1, the first molecule in the TIM family and the most important one, was first found in renal cells of the African Green Monkey [10]. In subsequent studies, it was confirmed to be the same molecule as the human hepatitis A virus receptor, hHAVcr-l[11], and the kidney injury molecule 1 (KIM-1)[12]. TIM-1 is selectively expressed on activated CD4+T cell surfaces, especially on Th2 cells, and regulates the Th2-type cell-mediated immune response (4, 6). It also has an effect on macrophages involved in local inflammation [13]. TIM-3 molecules are expressed mainly on the surfaces of Thl cells causing a negative effect on the regulation of those cells [14' 15] As the natural ligand of TIM-1, TIM-4 is exclusively expressed on the surface of antigen-presenting cells such as macrophages and dendritic cells. After binding to TIM-1, it sTIMulates the proliferation and differentiation of Th2 cells [16' 17l Therefore, the human TIM gene family is critical to Thl/Th2-mediated immunological regulation (5).Objective: To study the related factors of children with asthma in southwest Chongqing, to prevention and treatment of asthma in children in the region. To analyze the association of TIM-1 polymorphism and HAV infection ,TIM-4 polymorphism with childhood allergic asthma in southwest China.Methods: Four hundred and thirteen (413) cases asthma patients were admitted from out-patient paediatric department of southwest hospital of third military medical university during June 2007 to Dec 2010. Four hundred and tweenty 420 cases children as control group were from outpatients of our hospital, children in kindergarten or primary school who accept physical examination.A total of 549 children whom were suspected to have asthma were selected, between 2007 and 201 O.They were examined with the skin prick test ( SPT), serum total IgE (TIgE ) test and eosinophil count (EOS). According the clinical symptom and pulmonary function tests, three hundred and fivty eight (358) cases had been diagnosed, and the other 191 cases were consist of respiratory tract infection, pneumonia, eczema, hives, chronic cough (not cough variant asthma), allergic rhinitis, bronchi, tuberculosis and so on. Sensitivity, specificity, and accuracy of SPT, TIgE and EOS were compared using receiver operator characteristic curve (ROC) analysis, and the cut off points of TIgE and EOS is 88 IU/ml and 288x106/L.TIM-1 exon 4 (157insMTTTVP) and two polymorphism loci, -416G>C, -1454G>A at promoter region were selected; TIM-4 two polymorphism loci, rs6882076 at promoter region and rs4704727 at intron region were selected. Polymerase chain reaction was adopted to test the genotype of three polymorphism loci of 579 cases in asthma group (with average age of 7.2) and 524 cases in control group (with average age of 7.6), and FIAV infection status was also detected for case-control study and stratified analysis.Results: Total 10 factors were investigated and analyzed by Logistic regression analysis. Two factors were excluded and 8 factors were included in the end. There were 6 risk factors and 2 protective factors. High risk factor were heredofamilial of asthma, idiosyncratic physique, skin prick test (SPT) positive and high totle IgE. Protective factors included breastfeeding and HAV exposure.By non-parametric methods, the areas under ROC curves of SPT, TIgE and EOS respectively 0.806 (95% CI 0.766—0.847) ,0.827 (95% CI 0.793—0.862) and 0.699 (95% CI 0.655—0.744) in the childhood asthma diagnostic tests. The sensitivity, specificity, accuracy, positive and negative predictive values for the diagnosis of children asthma by SPT, TIgE , EOS, parallel tests TIgE plus SPT and serial tests TIgE plus SPT were 87.5%, 71.8%, 81.6%, 83.8%, 77.5%; 85.5%, 64.7%, 77.2%, 77.9%, 75.9%; 77.5%, 46.8%, 61.9%, 58.7%, 68.1%; 81.4%, 75.2%,79.6%, 89.1%, 61.8%; 94.2%, 64.1%, 79.2%, 72.6%, 91.6% respectively.HAV exposure level in asthma group was significantly different from that in control group, we found that HAV exposure level is associated with childhood allergic asthma susceptibility in our study population (OR=5.529, 3.850-7.939, P=0.000). -416G>C was related with asthma susceptibility (P=0.002 , OR=1.384, 95%CI 1.148-1.669), but the insertion variant 157delMTTTVP of exon 4 and -1454G>A were not related with asthma. rs4704727 of TIM-4 gene at intron region is associated with childhood allergic asthma susceptibility (P < 0.00, OR=1.603, 95%CI 1.304-1.971), but rs6882076 was not related with asthma.Conclusion: Genetic factors and environmental factors are closely related to the development of asthma in children. The atopic constitution was a risk factor of asthma. Protective factors included breastfeeding and HAV exposure.The sensitivity, specificity, accuracy, positive and negative predict value of TIgE is closely related to SPT and preferably to EOS. Both parallel tests and serial tests TIgE plus SPT are better than the other method in our study. The combined detection of TIgE and SPT is one of important value methods in the diagnosis efficacy of childhood asthma.-416G>C of TIM-1 gene is associated with childhood allergic asthma susceptibility, but it is not related with HAV infection. rs4704727 of TIM-4 gene at intron region is associated with childhood allergic asthma susceptibility, but rs6882076 at promoter region is not related with childhood allergic asthma susceptibility.