| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Understanding of the genetic basis of complex human disease including bronchial asthma has been increasingly emphasized as a means of achieving insight into disease pathogenesis, including the severity of the disease. In this project, we selected several candidate genes which may affect the severity and clinical course of asthma. Genes studied includes the gene for the β-chain of the high affinity receptor for IgE (FcεRI-β) (11q13), β2-adrenergic receptor, plasminogen activator inhibitor 1(PAI1) (7q21), osteopontin, IL-17F and human muscarinic cholinergic receptor (CHRM1). Candidate gene association analyses were performed in a case-control setting using about 800 unrelated Japanese subjects. A case-control study showed that individuals homozygous for both the FcεRI/-β-109T allele and the PAI-1 5G allele had a reduced susceptibility to asthma; the odds ratio associated with the PAI-1 5G/5G genotype was 1.13 (p=0.72) in carriers of the FaRI-16-109C allele, and 0.21 (p=0.00023) in carrie
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rs of the FcεRI/-β-109T/T genotype. CHRM1 is widely distributed in the lungs. In patients with asthma, CHRM1 may be involved in airway constriction, airway epithelial cell proliferation, and airway inflammation. The CHRM1 gene is located on chromosome 11q13, which is one of the candidate loci for asthma and atopy. This study, together with an in vitro functional study, suggests that the CHRM1 gene is an important susceptibility locus for asthma on chromosomellq13. IL-17F is a recently discovered cytokine that plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. The current findings indicate that the IL-17F H161R variant influences the risk of asthma and is a natural IL-17F antagonist, suggesting a potential role for IL-17F in the etiology of asthma. Based on the current findings, future studies will focus on integrating the knowledge of genetic variations into the picture of molecular and cellular mechanisms underlying the severity of asthma, which will in turn facilitates the identification of patients with poor prognosis and the development of strategies for individualized medicine. Less
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