Masanao Shibasaki

An association study of asthma and total serum immunoglobin E levels for Toll‐like receptor polymorphisms in a Japanese population

Background The prevalence of atopic diseases has been increasing in developed countries. This could be explained by the hygiene hypothesis, which states that exposure to specific infections or endotoxins during infancy drives the maturing immune system towards a Th1 phenotype and away from the Th2 phenotype, which is associated with allergic diseases. Toll‐like receptors (TLRs) play important roles in the signalling of many pathogen‐related molecules and endogenous proteins associated with immune activation.

Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese

Atopy, which is characterized by increased levels of immunoglobulin E (IgE) against common environmental allergens, is considered the strongest predisposing factor for asthma and atopic dermatitis (AD). Mutations in the gene encoding serine protease inhibitor Kazal-type 5 (SPINK5) are responsible for Netherton syndrome, a rare skin disorder characterized by greatly elevated IgE levels with atopic manifestations. A recent study of Caucasian AD families showed that maternally derived alleles of the SPINK5 gene are associated with development of AD and asthma, suggesting the parent-of-origin effect for the development of atopic diseases in the SPINK5 gene. We studied the possible association of the SPINK5 gene for the development of atopic diseases by determining the genotypes of five polymorphisms in a Japanese population. Ttransmission disequilibrium tests revealed an association of SPINK5 polymorphisms with AD but not with asthma. Our data indicate that the SPINK5 gene is associated with AD across ethnicities.

An association between asthma and TNF-308G/A polymorphism: meta-analysis

AbstractTumor necrosis factor (TNF) is a potent inflammatory cytokine that contributes to airway inflammation in asthma. Previous studies have reported that a G-to-A transition at position −308 (−308G/A, also referred to as TNF-α-308*1 and 308*2 respectively), is associated with asthma, but other studies have shown conflicting results. To investigate a possible association between the TNF-308G/A polymorphism and asthma, we performed transmission disequilibrium tests and a case-control study (family samples: 495 members in 165 Japanese trio families with one asthmatic child and both parents; case-control samples: 461 Japanese asthmatic children and 465 healthy controls). To increase the sample size and power, we performed a meta-analysis of all available relevant studies, including 2,477 asthmatics and 3,217 controls. We did not find a significant association between the TNF-308G/A polymorphism and childhood atopic asthma in two independent Japanese populations (P>0.05); however, meta-analysis revealed that the TNF-308G/A polymorphism was statistically significantly associated with asthma. The combined odds ratio with a fixed effects model and with a random effects for TNF-308A was 1.46 (95% confidence interval [CI], 1.27-1.68, P=0.0000001) and 1.46 (95% CI, 1.20-1.77, P=0.00014) respectively. Our data further support the importance of the TNF region in the development of asthma.

ADAM33 polymorphisms are associated with asthma susceptibility in a Japanese population.

Background Asthma is the most common chronic disorder in childhood, and asthma exacerbation is an important cause of childhood morbidity and hospitalization. Asthma is believed to be a complex disorder involving genetic and environmental factors, and several asthma susceptibility loci have been identified through genome‐wide screening. A disintegrin and metalloprotease 33 (ADAM33) was the first asthma susceptibility gene to be discovered by positional cloning in 2002.

A genome-wide linkage analysis of orchard grass- sensitive childhood seasonal allergic rhinitis in Japanese families

Seasonal allergic rhinitis (SAR) is an inflammatory disease of the nose and eyes that follows sensitization to air-born pollens. We conducted a genome-wide linkage screening of 48 Japanese families (188 members) with orchard grass (OG)-sensitive SAR children (67 affected sib-pairs) in a farming community in central Japan where OG was planted for apple farming and OG pollen is a major cause of SAR. We used the GENEHUNTER program to performed nonparametric multipoint linkage analysis for OG-sensitive SAR as a qualitative trait and for log total serum IgE levels and OG-RAST IgE levels as quantitative traits. Genotyping data of 400 microsatellite markers suggested linkage of SAR to chromosomes 1p36.2, 4q13.3, and 9q34.3 (P < 0.001), linkage of serum total IgE levels to 3p24.1, 5q33.1, 12p13.1, and 12q24.2 (P < 0.001), and linkage of OG-RAST IgE levels to 4p16.1, 11q14.3, and 16p12.3 (P < 0.001). Weak evidence for linkage of SAR to 5q33.1 was also observed (P = 0.01). All these regions, with the exception of 9q34.3, have been previously reported to be linked to asthma and/or atopy. These data suggest that, although loci linked to SAR are likely to be common to asthma, a strong contribution by specific gene(s) to OG-sensitive SAR is unlikely.

Insertion/deletion coding polymorphisms in hHAVcr-1 are not associated with atopic asthma in the Japanese population

Hepatitis A virus receptor (HAVcr-1) and T-cell immunoglobulin- and mucin-domain-containing molecule (TIM)-3 were recently implicated as asthma susceptibility genes in the study of congenic mice. In a genome-wide screen, we found strong evidence for linkage of atopic asthma with marker D5S820, located approximately 0.5 Mb from hHAVcr-1 and human TIM3. We screened for mutations in human HAVcr-1 (hHAVcr-1) and in TIM3 and found seven, including two insertion/deletion polymorphisms, in hHAVcr-1 and two in TIM3. We conducted transmission disequilibrium tests (TDTs) in families identified through children with atopic asthma. None of the hHAVcr-1 allele were transmitted preferentially to asthma-affected children (P>0.1). In quantitative TDT analysis, no association was observed between the log[total IgE] and either allele of the hHAVcr-1 polymorphism (P>0.1). The two TIM3 mutations were rare in the Japanese population, occurring in only one of 48 unrelated asthmatic subjects. Our results indicate that hHAVcr-1 polymorphisms are not likely to be associated with the development of atopy-related phenotypes in the Japanese population.

Expression profiling of genes related to asthma exacerbations

Background Asthma is a chronic airway inflammatory disease; however, the molecular mechanisms that underlie asthma exacerbation are only partially understood.

Relation between frequency of asthma and IgE antibody levels against Dermatophagoides farinae and total serum IgE levels in schoolchildren

The relation between the frequency of wheezing illness and IgE antibody levels against Dermatophagoides farinae (Df) and total IgE levels was examined in 457 randomly selected schoolchildren. From the response to the ATS-DLD-78-C respiratory symptoms questionnaire, 14 subjects (3.1%) were found to have asthma syndrome (recurrent episodes of attacks of shortness of breath with wheezing) and 17 subjects (3.7%), wheezing syndrome (only wheezing). The percentage of the asthma syndrome increased with increasing levels of Df-specific IgE, and there was an intimate correlation between the percentage of asthma syndrome and Df-specific IgE levels (r = 0.97; p less than 0.001), whereas such association was not found between the two (r = -0.19; p greater than 0.5). Similar relations were found between the frequencies of the specific syndromes and total IgE levels. There was a significant correlation between total IgE levels and Df-specific IgE levels in the total population (r = 0.7; p less than 0.001). These results suggest that allergic reaction greatly contributes to the development of asthma in children.

ADRB2 Polymorphisms and Asthma Susceptibility: Transmission Disequilibrium Test and Meta-Analysis

Background: The β2-adrenergic receptor (ADRB2) is the most common adrenergic receptor in the lung, and associations between ADRB2 polymorphisms and intermediate phenotypes of asthma have been reported. Four missense polymorphisms (Arg16Gly, Gln27Glu, Val34Met, and Thr164Ile) and one polymorphism in the 5′ leader cistron of the ADRB2 messenger RNA has been identified. In vitro studies have shown that these missense polymorphisms can affect ADRB2 function. Methods: To examine possible associations of ADRB2 polymorphisms with asthma susceptibility, we performed transmission disequilibrium tests (TDT) of 137 Japanese families identified through children with atopic asthma. Results: We did not find associations between any alleles of the ADRB2 polymorphisms and asthma by TDT (p > 0.1). We also performed a meta-analysis of data from all available studies. The random-effects model showed no significant odds ratio for the Arg16Gln (odds ratio = 1.05, p = 0.53) or Gln27Glu (odds ratio = 1.12, p = 0.22) polymorphism. Conclusion: Our data indicate that ADRB2 does not contribute substantially to susceptibility to asthma, but it is possible that these polymorphisms influence disease activity and drug responses in individuals with asthma.

Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan.

Background The tumour necrosis factor (TNF) gene family, which includes TNF, LTA, and LTB, is located consecutively on human chromosome 6p21 region, which has been linked to asthma by several genome‐wide screens. (LTA, lymphotoxin‐α; LTB, lymphotoxin‐β).