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Abstract Background Asthma is a complex phenotype that is influenced by both genetic and environmental factors. Genome-wide linkage and association studies have been performed to identify susceptibility genes for asthma. These studies identified new genes and pathways implicated in this disease, many of which were previously unknown. Objective To perform a large-scale genotyping study to identify asthma-susceptibility genes in the Japanese population. Methods We performed a large-scale, three-stage association study on 288 atopic asthmatics and 1032 controls, by using multiplex PCR-Invader assay methods at 82,935 single nucleotide polymorphisms (SNPs) (1st stage). SNPs that were strongly associated with asthma were further genotyped in samples from asthmatic families (216 families, 762 members, 2nd stage), 541 independent patients, and 744 controls (3rd stage). Results SNPs located in the 5' region of PEX19 (rs2820421) were significantly associated with P < 0.05 through the 1st to the 3rd stage analyses; however, the P values did not reach statistically significant levels (combined, P = 3.8 × 10-5; statistically significant levels with Bonferroni correction, P = 6.57 × 10-7). SNPs on HPCAL1 (rs3771140) and on IL18R1 (rs3213733) were associated with asthma in the 1st and 2nd stage analyses, but the associations were not observed in the 3rd stage analysis. Conclusion No association attained genome-wide significance, but several loci for possible association emerged. Future studies are required to validate these results for the prevention and treatment of asthma.

Pharmacologic studies have revealed that cysteinyl leukotrienes (CYSLTs) act through two receptors, cysteinyl leukotriene receptor 1 (CYSLTR1) and CYSLTR2. CYSLTR1 antagonists are widely used to treat asthma and rhinitis. In this study, we characterized the genomic structure and transcriptional regulation of CYSLTR1 and examined associations between CYSLTR1 polymorphisms and asthma/rhinitis. The experiment of rapid amplification of cDNA end revealed that CYSLTR1 contains three exons and that the entire open reading frame is located in exon 3. Reverse transcriptase-polymerase chain reaction showed that there were multiple splice variants of CYSLTR1 and that the transcript expression patterns differed from tissues and cell types. The promoter region of CYSLTR1 is from −665 to −30 bp relative to the transcription start site. We identified four polymorphisms (c.-618-434T/C, c.-618-275C/A, c.-618-136G/A, and 927C/T), and transmission disequilibrium tests revealed that none of these polymorphisms was associated with the development of asthma/rhinitis. However, the TCG and CAA haplotypes in the promoter region caused different transcriptional activity. Our findings indicate that CYSLTR1 polymorphisms are not likely to be involved in the development of asthma/rhinitis, but it is possible that these polymorphisms could influence drug responses in individuals with atopic diseases. [ABSTRACT FROM AUTHOR]

Chromosome 13 contains several candidate genes for asthma and atopy, and markers on this chromosome have been shown to be linked to phenotypes of atopy or asthma in two genome-wide searches. We conducted a linkage study for atopic asthma using markers spanning the whole of chromosome 13 in Japanese families ascertained through asthmatic children and examined associations of atopic asthma with markers where linkage was suggested. Data were analysed using MAPMAKER/SIBS for the multipoint lod score (MLS) analysis and SIB-PAIR for the transmission dis-equilibrium test (TDT). Three peaks which exceeded a lod score of 1.0 were observed (MLS 2.4 between D13S175 and D13S217, MLS 2.0 between D13S153 and D13S156, and MLS 1.4 between D13S285 and D13S293). The global TDT for atopic asthma was significant for the marker D13S153 (P = 0.0065) and the 96 bp allele of D13S153 was preferentially transmitted to atopic asthma-affected children (P = 0.0009, Bonferroni cor-rection 5% = 0.0037, 1% = 0.00072). These findings indicate that genes on chromosome 13 may play an important role in the development of atopy or asthma across various populations. [ABSTRACT FROM AUTHOR]

Abstract Platelet-activating factor (PAF), which has been implicated in the pathophysiology of inflammation in asthma, is degraded and inactivated by PAF acetylhy-drolase (PAFAH). Approximately 4% of the Japanese population lacks plasma PAFAH due to a loss-of-function variant (Val279Phe) in the PAFAH gene. Although lack of PAFAH activity is thought to be a risk factor for asthma, there are conflicting findings concerning association be-tween the Val279Phe variant and asthma. In this study, we conducted transmission disequilibrium tests of 118 Japanese parent-child trios identified through mite-sensi-tive atopic asthmatic children. A case-control study was also carried out. The Phe279/Phe279 genotype was found more frequently in children with atopic asthma (13%) than in their parents (6%) or in controls (4%). Results of the geno-typic transmission test were significant, and the Phe279/ Phe279 genotype was transmitted preferentially to asth-matic children. Our data support an association between deficiency in PAFAH activity and atopic asthma. Key words Asthma · Association · Genetic polymorphism · Platelet-activating factor acetylhydrolase · Transmission disequilibrium test. [ABSTRACT FROM AUTHOR]