Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity

Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma frequently coexist and are always present in patients with aspirin exacerbated respiratory disease (AERD). Although the pathogenic mechanisms of this condition are still unknown, AERD may be due, at least in part, to an imbalance in eicosanoid metabolism (increased production of cysteinyl leukotrienes (CysLTs) and reduced biosynthesis of prostaglandin (PG) E₂), possibly increasing and perpetuating the process of inflammation. PGE₂ results from the metabolism of arachidonic acid (AA) by cyclooxygenase (COX) enzymes, and seems to play a central role in homeostasis maintenance and inflammatory response modulation in airways. Therefore, the abnormal regulation of PGE₂ could contribute to the exacerbated processes observed in AERD. PGE₂ exerts its actions through four G-protein-coupled receptors designated E-prostanoid (EP) receptors EP1, EP2, EP3, and EP4. Altered PGE₂ production as well as differential EP receptor expression has been reported in both upper and lower airways of patients with AERD. Since the heterogeneity of these receptors is the key for the multiple biological effects of PGE₂ this review focuses on the studies available to elucidate the importance of these receptors in inflammatory airway diseases.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0100-7) contains supplementary material, which is available to authorized users.     

Functional polymorphisms of HSPA5: possible association with bipolar disorder

Altered endoplasmic reticulum stress (ER) response signaling is suggested in bipolar disorder. Previously, we preliminarily reported the genetic association of HSPA5 (GRP78/BiP) with bipolar disorder. Here, we extended our analysis by increasing the number of Japanese case-control samples and NIMH Genetics Initiative bipolar trio samples (NIMH trios), and also analyzed schizophrenia samples. In Japanese, nominally significant association of one haplotype was observed in extended samples of bipolar disorder but not in schizophrenia. In NIMH trios, no association was found in total samples. However, an exploratory analysis suggested that the other haplotype was significantly over-transmitted to probands only from the paternal side. The associated haplotype in Japanese or NIMH pedigrees shared three common polymorphisms in the promotor, which was found to alter promotor activity. These findings suggested promotor polymorphisms of HSPA5 may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder.     

Lack of association of HLA-DRA polymorphisms with aspirin exacerbated respiratory disease in a Korean population

The human HLA class II histocompatibility antigen, DR alpha chain (HLA-DRA) is a member of the MHC class II gene family that activates T cells allowing secretion in various cytokines to immune responses. Thus, we explored whether the genetic variations in HLA-DRA gene can influence susceptibility for aspirin exacerbated respiratory disease (AERD). To carry out the investigation, 22 single nucleotide polymorphisms (SNPs) in HLA-DRA were genotyped in 592 Korean asthma patients. Logistic and regression analyseis wereas used to evaluate the P-values for associations of HLA-DRA polymorphisms with AERD and a relevant phenotype, the fall rate of forced expiratory volume in the 1^st second (FEV₁). Logistic analyses revealed that two variants, rs6911777 and HLA_DRA_BL1_ht3 were initially associated with AERD via dominant and recessive models (P = 0.05 and 0.01, respectively), however, the signals did not reach the threshold of significance after multiple corrections. Furthermore, we observed that fall rate of FEV1 by aspirin provocation was marginally different between AERD cases and aspirin-tolerant asthma (ATA) controls (mean = 24.63 vs 3.54, respectively). This study provides result of first association analysis between the variants of HLA-DRA and the risk of AERD, and conclusions derived from the study do not support significant roles of polymorphisms in HLA-DRA with AERD.     

Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase

A recent study has demonstrated the possible involvement of a leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, whereas no significant association was noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) of the key enzymes involved in arachidonate metabolism, and the cysteinyl leukotriene receptor 1 (CYSLTR1) in a large Korean population with AIA: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls. The single-base extension method was used to genotype SNPs in 5-lipoxygenase (ALOX5, –1708GA, 21CT, 270GA, 1728GA), ALOX5-activating protein (ALOX5AP, 218AG), prostaglandin-endoperoxide synthase 2 (PTGS2, COX2, –162CG, 10TG, R228H, V511A), LTC4S (–444AC), and CYSLTR1 (927TC). Haplotype analyses were undertaken for the SNPs in ALOX5. No significant differences in allele and genotype frequencies of single SNPs were observed between the patient groups (P>0.05). However, the frequency of the ALOX5-ht1[G-C-G-A] haplotype in the AIA group was significantly higher than its frequency in the ATA group with a probability (P) of 0.01, odds ratio (OR) of 5.0, and 95% confidence interval (95%CI) of 1.54–17.9, and in the normal controls (P=0.03, OR=4.5, 95%CI=1.1–18.4), by using a dominant model. These results suggest a lack of association between the ALOX5AP, PTGS2, LTC4S, and CYSLTR1 gene polymorphisms and the AIA phenotype in the Korean population. However, the possible involvement of ALOX5-ht1[G-C-G-A] in AIA development is suggested.J.-H. Choi and H.-S. Park contributed equally to this work as first authors     

A study of the possible association between adenosine A2A receptor gene polymorphisms and attention‐deficit hyperactivity disorder traits

The adenosine A_2A receptor (ADORA2A) is linked to the dopamine neurotransmitter system and is also implicated in the regulation of alertness, suggesting a potential association with attention‐deficit hyperactivity disorder (ADHD) traits. Furthermore, animal studies suggest that the ADORA2A may influence ADHD‐like behavior. For that reason, the ADORA2A gene emerges as a promising candidate for studying the etiology of ADHD traits. The aim of this study was to examine the relationship between ADORA2A gene polymorphisms and ADHD traits in a large population‐based sample. This study was based on the Child and Adolescent Twin Study in Sweden (CATSS), and included 1747 twins. Attention‐deficit hyperactivity disorder traits were assessed through parental reports, and samples of DNA were collected. Associations between six single nucleotide polymorphisms (SNPs) and ADHD traits were examined, and results suggested a nominal association between ADHD traits and three of these SNPs: rs3761422, rs5751876 and rs35320474. For one of the SNPs, rs35320474, results remained significant after correction for multiple comparisons. These results indicate the possibility that the ADORA2A gene may be involved in ADHD traits. However, more studies replicating the present results are warranted before this association can be confirmed .     

Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma

Asthma is a heterogeneous disorder hallmarked by chronic inflammation in the respiratory system. Exacerbations of asthma are correlated with respiratory infections. Considering the implication of interferon regulatory factor 5 (IRF5) in innate and adaptive immunity, we investigated the preferential transmission patterns of ten IRF5 gene polymorphisms in two asthmatic family cohorts. A common IRF5 haplotype was found to be associated with asthma and the severity of asthmatic symptoms. Stratified analysis of subgroups of asthmatic individuals revealed that the associations were more pronounced in nonatopic asthmatic individuals. In addition, the risk alleles of IRF5 polymorphisms for asthma were almost completely opposite to those for autoimmune disorders. Our study provides the first evidence of association between IRF5 and asthma, and sheds light on the related but potentially distinct roles of IRF5 alleles in the pathogenesis of asthma and autoimmune disorders.     

A possible association of Y chromosome heterochromatin with stature

Summary A correlation between Y chromosome length and stature was statistically analyzed in a normal male population of 142 Japanese students with a mean age of 24.0 years. Evidence was obtained that increased length of the heterochromatic band Yq12 may be associated with increased height: The correlation coefficient between band Yq12 length and height was 0.17, statistically significant at the 5% level. And, taller males had longer Y chromosomes, in which the mean length of band Yq12 was significantly longer than that of shorter males. No correlation was seen between length of the euchromatic band Yq11 and stature. The present study reveals a possible effect of Yq heterochromatin on the development of body height in man.     

Association study between monoamine oxidase A (MAOA) gene polymorphisms and schizophrenia: lack of association with schizophrenia and possible association with affective disturbances of schizophrenia

Monoamine oxidase A (MAOA) catalyzes monoamine neurotransmitters including dopamine, 5-hydroxytryptamine (5-HT, serotonin), and norepinephrine. MAOA also plays a key role in emotional regulation. The aim of this study was to investigate the associations between the exonic single nucleotide polymorphisms (SNPs) of the MAOA gene located on the X chromosome and schizophrenia. We also analyzed the relationships between these SNPs and the common clinical symptoms of schizophrenia such as persecutory delusion, auditory hallucinations, affective disturbances, and poor concentration. Two hundred seventy five Korean schizophrenia patients and 289 control subjects were recruited. Three SNPs [rs6323 (Arg294Arg), rs1137070 (Asp470Asp), and rs3027407 (3′-untranslated region)] of the MAOA gene were selected and genotyped by direct sequencing. The common clinical symptoms of schizophrenia according to the Operation Criteria Checklist were analyzed. Three examined SNPs showed no associations with male and female schizophrenia, respectively (p > 0.05). In the analysis of the common clinical symptoms of schizophrenia patients, three examined SNPs were associated with affective disturbances, especially restricted affect and blunted affect in male schizophrenia, respectively (restricted affect, p = 0.002, OR = 2.71, 95 % CI 1.45–5.00; blunted affect, p = 0.009, OR 2.25, 95 % CI 1.22–4.12). The SNPs were not associated with other clinical symptoms of schizophrenia (persecutory delusion, auditory hallucinations, and poor concentration). These results suggest that exonic SNPs (rs6323, rs1137070, and rs3027407) of the MAOA gene may be contributed to affective disturbances of Korean males schizophrenia, especially restricted affect and blunted affect.     

No evidence of association of oxytocin polymorphisms with breastfeeding in 2 independent samples

Oxytocin has an important function in breastfeeding via its role in the milk ejection reflex and in attachment and bonding processes. Genetic factors account for a significant part of the individual differences in breastfeeding behavior. OXT and OXTR have been proposed as gene candidates for breastfeeding. Previous studies have focused on certain single‐nucleotide polymorphisms (SNPs) within these genes, finding null or inconsistent results. The present study analyses the associations between a wide coverage of polymorphisms in OXT and OXTR and breastfeeding duration from 2 large and independent unselected samples comprising a total of 580 and 2112 female twin mothers from the Murcia Twin Registry (Spain) and QIMR Berghofer Medical Research Institute (Australia), respectively. A total of 19 SNPs in OXT and 137 in OXTR SNPs were covered in both samples. Effects of the OXT and OXTR polymorphisms on breastfeeding duration were calculated by means of linear regression controlling for age at survey time, educational level, interaction between age and educational level and principal components of genetic ancestry. The analyses were conducted independently in the 2 samples and also meta‐analyzed. Although some SNPs were associated at an alpha level of .05 with breastfeeding, they did not survive multiple testing correction. We conclude that SNPs within or nearby OXT and OXTR are unlikely to have large effects on breastfeeding behavior.     

Genetic association of DRD2 polymorphisms with anxiety scores among alcohol-dependent patients

The dopaminergic neurotransmission system is one of the major factors in development of alcoholism and also contributes to anxiety and depression. In this study, the associations of the dopamine receptor type 2 (DRD2) polymorphisms with the symptoms of anxiety were analyzed. A total of 573 alcoholics and 273 controls were enrolled in the study from the Korean population. Five DRD2 SNPs, including −32869 A>G, −32768 insdel C, +11890 C>G, +11915 C>T, and +32806 C>T, were genotyped using a TaqMan assay and analyzed with various alcoholic phenotypes. Although no DRD2 polymorphisms were associated with the risk of alcoholism, +32806C>T and Block2-ht1 showed associations (in dominant models) with both the state anxiety level scale (STAI-S) and the trait anxiety level scale (STAI-T) (P = 0.004 and P = 0.003, and P = 0.01 and P = 0.005, respectively). In addition, the −32768 insdel C also showed positive association with both anxiety level scales in recessive models (P = 0.01 and P = 0.02, respectively).     

Lack of association of glutamate decarboxylase 2 gene polymorphisms with severe obesity in utah

Three polymorphisms of the glutamate decarboxylase 2 gene, which encodes the glutamic acid decarboxylase enzyme, have been associated with severe obesity in a large French cohort. One of these polymorphisms was shown to have functional consequences on promoter expression. Another polymorphism was associated with insulin levels and secretion. These associations were examined in 855 severely obese Utah subjects (mean BMI = 48 kg/m(2)) and a normal-weight and normoglycemic subset (N = 130, mean BMI = 22 kg/m(2)) of a random sample of the Utah population (N = 462). Comparisons of the normal-weight random group with the severely obese group did not result in significant genotype or allele frequency differences for any of the three polymorphisms, C61450A, T83897A, or A-243G (all p > or = 0.18). Haplotypes were also not related to severe obesity (p = 0.10). None of the polymorphisms was significantly related to fasting glucose, insulin levels, or homeostasis model assessment insulin resistance or secretion indices. This study of normal-weight and severely obese subjects from Utah does not provide evidence for involvement of the three genotyped polymorphisms in the glutamate decarboxylase 2 gene with obesity or with insulin- and glucose-related measures associated with obesity.     

CXCR3 polymorphisms associated with risk of asthma

The chemokine (C-X-C motif) receptor 3 (CXCR3) gene, on chromosome Xq13, is known to have critical roles in inflammatory and immune responses. In an effort to discover polymorphisms have been implicated in asthma, we investigated the genetic polymorphisms in CXCR3 to evaluate it as a potential candidate gene for a host genetic study of asthma. Statistical analysis revealed that one SNP in intron 1, c.12+234G > A, showed significant association with the risk of asthma development (P = 0.007, OR = 0.81). By subgroup analyses stratified by gender and atopic status, the genetic effect of c.12+234G > A on asthma was more apparent among male atopic subjects (P = 0.0009, OR = 0.61). Our findings suggest that polymorphisms in CXCR3 might be one of the genetic factors for the risk of asthma development, especially in male atopic subjects. CXCR3 variation/haplotype information identified in this study will provide valuable information and insight into strategies for the control of asthma and its subgroup, atopy.     

Association of FANCC polymorphisms with FEV1 decline in aspirin exacerbated respiratory disease

Aspirin exacerbated respiratory disease (AERD) is a clinical condition characterized by severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. The exacerbated inflammatory response in Fancc-deficient mice has been reported to be associated with hemopoietic responses that are also related to AERD pathogenesis. To investigate associations of FANCC polymorphisms with AERD and related phenotypes, this study genotyped 25 common single nucleotide polymorphisms (SNPs) in a total of 592 Korean asthmatics including 163 AERD and 429 aspirin-tolerant asthma (ATA) subjects. Logistic analysis revealed that genetic polymorphisms of the FANCC gene might not be directly related to AERD development and nasal polyposis (P?>?0.05). However, the FEV1 decline by aspirin provocation showed significant associations with FANCC polymorphisms (P?=?0.006?C0.04) and a haplotype (unique to rs4647416G?>?A, P?=?0.01 under co-dominant, P?=?0.006 under recessive model). In silico analysis showed that the ??A?? allele of rs4647376C?>?A, which was more prevalent in AERD than in ATA, could act as a potential branch point (BP) site for alternative splicing (BP score?=?4.16). Although replications in independent cohorts and further functional evaluations are still needed, our preliminary findings suggest that FANCC polymorphisms might be associated with the obstructive symptoms in allergic diseases.     

Seasonal waves of asthma: A possible botanical cause

The seasonal incidence of asthma and of shoot-growth in eucalypts in four Australian capital cities (Brisbane, Sydney, Adelaide and Melbourne) are compared. The incidence of asthma appears to be closely correlated with the initial stages of the seasonal flushes in shoot-growth of eucalypts, when rapid cell-division occurs. A spring to early summer growth flush invariably occurs in all capitals when the mean monthly temperature rises above 16–18°C; it is initiated progressively later with increasing latitude firstly in Brisbane, then in Sydney, then Adelaide and finally Melbourne. Although the correlation between asthma and eucalypt shoot-growth is high, there is not necessarily a cause-and-effect relationship. Volatile compounds evaporated from young and old leaves are probably not responsible, but the fine faecal pellets from the numerous small larvae and adult insects which attack the young eucalypt shoots may produce possible asthma-allergens. The concentration of these allergens in the atmosphere is reduced by heavy rainfall and by off-shore winds, and may accumulate during periods when temperature inversions occur at low levels in the atmosphere (e.g. during autumn in Brisbane).Supported by a grant from the Asthma Foundation of Queensland.