| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
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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, with the ultimate goal of improving preventive strategies, diagnostic tools, and therapies. For case-control genetic association studies, the biologic plausibility of a candidate gene is important. In this project, we selected several candidate genes based on the published database of the gene expression profiles of human asthmatic airways. Genes studied includes the gene for the β-chain of the high affinity receptor for IgE (FcεRI-β)(11q13), macrophage migration inhibitory factor (MIF) (22q11) and plasminogen activator inhibitor 1(PAI1)(7q21). Candidate gene association analyzes were performed in a case-control setting using about 800 unrelated Japanese subjects. MIF is a pleiotrophic lymphocyte and macrophage cytokine ; it is likely to play an important role in innate immunity. Evidence for significant assoc
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iation between the -173G/C and -794[CATT]_<5-8> repeat polymorphisms and atopy was found ; OR for homozygotes of -173C allele was 3.67, and OR for non-carriers of the -794[5-CATT] allele was 3.51 (compared to 5-CATT repeat homozygotes, 95% CI=1.82-6.78, p<0.0005). We previously detected a promoter polymorphism (-109C/T) in the FcεRI-β, which was associated with total serum IgE levels, but not with asthma. A case-control study using 748 Japanese 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 1.14 (p=0.67) in carriers of the FcεRI-β -109C allele, and 0.29 (p=0.0020) in carriers of the FcεRI-β-109T/T genotype. These results indicate that polymorphisms in the MIF promoter region are risk factors for atopy and implicate MIF in the pathogenesis of atopy in Japanese, and also suggest a synergistic interaction between FcεRI-β and PAI-1 genes in asthma susceptibility. Less
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