The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

Changes in apolipoprotein B and oxidized low-density lipoprotein levels in gingival crevicular fluids as a result of periodontal tissue conditions.

BACKGROUND AND OBJECTIVE: Periodontal disease is a chronic inflammatory disease caused by bacterial infection that can lead to tooth loss. Gingival crevicular fluid can be collected easily and noninvasively. We previously discovered the presence of apolipoprotein B (apoB), the main constituent of low-density lipoprotein, and oxidized low-density lipoprotein (oxLDL) in the gingival crevicular fluid of healthy subjects. In this study, we investigated whether periodontal conditions affect the levels of apoB and oxLDL in gingival crevicular fluid. MATERIAL AND METHODS: The study population comprised 11 patients with chronic periodontitis. A pair of gingival crevicular fluid samples was collected from each patient at a healthy site and at a site with periodontitis (baseline samples). Thereafter, gingival crevicular fluid samples were collected from the same patients again at 4 and 8 wk after scaling and root planing (SRP). The levels of apoB, oxLDL, protein and cytokines in gingival crevicular fluid, in addition to gingival crevicular fluid volume, were measured. RESULTS: At baseline, the levels of apoB and oxLDL in gingival crevicular fluid were higher at the sites with periodontitis than at the healthy sites. The levels of apoB and oxLDL at periodontal sites decreased after SRP. The level of oxLDL in gingival crevicular fluid correlated well with the probing pocket depth. The oxLDL : apoB ratio in gingival crevicular fluid was significantly higher than that in plasma. CONCLUSIONS: The levels of apoB and oxLDL in gingival crevicular fluid change according to the periodontal tissue conditions.

A rare variant in CYP27A1 and its association with atopic dermatitis with high serum total IgE.

This study investigated rare variants associated with atopic dermatitis. We performed exome analyses on 37 patients who were diagnosed with atopic dermatitis by board-certified dermatologists and had total serum IgE levels greater than 1000 IU/ml. The exome analysis identified seven variants with <1% allele frequency in Asian (ASN) population of 1000 Genomes Project phase 1 data and >5% allele frequency in the atopic dermatitis exome samples. We then conducted a replication study using 469 atopic dermatitis patients with total serum IgE ≥1000 IU/ml and 935 Japanese controls to assess the presence of these 7 candidate variants. The replication study confirmed that CYP27A1 rs199691576 (A/G) was associated with atopic dermatitis with high serum IgE levels (P = 0.012, odds ratio = 2.1). CYP27A1 is involved in the metabolism of vitamin D3, which plays important roles in modulating immune function. Previous studies have reported polymorphisms in vitamin D pathway genes that are associated with allergy-related phenotypes. Our data confirm the importance of genes regulating the vitamin D pathway in the development of atopic dermatitis.

Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study.

BACKGROUND: Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS. METHODS: This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS. RESULTS: We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence. CONCLUSION: We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia.

Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30-50 mg m(-2) in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m(-2), P=0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population.

BACKGROUND: It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. OBJECTIVE: To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. METHODS: We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. RESULTS: In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. CONCLUSIONS: Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.

DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia.

We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.

Associations between decay-accelerating factor polymorphisms and allergic respiratory diseases.

BACKGROUND: Allergic diseases such as asthma and allergic rhinitis are major causes of morbidity in developed countries. The pathology underlying allergic respiratory diseases is considered to be IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. They are common diseases involving a complex inheritance. Complement systems are known to play an important role in allergic diseases. Decay-accelerating factor (DAF) is important for the regulation of the complement system and is a good candidate for determining the susceptibility to allergic diseases. OBJECTIVE: The present study aimed to investigate whether polymorphisms in the DAF gene are associated with allergic respiratory diseases in the Japanese population. METHODS: We performed mutation screenings of DAF and conducted a tag single-nucleotide polymorphisms (SNP) association analysis for 684 unrelated adult individuals with seasonal allergic rhinitis (SAR) with Japanese ceder pollen, 188 mite-sensitive adults with asthma, and 346 unrelated non-allergic healthy controls. RESULTS: DAF is located in the tight linkage disequilibrium (LD) block spanning 62 kb. The tag SNP analysis revealed that rs10746463 was significantly associated with SAR (P=0.00033) and mite-sensitive adult asthma (P=0.044). The rs2564978 and rs3841376 haplotypes, which are located in the promoter region of DAF, were in complete LD with rs10746463 (r2=1). Luciferase reporter assays with constructs containing the 5' flanking regions of DAF showed that the plasmid with rs2564978 C/rs3841376 deletion (the risk haplotype) had a statistically significantly lower transcriptional activity than that containing the rs2564978 T/rs3841376 insertion. CONCLUSIONS: Our results suggest that DAF is one of the genes involved in conferring susceptibility to allergic respiratory diseases and show that decreased levels of DAF may be associated with the enhanced specific IgE responses occurring in allergic diseases 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. OBJECTIVE: To identify gene expression signatures that reflect the acute exacerbation of asthma, we examined the differential expression of genes during asthma exacerbation and stable condition by using microarray analysis. METHODS: The subjects were mite-sensitive asthmatic children and non-asthmatic control children. The children were divided into four groups (AE: asthma exacerbation, n=12; SA: stable asthma, n=11; IC: infected control, n=6; and NC: non-infected control, n=5). Total RNA was extracted from peripheral blood mononuclear cells and subjected to microarray analysis with Illumina Human Ref8 BeadChip arrays. Welch's t-test was performed to identify genes whose expression was altered during asthma exacerbation. Quantitative real-time RT-PCR was performed on samples collected from 43 asthmatic children and 11 control children to verify the microarray results. RESULTS: The expression of 137/16 genes was significantly up/down-regulated during asthma exacerbation assessed by microarray analysis. Of the genes, 62 were also differentially expressed during upper respiratory infection. Many of the asthma exacerbation related genes were involved in defence responses and responses to external stimuli, but these associations disappeared after excluding the infection-related genes. Quantitative real-time RT-PCR confirmed that the genes related (S100A8 and GAS6) and unrelated to infections (CD200 and RBP7) were differentially expressed during asthma exacerbation (P<0.01). CONCLUSIONS: Previously unidentified immune responses during asthma exacerbation may provide further clarification of the molecular mechanisms underlying asthma.

Enhancement of methoxamine-induced contractile responses of rat ventricular muscle in streptozotocin-induced diabetes is associated with alpha1A adrenoceptor upregulation.

AIM: To clarify the time-related changes in cardiac function and the mechanism underlying the cardiac dysfunction present in diabetes mellitus, we studied mechanical responses induced by alpha(1)- and beta-adrenoceptors, the Ca(2+)-entry promoter Bay K 8644- and ryanodine (an agent known to inhibit Ca(2+) release from the sarcoplasmic reticulum) in papillary muscles from streptozotocin (STZ)-induced diabetic and age-matched control rats. METHODS: Male Wistar rats received a single injection of STZ (60 mg kg(-1)) via the tail vein to induce diabetes. For the mechanical studies, papillary muscle preparations were suspended in an organ bath and isometric contractions were measured in 1-, 4-, and 10-week STZ-induced diabetic and age-matched control rats. RESULTS: In 1-week diabetic rats, the contractions induced by isoproterenol, methoxamine and Bay K 8644 were unchanged (vs. age-matched controls). In 4-week diabetic rats, (a) the isoproterenol- and Bay K 8644-induced contractions were impaired, (b) sensitivity to ryanodine was reduced, whereas (c) the methoxamine-induced contraction was unchanged. In 10-week diabetic rats, the isoproterenol- and Bay K 8644-induced contractile responses were impaired and the sensitivity to ryanodine was reduced, but in sharp contrast the methoxamine-induced contraction was enhanced. Both the mRNA level for the alpha(1A) adrenoceptor (but not the alpha(1B) or alpha(1D) mRNAs) and alpha(1A) adrenoceptor protein were increased in 10-week diabetic rats (vs. age-matched controls). CONCLUSION: These results suggest that impairments of beta-adrenergic and Ca(2+)-handling mechanisms occur early in the development of cardiomyopathy in STZ-induced diabetic rats, and that this is followed by augmentation of alpha(1A) adrenoceptor-mediated inotropy due to alpha(1A) adrenoceptor upregulation.

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. OBJECTIVE: The aim of the present study was to investigate whether single-nucleotide polymorphisms (SNPs) in ADAM33 are associated with childhood asthma in the Japanese population. METHODS: Twenty-three ADAM33 SNPs were genotyped by fluorescence correlation spectroscopy with the use of DNA from 155 families (538 members) identified through children with atopic asthma. The transmission disequilibrium test (TDT) was performed for family-based association study. RESULTS: TDT revealed that minor alleles of S+1, ST+4, and T2 SNPs were over-transmitted to asthma-affected offspring (P<0.05). According to the haplotype TDT, no haplotype of ADAM33 was transmitted preferentially to asthmatic offspring. CONCLUSION: Our results confirm the involvement of ADAM33 in the development of childhood asthma among the Japanese.

A clinical, genetic, and neuropathologic study in a family with 16q-linked ADCA type III.

Presented is the new kindred with autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 (16q-ADCA type III) associated with progressive hearing loss. By haplotype analysis, the critical interval was slightly narrowed to three megabase regions between GATA01 and D16S3095. Neuropathologic study of 16q-ADCA type III demonstrated characteristic shrinkage of Purkinje cell bodies surrounded by synaptophysin-immunoreactive amorphous material containing calbindin- and ubiquitin-positive granules.

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-alpha; LTB, lymphotoxin-beta). OBJECTIVE: The aim of the present study was to determine whether genes on 6q21 are related to development of atopic asthma. Methods We screened for mutations in the coding and promoter regions of genes in the TNF-LTA region, including BAT1, NFKBIL1, LTA, TNF, LTB, AIF, and BAT2, and conducted a transmission disequilibrium test of 41 polymorphisms in 137 families identified through pro-bands with childhood-onset atopic asthma. (BAT1, HLA-B-associated transcript 1; NFKBIL1, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-like 1; AIF, allograft inflammatory factor 1). RESULTS: Haplotypes of the LTA/TNF linkage disequilibrium block were associated significantly with asthma (global P=0.0097). Transmission patterns of the common haplotypes to asthmatic offspring were predicted by a single-nucleotide polymorphism in the LTA promoter region. The G allele of the LTA-753G/A polymorphism was transmitted preferentially to asthma-affected individuals (P=0.001). Luciferase reporter assays with constructs containing the 5' and 3' flanking regions of the LTA gene showed 30-50% lower transcriptional activity when the -753A allele was present than that of other haplotypes. CONCLUSION: Our results suggest that LTA is one of the genes that contributes to susceptibility to atopic asthma, and that the association of the TNF/LTA haplotypes to asthma may be defined by the polymorphism in the LTA promoter region in the Japanese population.

Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18.

BACKGROUND: Febrile seizures (FSs) are the most common form of childhood seizures, and genetic factors play a role in susceptibility to FS. OBJECTIVE: To identify novel loci and genes associated with susceptibility to FS. METHODS: Study participants were the FS probands and family members of 59 Japanese nuclear families (223 members including 112 affected children). Forty-eight of these families had at least two affected children for which genome-wide linkage screening was carried out. The Genehunter software was used to perform nonparametric multipoint linkage analysis. Mutational and association analyses were conducted in all 59 Japanese FS families. RESULTS: Genotyping data of 407 microsatellite markers suggested linkage of FSs to chromosome 18p11.2 (non-parametric linkage score = 3.68, p = 0.0001). This region includes the IMPA2 gene, which encodes myo-inositol monophosphatase (IMPase) 2. In the phosphatidylinositol-signaling pathway, IMPase is inhibited by lithium, which has a proconvulsant effect, and is stimulated by carbamazepine, an anticonvulsant. A systematic search was performed for mutations in IMPA2 in 24 unrelated randomly selected Japanese FS patients; seven variants were detected. Haplotype analysis revealed an association of a common haplotype in IMPA2 with FSs (p = 0.0009). CONCLUSION: The authors found a novel locus on chromosome 18p11.2 for febrile seizures (FSs). IMPA2 is likely to be an FS susceptibility gene.

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. OBJECTIVE: The aim of the present study was to investigate whether polymorphisms in genes encoding TLRs are associated with asthma or total serum IgE levels. METHODS: We screened the 5' flanking and coding regions of the TLR2,TLR3, TLR4, and TLR9 genes for polymorphisms by direct sequencing of DNA from 32 asthmatics, and analysed the effect of the polymorphisms on the development of atopic asthma and on total serum IgE levels. RESULTS: We identified 16 variants in TLRs. The transmission disequilibrium test of the families revealed that none of the alleles or haplotypes were associated with asthma or total IgE levels (P>0.05). However, we found an insertion/deletion polymorphism in the 5' untranslated region of TLR2, and an expression construct containing the deletion allele showed lower luciferase activity than the wild-type alleles, suggesting that the deletion allele has reduced transcriptional activity. CONCLUSION: Our results indicate that polymorphisms in TLRs are not likely to be associated with the development of atopy-related phenotypes in a Japanese population.

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.

No evidence for association between the -112G/A polymorphism of UGRP1 and childhood atopic asthma.

BACKGROUND: Susceptibility to asthma is known to involve genetic factors. Genome-wide screens have indicated that the chromosome 5q31-q34 region is linked to and/or associated with asthma. A new gene, named UGRP1 and reported by Niimi et al., encodes uteroglobin-related protein and is expressed in the lung and trachea. Niimi et al. showed the -112G/A polymorphism of the UGRP1 gene to be associated with asthma in a case-control study. OBJECTIVE: The objective of the present study was to replicate this association and confirm the possible role of the UGRP1-112G/A polymorphism in the aetiology of childhood asthma in a Japanese population. METHODS AND RESULTS: We conducted a transmission disequilibrium test (TDT) in 131 families identified through paediatric patients being treated for asthma. A case-control study was also carried out by comparing the probands and 137 unrelated non-atopic non-asthmatic Japanese children and 211 unrelated healthy Japanese adults. The -112G/A polymorphism was genotyped by the PCR-RFLP method. The TDT revealed that the -112A allele was not preferentially transmitted to asthma-affected children (P=0.85). Neither the presence of at least one A allele in an individual's genotype (sum of the G/A and A/A genotypes) nor the -112A allele was more prevalent among the asthma subjects than among the control subjects. CONCLUSION: Our findings indicate that the UGRP1-112G/A polymorphism does not play a substantial role in genetic predisposition to childhood asthma in this Japanese population.

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.

New polymorphisms of haematopoietic prostaglandin D synthase and human prostanoid DP receptor genes.

BACKGROUND: Prostaglandin D2 (PGD2), a major cyclo-oxygenase metabolite of arachidonic acid in mast cells, induces bronchoconstriction in the human lung. It has been reported that mice lacking PGD receptor fail to develop the bronchial hyper-responsiveness upon ovalbumin challenge, suggesting that PGD2 functions as a mediator of allergic asthma. OBJECTIVE: To determine if there are any mutations associated with the development of asthma in the haematopoietic prostaglandin D synthase (H-PGDS) gene and the human prostanoid DP receptor (PTGDR) gene. METHODS AND RESULTS: We screened the 5'flanking and coding regions of the H-PGDS gene and the PTGDR gene by direct sequence. We identified one variant in intron 2 (IVS2 + 11 A > C) and one variant in intron 3 (IVS3 + 13T > C) of the H-PGDS gene, and two variants in the 5'flanking region of the PTGDR gene (-197T > C and -2C > T). The IVS3 + 13T > C and -197T > C variants were rare, appearing only once in 48 subjects. transmission disequilibrium test (TDT) analysis of 144 asthmatic families revealed that the IVS2 + 11 A allele of the H-PGDS gene was significantly transmitted preferentially to asthma-affected children (P = 0.0056), but no association was observed between -2C/T polymorphism of the PTGDR gene and asthma (P > 0.05). CONCLUSION: Our results suggest that the IVS2 + 11A/C allele may be involved in the development of asthma in the Japanese population.