Background
The aim of this study was to evaluate the effects and the utility of second-line everolimus treatment for regrown renal angiomyolipoma (AML) with tuberous sclerosis complex (TSC) after ...transcatheter arterial embolization (TAE).
Methods
We investigated a total of 14 patients who underwent second-line everolimus treatment for TSC–AML that regrew after TAE, and assessed their effects and adverse events. Everolimus treatment was performed for AML with a maximum diameter of 4 cm. To determine the reduction ratio of AML, the volume of AML was measured using multislice helical computed tomography. Adverse events were evaluated according to CTCAE v4.0-JCOG. We further compared the treatment effect and adverse events with those in patients receiving first-line everolimus treatment.
Results
The AML volume decreased in all patients, with a ≥ 50% volume decrease in 57% (8 of 14) of the cases, and the mean reduction rate was 53%. We observed no significant difference in the mean reduction rate of AML between second-line everolimus treatment for regrown TSC–AML after TAE and first-line everolimus treatment for TSC–AML. The adverse events were mild and consistent with those reported in our previous study.
Conclusion
Although further studies are needed, everolimus appears to be effective as second-line treatment for TSC–AML that regrew after TAE and a beneficial treatment option for TSC–AML.
•Long-term sublingual immunotherapy (SLIT) reduced the serum levels of IL-17A.•Long-term SLIT reduced the serum levels of C3a and C5a.•A significant correlation was found between the clinical scores ...and the levels of IL-17A.
Allergen-specific immunotherapy is the only treatment that can alter the natural course of allergic disease. We performed long-term sublingual immunotherapy (SLIT) for patients with seasonal allergic rhinitis caused by Japanese cedar pollen (SAR-JCP), screened molecules as candidate biomarkers, and investigated serum IL-17A and complement components 3a (C3a) and C5a in order to evaluate whether these molecules show changes correlated to symptom scores. In this study, we found that the long-term SLIT reduced the serum levels of IL-17A and C3a and C5a. The levels of C3a in the patients significantly decreased from year 1 compared with those at the baseline, and their levels of IL-17A significantly decreased from year 2 compared with those at baseline. The levels of IL-17A, C3a, and C5a at year 4 of SLIT were significantly lower than not only those at baseline, but also those at year 1. A significant positive correlation was found between the symptom medication scores and the levels of IL-17A at year 4. The symptom medication scores in the group in which IL-17A levels decreased at year 4 were significantly lower than those in the group without such a decrease. The serum level of IL-17A might prove useful as a biological parameter to ascertain the effectiveness of SLIT for patients with SAR-JCP. It is necessary to produce new therapeutics for non-responders in whom serum IL-17A levels are still higher against long-term SLIT.
Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese ...population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 × 10(-4)) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction.
In asthma genetics, the association of highly replicated susceptibility genes lacks consistency across populations. To identify genuine associations, we investigated the reproducibility of the 23 ...most promising asthma and asthma-related candidate genes in a moderately sized sample from the Japanese population. We compared the frequency of 33 polymorphisms in unrelated cases and controls and tested for their association with asthma, atopy and serum total IgE levels using allele frequency, codominant, dominant and recessive genotype models. On the basis of the consistency of our findings with previous meta-analyses and large replication studies, IL13, TNF, ADAM33, IL4RA and TBXA2R might represent common major asthma and asthma-related trait genes. Individual gene assessment was extended to the interactions between two polymorphisms using our original method. Interactions between TBXA2R and ADAM33, and IL4RA and C3 were suggested to increase the risk for childhood and all asthma (adult and childhood asthma combined). The confirmation of previously reported associations between gene polymorphisms and phenotypes was problematic when as few as several hundred samples per group were used. Stratification of the subjects by environmental factors or other confounding factors may be necessary to improve the sensitivity and reliability of association results.
To the Editor: Bronchial asthma is a complex disease caused by a combination of genetic and environmental factors.1 A recent study using genome-wide association analysis has shown that single ...nucleotide polymorphisms (SNPs) on the chromosome 17q21.1 locus contribute to the risk of childhood asthma.2 Genetic variants of the region were strongly associated in cis with transcript levels of ORM1-like 3 (S cerevisiae; ORMDL3) in EBV-transformed lymphoblastoid cell lines from children with asthma.2 The ORMDL3 transcripts were strongly and positively associated with the SNPs (P < 10-22 for rs7216389) in the disease-associated locus, and rs7216389 was the marker most strongly associated with the disease in combined genome-wide association analysis.2ORMDL3 is a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum; however, the gene function is unclear.3 It was reported that ORMDL3 was expressed in many tissues, particularly in liver and peripheral blood lymphocytes.2 In the induction of asthma, the important role of respiratory tract infections has been recognized.4,5 Clinical studies suggest that the proportion of virus-induced asthma exacerbations is likely to be around 80% to 85% in school-age children.6 To assess whether the genetic variations regulating ORMDL3 expression contribute to the susceptibility in childhood atopic asthma in a Japanese population, we conducted association studies using the marker rs7216389.
The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in ...patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes.
This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters.
In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027).
The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.
Methods A genetic association study was conducted on the loss-of-function mutations in the filaggrin gene in Japanese individuals, using DNA for genomic analysis of patients who developed this ...serious wheat allergy due to GP19S (n=480).
Background Single nucleotide polymorphisms (SNPs) influence a patient’s response to inhaled corticosteroids and β2 -agonists, and the effect of treatment with inhaled corticosteroids is synergistic ...with the effect of β2 -agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with a bronchodilator response. Objective To assess whether, among subjects with asthma, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids versus those on placebo. Methods A genome-wide association analysis was conducted by using 581 white subjects from the Childhood Asthma Management Program. By using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial. Results The combined P value for the Childhood Asthma Management Program and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial populations was 4.8 × 10−8 for rs3752120, which is located in the zinc finger protein gene ZNF432 and has an unknown function. Conclusions Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma.
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