The primary ciliary dyskinesia-related genetic risk score is associated with susceptibility to adult-onset asthma.

BACKGROUND: Disturbance of mucociliary clearance is an important factor in the pathogenesis of asthma. We hypothesized that common variants in genes responsible for ciliary function may contribute to the development of asthma with certain phenotypes. METHODS: Three independent adult Japanese populations (including a total of 1,158 patients with asthma and 2,203 non-asthmatic healthy participants) were studied. First, based on the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), we selected 12 common single-nucleotide polymorphisms (SNPs) with molecular consequences (missense, nonsense, and 3'-untranslated region mutation) in 5 primary ciliary dyskinesia (PCD)-related genes and calculated a PCD-genetic risk score (GRS) as a cumulative effect of these PCD-related genes. Second, we performed a two-step cluster analysis using 3 variables, including PCD-GRS, forced expiratory volume in 1 second (%predicted FEV1), and age of asthma onset. RESULTS: Compared to adult asthma clusters with an average PCD-GRS, clusters with high and low PCD-GRS had similar overall characteristics: adult-onset, female predominance, preserved lung function, and fewer features of type 2 immunity as determined by IgE reactivity and blood eosinophil counts. The allele frequency of rs1530496, a SNP representing an expression quantitative trait locus (eQTL) of DNAH5 in the lung, showed the largest statistically significant difference between the PCD-GRS-High and PCD-GRS-Low asthma clusters (p = 1.4 x 10-15). CONCLUSION: Genes associated with PCD, particularly the common SNPs associated with abnormal expression of DNAH5, may have a certain influence on the development of adult-onset asthma, perhaps through impaired mucociliary clearance.

Organizing Pneumonia in a Case of cold Agglutinin Disease with Pulmonary Thrombosis.

Cold agglutinin disease is a subtype of autoimmune hemolytic anemia that occurs via the activation of specific anti-red blood cell antibodies (agglutinins) at low temperatures. Autoimmune hemolytic anemia has been reported to cause interstitial pneumonia; however, the underlying mechanism remains unclear. We herein report a 46-year-old man diagnosed with cold agglutinin disease complicated by pulmonary thrombosis and organizing pneumonia. Treatment with prednisolone improved the course of cold agglutinin disease and organizing pneumonia in a similar manner. To our knowledge, this is the first report of cold agglutinin associated with organizing pneumonia, suggesting a potential link between the two.

Usefulness of malignant pleural effusion for early cytological diagnosis of mesothelioma in situ: A case report.

Mesothelioma in situ (MIS) is defined as a preinvasive mesothelioma that forms a single layer of mild atypical mesothelial cells lining on the serosa surface of pleura. The atypical mesothelial cells present loss of BRCA-1 associated protein-1 (BAP-1) and/or methylthioadenosine phosphorylase as examined by immunohistochemistry (IHC) and/or homozygous deletion of cyclin-dependent kinase inhibitor 2A/p16 as examined by fluorescence in situ hybridization. It is difficult to diagnose because of the unremarkable clinical findings except for pleural effusion. The present report describes a case in which MIS was diagnosed at the time of sampling due to the presence of clearly malignant mesothelial cells in the pleural fluid. In 2016, a 74-year-old man with a history of past exposure to asbestos was admitted to Ibaraki Higashi National Hospital (Tokai-mura, Japan) with dyspnea. Chest CT indicated only right pleural effusion. Malignant mesothelial cells were suspected in a cell block made using pleural effusion; therefore, right pleural biopsy was performed. Pathologically, there was proliferation of mesothelial cells with mild atypia that formed a single-flat layer on the pleural surface; however, there was no invasion. Furthermore, IHC revealed loss of BAP-1 in cells from the biopsied pleura and pleural effusion. MIS was suspected at the time; however, the patient arbitrarily quit his medical check-ups. After 44 months, the patient was readmitted to our hospital complaining of dyspnea. CT indicated a large right pleural mass. A specimen of the mass obtained via CT-guided needle biopsy revealed malignant mesothelioma. The patient continued to deteriorate and eventually died. This case indicated that pleural effusion could be used to demonstrate overtly malignant mesothelial cells and diagnose MIS at the time of sampling. To the best of our knowledge, this is first report of MIS with overtly malignant mesothelial cells in pleural effusion. Pleural effusion may serve an important role in MIS diagnosis.

Impact of sleep-related hypoventilation in patients with pleuroparenchymal fibroelastosis.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare fibrosing lung disease with a predilection for the upper lobe and its progression causes hypoventilation, resulting in hypercapnia. Even though the association between sleep-related hypoventilation (SRH) and chronic obstructive pulmonary disease was well documented, its impact in patients with PPFE was not evaluated. The aim of this study is to clarify the impact of SRH on prognosis in PPFE. METHODS: A retrospective review of the medical records of 52 patients with PPFE who underwent transcutaneous carbon dioxide monitoring during sleep was done. Patients were stratified into SRH (n = 28) and non-SRH (n = 24) groups based on American Academy of Sleep Medicine criteria. The impact of SRH on the prognosis of PPFE, as well as the clinical factors and comorbidities of PPFE associated with SRH, were evaluated. RESULTS: Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and carbon monoxide diffusing capacity (DLco) in the SRH group were significantly lower than the non-SRH group (P < .01). Chronic pulmonary aspergillosis (CPA) was found at a higher rate in the SRH group (P = .02). The median survival time for SRH patients was 330 days, whereas roughly 80% of non-SRH patients were alive during the 3-year observation period (P < .01). Body mass index was a significant prognostic factor in PPFE patients with SRH (HR .78; 95% CI; .64-.94; P < .01). Home oxygen therapy (HOT) during the day and noninvasive positive pressure ventilation (NPPV) at night while sleeping tended to improve prognosis in the SRH group, as indicated by HR of .25 (P = .07). CONCLUSIONS: SRH may be a poor prognostic factor for PPFE. Additionally, SRH may modify susceptibility to Aspergillosis in patients with PPFE. HOT plus NPPV may improve the disease outcomes in patients with SRH.

Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD).

BACKGROUND AND OBJECTIVES: Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. In this study, using common and shared risk factors for the exacerbation of asthma and COPD, we sought to clarify the exacerbation-prone phenotypes beyond disease labels, and to specifically investigate the role of the IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes. METHODS: The study population comprised patients with asthma (n = 117), asthma-COPD overlap (ACO; n = 37) or COPD (n = 48) and a history of exacerbation within the previous year. Cluster analyses were performed using factors associated with both asthma and COPD exacerbation. The association of the IL4RA gene polymorphism rs8832 with each exacerbation-prone phenotype was evaluated by multinomial logistic analyses using non-asthma non-COPD healthy adults as controls (n = 1,529). In addition, the genetic influence of rs8832 was also examined in asthma patients with allergic rhinitis and no history of exacerbation (n = 130). RESULTS: Two-step cluster analyses identified five clusters that did not necessarily correspond to the diagnostic disease labels. Cluster 1 was characterized by high eosinophil counts, cluster 2 was characterized by smokers with impaired lung function, cluster 3 was characterized by the presence of gastroesophageal reflux, cluster 4 was characterized by non-allergic females, and cluster 5 was characterized by allergic rhinitis and elevated total immunoglobulin E levels. A significant association with rs8832 was observed for cluster 5 (odds ratio, 3.88 (1.34-11.26), p = 0.013) and also for the type 2 exacerbation-prone phenotypes (clusters 1 and 5: odds ratio, 2.73 (1.45-5.15), p = 1.9 × 10-3). DISCUSSION: Our results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the prevention of exacerbations in patients with chronic inflammatory airway diseases.

Pulmonary hypertension due to silicosis and right upper pulmonary artery occlusion with bronchial anthracofibrosis.

Bronchial anthracofibrosis is a rare disease defined as bronchial stenosis with black pigmentation and usually not associated with artery occlusion. The patient was an 81-year-old man with silicosis. He presented with dyspnea on exertion, and pulmonary hypertension due to right upper pulmonary artery occlusion without thromboembolism was diagnosed on the basis of the results of right heart catheterization and pulmonary angiography. Bronchoscopy demonstrated bronchial anthracofibrosis in the right upper lobe. These findings suggested that the cause of PH was silicosis and pulmonary artery occlusion with bronchial anthracofibrosis. He has been treated with home oxygen therapy and tadalafil, and his symptom and 6MWD remain stable.

ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization.

BACKGROUND: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization. METHODS: We conducted a case-control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined. RESULTS: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p < 0.0005), but not allergic sensitization (p > 0.1). CONCLUSIONS: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.

Genetic impact of CDHR3 on the adult onset of asthma and COPD.

BACKGROUND: Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases caused by complex gene-environment interactions. A functional single nucleotide polymorphism of cadherin-related family member 3 (CDHR3), known as a receptor of rhinovirus-C, is associated with childhood-onset asthma especially in atopic individuals. OBJECTIVE: Here, we identified risk factors for adult-onset asthma and COPD, focusing on the impact of the CDHR3 variant in atopic individuals. METHODS: We conducted a longitudinal, retrospective, observational cohort study of 1523 healthy adults with baseline examinations at Tsukuba Medical Center Hospital in 2008 and retrospectively identified new-onset, physician-diagnosed asthma or COPD from 2009 to 2018. We assessed risk factors by the Cox regression analysis. The impact of CDHR3 variant rs6967330 was also examined in individuals with pre-existing atopy. RESULTS: Over 10 study years, 103 people developed airway diseases (79 asthma and 24 COPD; 52 females, average onset-age 55 years old, range 38-80). Higher body mass index (BMI) and lower forced expiratory volume in one second/forced vital capacity (FEV1 /FVC) ratio were significant risk factors (BMI: HR 1.072 [95% CI 1.005-1.14], P = .034; FEV1 /FVC ratio: HR 1.091 [1.044-1.14], P = .00011). Restriction to atopic individuals saw the A allele at rs6967330 and lower FEV1 /FVC ratio to associate with adult-onset disease (A allele: HR 2.89 [1.57-5.20], P = .00062; FEV1 /FVC ratio: HR 1.10 [1.04-1.17], P = .0010). CONCLUSION AND CLINICAL RELEVANCE: Genetic susceptibility to rhinovirus-C infection in atopic individuals is a risk factor for chronic airway diseases even in later life.

A Case of Pulmonary Metastasis of Breast Cancer 23 Years after Surgery Accompanied with Non-Tuberculous Mycobacterium Infection.

Recurrence of oestrogen receptor (ER)-positive breast cancer rarely occurs postoperatively after a long period. Breast cancer cells survive and settle in distant organs in a dormant state, a phenomenon known as "tumour dormancy." Here, we present a 66-year-old woman with recurrence of ER-positive breast cancer in the left lung 23 years after surgery accompanied with non-tuberculous mycobacterium infection (NTM). At the age of 43 years, the patient underwent a right mastectomy and adjuvant hormonotherapy to completely cure breast cancer. Twenty-three years after the operation, when the patient was 66 years old, computed tomography presented nodular shadows in the lower lobes bilaterally with bronchiectasis and ill-defined satellite tree-in-bud nodules. Mycobacterium intracellulare was detected in cultured bronchoalveolar lavage fluid obtained from the left lower lobe by bronchoscopy. Rifampicin, ethambutol, and clarithromycin were started, which resulted in shrinkage of the nodule in the right lower lobe and satellite nodules; however, the nodule in the left lower lobe increased in size gradually. Wedge resection of the left lower lobe containing the nodule by video-assisted thoracoscopic surgery was performed, which demonstrated that the nodule was adenocarcinoma in intraoperative pathological diagnosis; therefore, a left lower lobectomy and mediastinal lymph node dissection were performed. The tumour was revealed to be consistent with recurrence of previous breast cancer according to its morphology and immunohistochemical staining. Furthermore, caseous epithelioid cell granulomas existed in the periphery of the tumour. It is reported that inflammatory cytokines induce reawakening of dormant oestrogen-dependent breast cancer and, in our case, NTM infection might have stimulated the dormant tumour cells in the lower lobe.

Differences in distribution of anterior segmental medullary arteries in the cervical and thoracolumbar spinal cord: the "inseln" were characteristics in the cervical spinal cord.

Anterior segmental medullary arteries cause spinal cord infarction due to circulatory disturbance, but are difficult to identify in diagnostic images. This study investigated the arterial distribution from the cervical to lumbar segments of the dissecting spinal cord in 100 cadavers. The 488 arteries were distributed from C2 to L2, of which 252 arteries from C2 to C8 were slightly dominant on the right side, but 236 arteries from Th1 to L2 were obviously dominant on the left side. This change occurred at the C8 and Th1 segments. Of the 252 arteries, 37.30% (94 arteries) were divided into ascending and descending branches. Both branches formed loops by anastomosis with the anterior spinal arteries. The loops, called "insel", have an unclear distribution and form. We focused on the features of inseln and found 63 of them in the cervical spinal cord of 45 cadavers. Their numbers and forms differed depending on whether the 94 arteries were bilateral (type A) or unilateral (type B), but the long axis of the insel was limited to one cervical segment. 90.63% of type A were bilateral at the same level, and 70% of type B were on the right side. The former always formed the insel. Further, 94 arteries were distributed from C2 to C7, 82.98% of which were concentrated at C3-C5. Therefore, the arterial blood supply of the spinal cord may differ between the cervical spinal cord and the thoracolumbar cord.

The Concavity of the Maximal Expiratory Flow-Volume Curve Reflects the Extent of Emphysema in Obstructive Lung Diseases.

A concave-shaped maximal expiratory flow-volume (MEFV) curve is a spirometric feature in chronic obstructive pulmonary disease (COPD). The MEFV curve is characterized by an increase in the Obstructive Index, which is defined as a ratio of forced vital capacity to the volume-difference between two points of half of the peak expiratory flow on the MEFV curve. We hypothesized that the Obstructive Index would reflect the severity of emphysema in patients with COPD and asthma-COPD overlap (ACO). Thus, the aim of this retrospective study was to evaluate whether the Obstructive Index on spirometry is associated with the extent of emphysema on computed tomography (CT) in patients with COPD, ACO, and asthma (N = 65, 15, and 53, respectively). The percentage of low-attenuation volume (LAV%) and wall area (WA%) were measured on CT. The Obstructive Index was higher in patients with COPD and ACO than in those with asthma. Spearman correlation showed that a greater Obstructive Index was associated with a higher LAV%, but not WA%. Multivariate analysis showed that Obstructive Index was associated with LAV% (standardized ß = 0.43, P < 0.0001) independent of other spirometric indices. The Obstructive Index is a useful spirometric index that reflects the extent of emphysema.

A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Association analyses of eQTLs of the TYRO3 gene and allergic diseases in Japanese populations.

BACKGROUND: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations. METHODS: We performed a candidate gene case-control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations. RESULTS: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene-gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively. CONCLUSIONS: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese.

The R81T mutation in the nicotinic acetylcholine receptor of Aphis gossypii is associated with neonicotinoid insecticide resistance with differential effects for cyano- and nitro-substituted neonicotinoids.

The cotton aphid, Aphis gossypii Glover, is one of the most agriculturally important insect pests. Neonicotinoid insecticides and sulfoxaflor have generally shown excellent control of A. gossypii, but these aphids have recently developed resistance against neonicotinoid insecticides. We previously characterized a field-collected A. gossypii Kushima clone that showed higher resistance to nitro-substituted neonicotinoids, such as imidacloprid, than to cyano-substituted neonicotinoids, such as acetamiprid. This Kushima clone harbors the R81T mutation in the nicotinic acetylcholine receptor (nAChR) ß1 subunit; this mutation is the source of neonicotinoid insecticide resistance. In the present study, electrophysiological analyses and molecular modeling were employed to investigate the differential effects of the R81T mutation on cyano- and nitro-substituted neonicotinoids and sulfoxaflor. We isolated full-length coding sequences of A. gossypii nAChR α1, α2, and ß1 subunits. When co-expressed in Xenopus laevis oocytes with chicken ß2 nAChR, A. gossypii α1 evoked inward currents in a concentration-dependent manner in response to acetylcholine (ACh) and showed sensitivity to neonicotinoid and sulfoxaflor. Additionally, the chicken ß2 T77R+E79V (equivalent double mutant of R81T) mutation resulted in a lower effect to cyano-substituted neonicotinoids and sulfoxaflor than to nitro-substituted neonicotinoids. Electrophysiological data and nAChR homology modeling analysis suggested that the Kushima clone exhibited different levels of resistance to cyano- and nitro-substituted neonicotinoid insecticides.

Genetic association of the functional CDHR3 genotype with early-onset adult asthma in Japanese populations.

BACKGROUND: Recent studies have demonstrated that a coding SNP (rs6967330, Cys529→Tyr) in cadherin-related family member 3 (CDHR3), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of this variant to the development of adult asthma. METHODS: We performed a candidate gene case-control association study of 2 independent Japanese populations (a total of 3366 adults). The odds ratios (ORs) for association of the A allele at rs6967330 with adult asthma were calculated according to age at onset of asthma. In addition, the effect of the CDHR3 genotype on the development of specific asthma phenotypes was examined. RESULTS: The A allele was associated with asthma (OR = 1.56; Mantel-Haenszel p = 0.0040) when the analysis was limited to patients with early-onset adult asthma. In addition, when the analysis was limited to atopic individuals, a stronger association of the CDHR3 variant with early-onset asthma was found, and interaction of the CDHR3 genotype with atopy was demonstrated. Finally, a significant association of this variant was specifically found with a phenotype of asthma characterized by atopy, early-onset, and lower lung function. CONCLUSIONS: Our study supports the concept that the CDHR3 variant is an important susceptibility factor for severe adult asthma in individuals who develop the disease in early life. The interaction between the CDHR3 variant and atopy indicates that genetic predisposition to early respiratory viral infection is combined with atopy in promoting asthma.

The right-sided aortic arch with unusual course of bilateral recurrent laryngeal nerves: a report of rare variations.

We describe a rare case of the right-sided aortic arch, the unusual origin of the main arterial vessels and the unusual courses of bilateral recurrent laryngeal nerves in a Japanese cadaver. Chiefly, the right-sided aortic arch turned to the left side from the dorsal part of the trachea and esophagus, and Kommerell's diverticulum was found at the end of the arch. The right common carotid artery arose from the end part of the ascending aorta, but the left common carotid artery arose from the proximal portion of the ascending aorta. The right subclavian artery arose from the upper edge of the aortic arch, but the left one arose from the front wall at the upper side of the ligamentum arteriosum. The right recurrent laryngeal nerve hooked around the aortic arch (but not the right subclavian artery) dorsoventrally, and the left recurrent laryngeal nerve hooked around the ligamentum arteriosum and arose from the ventral side (but not dorsal) of the aortic arch. These variations are very rare, and understanding them is useful and important for clinical research.

GENETIC INTERACTIONS BETWEEN ADRB2 AND PTGER4 ON RESPONSES TO SALMETEROL OR MONTELUKAST IN JAPANESE PATIENTS WITH MILD PERSISTENT ASTHMA.

BACKGROUND: Long-acting ß2-agonists (LABA) and leukotriene receptor antagonists (LTRA) are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. In our previous study, the Gly16Arg genotype of the ß2-adrenergic receptor (ADRB2) gene did not influence the differential bronchodilator effect of salmeterol versus montelukast as an add-on therapy to ICS within 16 weeks of follow-up (the J-Blossom study). METHODS: We examined if genes encoding CYSLTR1, CYSLTR2, PTGER2 or PTGER4 could explain differential responses to salmeterol versus montelukast using the participants of the J-Blossom study. This study included 76 patients with mild-to-moderate asthma. The difference in peak expiratory flow (PEF) (ΔPEF, l/min) after 16 weeks of treatment with salmeterol (ΔPEFsal) versus montelukast (ΔPEFmon) was associated with the genotypes at each of 4 genes. In addition, multivariate analyses were used to identify a gene-gene interaction between ADRB2 gene and each of these 4 genes. RESULTS: Although none of 4 genes were associated with ΔPEFsal-ΔPEFmon in the univariate analyses, multivariate analysis showed that PTGER4 gene, interacting with ADRB2 Gly16Arg, was associated with ΔPEFsal-ΔPEFmon (p=0.0032). CONCLUSION: Our findings suggested that the interactions between two genetic loci at ADRB2 and PTGER4 is important in determining the differential response to salmeterol versus montelukast in patients with chronic adult asthma.