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1.  Active or Passive Exposure to Tobacco Smoking and Allergic Rhinitis, Allergic Dermatitis, and Food Allergy in Adults and Children: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(3):e1001611.
In a systematic review and meta-analysis, Bahi Takkouche and colleagues examine the associations between exposure to tobacco smoke and allergic disorders in children and adults.
Please see later in the article for the Editors' Summary
Background
Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions.
Methods and Findings
We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children.
We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92–1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06–1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14–1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03–1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24–1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04–1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17–1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01–1.11]). Food allergy was associated with SHS (1.43 [1.12–1.83]) when cohort studies only were examined, but not when all studies were combined.
The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification.
Conclusions
We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The immune system protects the human body from viruses, bacteria, and other pathogens. Whenever a pathogen enters the body, immune system cells called T lymphocytes recognize specific molecules on its surface and release chemical messengers that recruit and activate other types of immune cells, which then attack the pathogen. Sometimes, however, the immune system responds to harmless materials (for example, pollen; scientists call these materials allergens) and triggers an allergic disease such as allergic rhinitis (inflammation of the inside of the nose; hay fever is a type of allergic rhinitis), allergic dermatitis (also known as eczema, a disease characterized by dry, itchy patches on the skin), and food allergy. Recent studies suggest that all these allergic (atopic) diseases are part of a continuous state called the “atopic march” in which individuals develop allergic diseases in a specific sequence that starts with allergic dermatitis during infancy, and progresses to food allergy, allergic rhinitis, and finally asthma (inflammation of the airways).
Why Was This Study Done?
Allergic diseases are extremely common, particularly in children. Allergic rhinitis alone affects 10%–30% of the world's population and up to 40% of children in some countries. Moreover, allergic diseases are becoming increasingly common. Allergic diseases affect the quality of life of patients and are financially costly to both patients and health systems. It is important, therefore, to identify the factors that cause or potentiate their development. One potential risk factor for allergic diseases is active or passive exposure to tobacco smoke. In some countries up to 80% of children are exposed to second-hand smoke so, from a public health point of view, it would be useful to know whether exposure to tobacco smoke is associated with the development of allergic diseases. Here, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical approach for combining the results of several studies) to investigate this issue.
What Did the Researchers Do and Find?
The researchers identified 196 observational studies (investigations that observe outcomes in populations without trying to affect these outcomes in any way) that examined the association between smoke exposure and allergic rhinitis, allergic dermatitis, or food allergy. When all studies were analyzed together, allergic rhinitis was not associated with active smoking but was slightly associated with exposure to second-hand smoke. Specifically, compared to people not exposed to second-hand smoke, the pooled relative risk (RR) of allergic rhinitis among people exposed to second-hand smoke was 1.10 (an RR of greater than 1 indicates an increased risk of disease development in an exposed population compared to an unexposed population). Allergic dermatitis was associated with both active smoking (RR = 1.21) and exposure to second-hand smoke (RR = 1.07). In the populations of children and adolescents included in the studies, allergic rhinitis was associated with both active smoking and exposure to second-hand smoke (RRs of 1.40 and 1.09, respectively), as was allergic dermatitis (RRs of 1.36 and 1.06, respectively). Finally food allergy was associated with exposure to second-hand smoke (RR = 1.43) when cohort studies (a specific type of observational study) only were examined but not when all the studies were combined.
What Do These Findings Mean?
These findings provide limited evidence for a weak association between smoke exposure and allergic disease in adults but suggest that both active and passive smoking are associated with a modestly increased risk of allergic diseases in children and adolescents. The accuracy of these findings may be affected by the use of questionnaires to assess smoke exposure and allergic disease development in most of the studies in the meta-analysis and by the possibility that individuals exposed to smoke may have shared other characteristics that were actually responsible for their increased risk of allergic diseases. To shed more light on the role of smoking in allergic diseases, additional studies are needed that accurately measure exposure and outcomes. However, the present findings suggest that, in countries where many people smoke, 14% and 13% of allergic rhinitis and allergic dermatitis, respectively, among children may be attributable to active smoking. Thus, the elimination of active smoking among children and adolescents could prevent one in seven cases of allergic rhinitis and one in eight cases of allergic dermatitis in such countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001611.
The UK National Health Service Choices website provides information about allergic rhinitis, hay fever (including personal stories), allergic dermatitis (including personal stories), and food allergy (including personal stories)
The US National Institute of Allergy and Infectious Disease provides information about allergic diseases
The UK not-for-profit organization Allergy UK provides information about all aspects of allergic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on allergic rhinitis and allergic dermatitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and food allergy (in English and Spanish)
doi:10.1371/journal.pmed.1001611
PMCID: PMC3949681  PMID: 24618794
2.  TAP1 and TAP2 Gene Polymorphisms in Korean Patients with Allergic Rhinitis 
Journal of Korean Medical Science  2007;22(5):825-831.
Antigen peptides are actively transported across the endoplasmic reticulum by the transporters associated with antigen presentation (TAP). TAP genes polymorphism could influence the selection process that determines which antigen peptides play a role in the pathogenesis of allergic rhinitis. The aim of this study was to investigate the association of TAP genes polymorphism with allergic rhinitis. TAP1 and TAP2 genotyping were performed on 110 allergic rhinitis patients and 107 healthy controls. TAP1 polymorphic residues at codons 333 and 637, and TAP2 polymorphic residues at codons 379, 565, 651, and 665 were analyzed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Analysis of TAP1 gene polymorphism demonstrated decreased frequencies of Ile/Val genotype at codon 333, Asp/Gly genotype at codon 637, and haplotype A and B in allergic rhinitis patients when compared to controls (p<0.05). However, there was no significant difference in the genotype, phenotype, or allele frequencies at four TAP2 codons between controls and allergic rhinitis patients. In conclusion, TAP1 gene polymorphism may be an important factor contributing to the genetic susceptibility in the development of allergic rhinitis in the Korean population.
doi:10.3346/jkms.2007.22.5.825
PMCID: PMC2693848  PMID: 17982230
Allergic Rhinitis; TAP1; TAP2; Polymorphism
3.  Variation in Uteroglobin-Related Protein 1 (UGRP1) gene is associated with Allergic Rhinitis in Singapore Chinese 
BMC Medical Genetics  2011;12:39.
Background
Uteroglobin-Related Protein 1 (UGRP1) is a secretoglobulin protein which has been suggested to play a role in lung inflammation and allergic diseases. UGRP1 has also been shown to be an important pneumoprotein, with diagnostic potential as a biomarker of lung damage. Previous genetic studies evaluating the association between variations on UGRP1 and allergic phenotypes have yielded mixed results. The aim of this present study was to identify genetic polymorphisms in UGRP1 and investigate if they were associated with asthma and allergic rhinitis in the Singapore Chinese population.
Methods
Resequencing of the UGRP1 gene was conducted on 40 randomly selected individuals from Singapore of ethnic Chinese origin. The polymorphisms identified were then tagged and genotyped in a population of 1893 Singapore Chinese individuals. Genetic associations were evaluated in this population comparing 795 individuals with allergic rhinitis, 718 with asthma (of which 337 had both asthma and allergic rhinitis) and 717 healthy controls with no history of allergy or allergic diseases.
Results
By resequencing the UGRP1 gene within our population, we identified 11 novel and 16 known single nucleotide polymorphisms (SNPs). TagSNPs were then genotyped, revealing a significant association between rs7726552 and allergic rhinitis (Odds Ratio: 0.81, 95% Confidence Interval: 0.66-0.98, P = 0.039). This association remained statistically significant when it was analyzed genotypically or when stratified according to haplotypes. When variations on UGRP1 were evaluated against asthma, no association was observed.
Conclusion
This study documents the association between polymorphisms in UGRP1 and allergic rhinitis, suggesting a potential role in its pathogenesis.
doi:10.1186/1471-2350-12-39
PMCID: PMC3070627  PMID: 21410962
4.  Impact of Allergic Rhinitis on Quality of Life in Patients with Bronchial Asthma 
Allergy and asthma can reduce HRQOL as a result of profound physical and psychosocial complications. Most patients with asthma also suffer from rhinitis, which also impairs quality of life. However, the impact of allergic rhinitis on asthmatic patients has not been investigated.
Objective
To assess Quality of life (QOL) in asthmatic patients and assess relative burden of allergic rhinitis on asthmatics’ QOL.
Patients and Methods
we analysed HRQOL questionnaire (SF-36) answers of 219 patients (118 allergic rhinitis, 79 asthma and 22 asthma with allergic rhinitis) and controls (30 healthy individuals), in addition to analysis of questionnaire scores according to patients’ characteristic including gender, BMI and duration of symptoms. Moreover, pulmonary function test were done for all patients and control.
Results
HRQOL parameters were significantly lower in females more than males and in patients with BMI>25 if compared with those with BMI<25. Moreover, HRQOL was significantly lower in all 3 patients’ groups if compared with control group (P<0.001) in all parameters except mental health and role emotional. Significantly higher scores (SF-36 sub-scales for physical functioning, role-physical, bodily pain) were found among allergic rhinitis patients compared with asthmatics with or without allergic rhinitis. Although, quality of life was worse in asthmatic patients compared to patients with rhinitis alone, no significant difference was found between asthmatics and those with both diseases. Both PCS and MCS scores are significantly lower in patients’ groups compared with the control (p<0.05). Asthmatic patients with or without rhinitis tended to have lower PCS and MCS scores than subjects with isolated allergic rhinitis, the difference between the groups was statistically significant only for PCS scores. Moreover, highly significant positive correlation between PCS score and FEV1 in asthmatics with or without allergic rhinitis was detected denoting that PCS score is markedly affected by severity of asthma. (r=0.949, P<0.001).
Conclusions
Allergic rhinitis has a limited role in reduction of HRQOL. HRQOL is markedly reduced in patients with asthma with or without rhinitis than in those with allergic rhinitis only; this could be related to the severity of asthma more than the presence of associated allergic rhinitis. These findings indicated that allergic rhinitis does not seem to further impair quality of life in subjects with asthma. We recommend that patients with bronchial asthma with or without allergic rhinitis in need of great help from physicians and social workers to improve their physical and mental health. Moreover, further studies with larger populations and longer duration are needed in order to determine the extent to which asthma and rhinitis comorbidities are associated in HRQOL.
PMCID: PMC3616948  PMID: 23580898
asthma; allergic rhinitis; HRQOL; SF-36 questionnaire
5.  Patterns of GATA3 and IL13 gene polymorphisms associated with childhood rhinitis and atopy in a birth cohort 
Background
GATA3 activates transcription of the TH2 cytokines, including IL13, an important step in the allergic inflammatory pathway.
Objective
We sought to identify associations of single nucleotide polymorphisms of the genes GATA3 and IL13 and their interactions with rhinitis and allergic sensitization during childhood.
Methods
We performed genetic association studies in a cohort of children (n = 923) who have been evaluated for the development of rhinitis and allergic sensitization by means of skin prick tests (SPTs) at age 10 years. Pyrosequencing was used to genotype 7 polymorphisms from GATA3 and 5 from IL13. A novel model-selection procedure combining logistic regression models and classification was used to study the contributions of the polymorphisms and their interactions.
Results
Combinations of polymorphisms and their interactions increase the risk for rhinitis and allergic sensitization at age 10 years. A model with rs1058240, rs379568, and rs4143094 (GATA3) and rs1800925 (IL13) and their interactions was selected to predict rhinitis and positive SPT responses. rs1058240 was associated with rhinitis and allergic rhinitis (P < .05), and the gene-gene interaction rs1058240:rs1800925 was associated with rhinitis (P = .043). The odds ratios for 4 genotype combinations were significant for rhinitis or SPTs (P < .044).
Conclusion
Gene-gene interaction between GATA3 and IL13 polymorphisms can influence the risk of childhood rhinitis. Our study suggests that set associations of polymorphisms are important in studying genetic associations for complex phenotypes, such as rhinitis and atopy.
doi:10.1016/j.jaci.2007.09.020
PMCID: PMC2705662  PMID: 18037162
Rhinitis; allergic rhinitis; atopy; GATA3; IL13; genetic association; gene-gene interactions
6.  Comprehensive evaluation of genetic variation in S100A7 suggests an association with the occurrence of allergic rhinitis 
Respiratory Research  2008;9(1):29.
Background
S100A7 is a calcium-binding protein with chemotactic and antimicrobial properties. S100A7 protein levels are decreased in nasal lavage fluid from individuals with ongoing allergic rhinitis, suggesting a role for S100A7 in allergic airway inflammation. The aims of this study were to describe genetic variation in S100A7 and search for associations between this variation and allergic rhinitis.
Methods
Peripheral blood was collected from 184 atopic patients with a history of pollen-induced allergic rhinitis and 378 non-atopic individuals, all of Swedish origin. DNA was extracted and the S100A7 gene was resequenced in a subset of 47 randomly selected atopic individuals. Nine polymorphisms were genotyped in 184 atopic and 378 non-atopic individuals and subsequently investigated for associations with allergic rhinitis as well as skin prick test results. Haplotypes were estimated and compared in the two groups.
Results
Thirteen polymorphisms were identified in S100A7, of which 7 were previously undescribed. rs3014837 (G/C), which gives rise to an Asp → Glu amino acid shift, had significantly increased minor allele frequency in atopic individuals. The major haplotype, containing the major allele at all sites, was more common in non-atopic individuals, while the haplotype containing the minor allele at rs3014837 was equally more common among the atopic individuals. Additionally, heterozygotes at this site had significantly higher scores in skin prick tests for 9 out of 11 tested allergens, compared to homozygotes.
Conclusion
This is the first study describing genetic variation, associated with allergy, in S100A7. The results indicate that rs3014837 is linked to allergic rhinitis in our Swedish population and render S100A7 a strong candidate for further investigations regarding its role in allergic inflammation.
doi:10.1186/1465-9921-9-29
PMCID: PMC2335106  PMID: 18373864
7.  Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies 
PLoS Medicine  2014;11(10):e1001748.
Using data from two population-based birth cohorts, Danielle Belgrave and colleagues examine the evidence for atopic march in developmental profiles for allergic disorders.
Please see later in the article for the Editors' Summary
Background
The term “atopic march” has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level.
Methods and Findings
Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time.
Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts.
Conclusions
The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (∼7% of those with symptoms) follow trajectory profiles resembling the atopic march.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Our immune system protects us from viruses, bacteria, and other pathogens by recognizing specific molecules on the invader's surface and initiating a sequence of events that culminates in the death of the pathogen. Sometimes, however, our immune system responds to harmless materials (allergens such as pollen) and triggers allergic, or atopic, symptoms. Common atopic symptoms include eczema (transient dry itchy patches on the skin), wheeze (high pitched whistling in the chest, a symptom of asthma), and rhinitis (sneezing or a runny nose in the absence of a cold or influenza). All these symptoms are very common during childhood, but recent epidemiological studies (examinations of the patterns and causes of diseases in a population) have revealed age-related changes in the proportions of children affected by each symptom. So, for example, eczema is more common in infants than in school-age children. These findings have led to the idea of “atopic march,” a natural progression of symptoms within individual children that starts with eczema, then progresses to wheeze and finally rhinitis.
Why Was This Study Done?
The concept of atopic march has led to the initiation of studies that aim to prevent the development of asthma in children who are thought to be at risk of asthma because they have eczema. Moreover, some guidelines recommend that clinicians tell parents that children with eczema may later develop asthma or rhinitis. However, because of the design of the epidemiological studies that support the concept of atopic march, children with eczema who later develop wheeze and rhinitis may actually belong to a distinct subgroup of children, rather than representing the typical progression of atopic diseases. It is important to know whether atopic march adequately describes the natural history of atopic diseases during childhood to avoid the imposition of unnecessary strategies on children with eczema to prevent asthma. Here, the researchers use machine learning techniques to model the developmental profiles of eczema, wheeze, and rhinitis during childhood in two large population-based birth cohorts by taking into account time-related (longitudinal) changes in symptoms within individuals. Machine learning is a data-driven approach that identifies structure within the data (for example, a typical progression of symptoms) using unsupervised learning of latent variables (variables that are not directly measured but are inferred from other observable characteristics).
What Did the Researchers Do and Find?
The researchers used data from two UK birth cohorts—the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Manchester Asthma and Allergy Study (MAAS)—for their study (9,801 children in total). Both studies enrolled children at birth and monitored their subsequent health at regular review clinics. At each review clinic, information about eczema, wheeze, and rhinitis was collected from the parents using validated questionnaires. The researchers then used these data and machine learning methods to identify groups of children with similar patterns of onset of eczema, wheeze, and rhinitis over the first 11 years of life. Using a type of statistical model called a latent disease profile model, the researchers found that the data were best described by eight latent classes—no disease (51.3% of the children), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%).
What Do These Findings Mean?
These findings show that, in two large UK birth cohorts, the developmental profiles of eczema, wheeze, and rhinitis were heterogeneous. Most notably, the progression of symptoms fitted the profile of atopic march in fewer than 7% of children with symptoms. The researchers acknowledge that their study has some limitations. For example, small differences in the wording of the questions used to gather information from parents about their children's symptoms in the two cohorts may have slightly affected the findings. However, based on their findings, the researchers propose that, because eczema, wheeze, and rhinitis are common, these symptoms often coexist in individuals, but as independent entities rather than as a linked progression of symptoms. Thus, using eczema as an indicator of subsequent asthma risk and assigning “preventative” measures to children with eczema is flawed. Importantly, clinicians need to understand the heterogeneity of patterns of atopic diseases in children and to communicate this variability to parents when advising them about the development and resolution of atopic symptoms in their children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001748.
The UK National Health Service Choices website provides information about eczema (including personal stories), asthma (including personal stories), and rhinitis
The US National Institute of Allergy and Infectious Diseases provides information about atopic diseases
The UK not-for-profit organization Allergy UK provides information about atopic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on eczema, wheezing, and rhinitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and asthma (in English and Spanish)
Information about ALSPAC and MAAS is available
Wikipedia has pages on machine learning and latent disease profile models (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001748
PMCID: PMC4204810  PMID: 25335105
8.  Case-control study of IL13 polymorphisms, smoking, and rhinoconjunctivitis in Japanese women: the Kyushu Okinawa Maternal and Child Health Study 
BMC Medical Genetics  2011;12:143.
Background
Six previous studies have examined the relationships between single nucleotide polymorphisms (SNPs) in the IL13 gene and allergic rhinitis, but the results have been inconsistent. However, a recent meta-analysis using data from these 6 studies has shown that the A allele of IL13 SNP rs20541 was associated with an increased risk of allergic rhinitis, whereas no such relationship existed between IL13 SNP rs1800925 and allergic rhinitis. We investigated the associations between IL13 SNPs rs1800925 and rs20541 and the risk of rhinoconjunctivitis in Japanese women.
Methods
Included were 393 cases who met the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC) for rhinoconjunctivitis. Control subjects were 767 women without rhinoconjunctivitis according to the ISAAC criteria, who had also not been diagnosed with allergic rhinitis by a doctor. Adjustment was made for age, region of residence, presence of older siblings, smoking, family history of allergic rhinitis, and education.
Results
Compared with the GG genotype of IL13 SNP rs20541, the AA genotype, occurring in 7.1% of control subjects, was significantly positively related to the risk of rhinoconjunctivitis: the adjusted odds ratio was 1.65 (95% confidence interval: 1.05 - 2.60). SNP rs1800925 was not associated with rhinoconjunctivitis. The haplotype comprising the rs1800925 C allele and the rs20541 A allele was significantly positively related to rhinoconjunctivitis. The multiplicative interactions between the two SNPs under study and smoking on the risk of rhinoconjunctivitis were not statistically significant. Based on the recessive model, however, the additive interaction between SNP rs1800925, but not rs20541, and smoking was significant.
Conclusions
This study suggests that the minor genotype of IL13 SNP rs20541 and the CA haplotype are significantly positively associated with the risk of rhinoconjunctivitis. In addition, a new pattern of biological interaction that affects the risk of rhinoconjunctivitis is described between SNP rs1800925 and smoking.
doi:10.1186/1471-2350-12-143
PMCID: PMC3214177  PMID: 22023794
9.  Association Study on ADAM33 Polymorphisms in Mite-Sensitized Persistent Allergic Rhinitis in a Chinese Population 
PLoS ONE  2014;9(4):e95033.
Background
The ADAM33 gene has been identified as a potentially important asthma candidate gene and polymorphisms in this gene have been shown to be associated with asthma and seasonal allergic rhinitis.
Objective
To assess whether the ADAM33 polymorphisms are associated with persistent allergic rhinitis (PER) due to house dust mites in a Chinese population.
Methods
In a hospital-based case-control study of 515 patients with mite-sensitized PER and 495 healthy controls, we genotyped seven single nucleotide polymorphisms (SNPs) in ADAM33. Serum levels of eosinophil cationic protein, total IgE and allergen-specific IgE against Dermatophagoides pteronyssinus and Dermatophagoides farinae were measured by the ImmunoCAP assays.
Results
In the single-locus analysis, three polymorphisms, rs3918392 (F1), rs528557 (S2) and rs2787093, were significantly associated with mite-sensitized PER. SNP S2 was associated with significantly increased risk both of asthmatic and nonasthmatic mite-sensitized PER. In the combined genotypes analysis, individuals with 2–4 risk alleles had a significantly higher risk of mite-sensitized PER (adjusted OR = 1.99, 95% CI = 1.50–2.62) than those with 0–1 risk alleles. Haplotype-based association analysis revealed that the ACAGCCT haplotype might have potential to protect against mite-sensitized PER (adjusted OR = 0.67; 95% CI = 0.49–0.90).
Conclusions
Polymorphisms in the ADAM33 gene may contribute to susceptibility of mite-sensitized PER in this Chinese population.
doi:10.1371/journal.pone.0095033
PMCID: PMC3994017  PMID: 24751681
10.  Traffic exposure associated with allergic asthma and allergic rhinitis in adults. A cross-sectional study in southern Sweden 
Background
There is conflicting evidence that traffic-related air pollution is a risk factor for allergic conditions. Few studies have investigated this in adults. In adults, a high proportion of asthma, rhinitis and eczema is triggered by non-allergic factors. We investigated traffic as a risk factor for allergic versus non-allergic asthma and rhinitis, and eczema, in adults.
A questionnaire from 2000 (n = 9319, 18–77 years) provided individual data about disease outcome and self-reported traffic exposure. Additional exposure assessments were obtained using Geographical Informations Systems (GIS). Residential addresses were linked to the national Swedish Road Database and to a pollutant database with modelled annual means of NOx (Nitrogen Oxids).
Results
Living within 100 m from a road with a traffic intensity of >10 cars/min (24 hour mean) was associated with prevalence of current asthma reported to be triggered by allergic factors (OR = 1.83, 95% CI = 1.23–2.72) and with allergic rhinitis (OR = 1.30, 95%CI = (1.05–1.61). No relation was seen with asthma or rhinitis triggered by other factors. Living within 100 m of a road with >10 cars/min was also associated with hand-eczema during the last 12 months (OR = 1.63, 95% CI = 1.19–2.23), but not with allergic eczema or diagnosed hand-eczema. Consistent results were seen using self-reported traffic, but the associations with NOx were less consistent.
Conclusion
Exposure to traffic was associated with a higher prevalence of allergic asthma and allergic rhinitis, but not with asthma or rhinitis triggered by non-allergic factors. This difference was suggested by the overall pattern, but only clear using GIS-measured traffic intensity as a proxy for traffic exposure. An association was also found with hand-eczema during the last 12 months. We suggest that asthma and rhinitis should not be treated as homogenous groups when estimating effects from traffic in adults.
doi:10.1186/1476-072X-8-25
PMCID: PMC2687434  PMID: 19419561
11.  Allergic rhinitis: evidence for impact on asthma 
BMC Pulmonary Medicine  2006;6(Suppl 1):S4.
Background
This paper reviews the current evidence indicating that comorbid allergic rhinitis may have clinically relevant effects on asthma.
Discussion
Allergic rhinitis is very common in patients with asthma, with a reported prevalence of up to 100% in those with allergic asthma. While the temporal relation of allergic rhinitis and asthma diagnoses can be variable, the diagnosis of allergic rhinitis often precedes that of asthma. Rhinitis is an independent risk factor for the subsequent development of asthma in both atopic and nonatopic individuals. Controlled studies have provided conflicting results regarding the benefits for asthma symptoms of treating comorbid allergic rhinitis with intranasal corticosteroids. Effects of other treatments for comorbid allergic rhinitis, including antihistamines, allergen immunotherapy, systemic anti-IgE therapy, and antileukotriene agents, have been examined in a limited number of studies; anti-IgE therapy and antileukotriene agents such as the leukotriene receptor antagonists have benefits for treating both allergic rhinitis and asthma. Results of observational studies indicate that treating comorbid allergic rhinitis results in a lowered risk of asthma-related hospitalizations and emergency visits. Results of several retrospective database studies in the United States and in Europe indicate that, for patients with asthma, the presence of comorbid allergic rhinitis is associated with higher total annual medical costs, greater prescribing frequency of asthma-related medications, as well as increased likelihood of asthma-related hospital admissions and emergency visits. There is therefore evidence suggesting that comorbid allergic rhinitis is a marker for more difficult to control asthma and worsened asthma outcomes.
Conclusion
These findings highlight the potential for improving asthma outcomes by following a combined therapeutic approach to comorbid allergic rhinitis and asthma rather than targeting each condition separately.
doi:10.1186/1471-2466-6-S1-S4
PMCID: PMC1698497  PMID: 17140422
12.  Association Pattern of Interleukin-1 Receptor-Associated Kinase-4 Gene Polymorphisms with Allergic Rhinitis in a Han Chinese Population 
PLoS ONE  2011;6(6):e21769.
Objective
Interleukin-1 receptor-associated kinase-4 (IRAK-4) encodes a kinase that is essential for NF-kB activation in Toll-like receptor and T-cell receptor signaling pathways, indicating a possible crosstalk between innate and acquired immunities. We attempted to determine whether the polymorphisms in the Interleukin-1 receptor-associated kinase-4 (IRAK-4) gene are associated with allergic rhinitis (AR) in the Han Chinese population.
Methods
A population of 379 patients with AR and 333 healthy controls was studied. Blood was drawn for DNA extraction and total serum immunoglobulin E (IgE). A total of 11 single nucleotide polymorphisms (SNPs) in IRAK-4 were selected and individually genotyped.
Results
Significant allelic differences between cases and controls were obtained for the SNP of rs3794262 in the IRAK-4 gene. In the stratified analysis for gender, two SNPs (rs4251431 and rs6582484) in males appeared as significant associations. Subgroup analysis for the presence of different allergen sensitivities displayed associations only in the house dust mite-allergic cohorts (rs3794262, rs4251481). None of the selected SNPs in IRAK-4 was associated with total IgE level. The haplotype analyisis indicated GCCTGCGA was significantly associated with AR. The SNP-SNP interaction information analysis indicated that the selected sets of polymorphisms had no synergistic effect.
Conclusions
Our findings did not support the potential contribution of the IRAK-4 gene to serum IgE levels. However, the results demonstrated a gender- and allergen-dependant association pattern between polymorphisms in IRAK-4 and AR in Chinese population.
doi:10.1371/journal.pone.0021769
PMCID: PMC3128076  PMID: 21738793
13.  A longitudinal analysis of associations between traffic-related air pollution with asthma, allergies and sensitization in the GINIplus and LISAplus birth cohorts 
PeerJ  2013;1:e193.
Background. There is a need to study whether the adverse effects of traffic-related air pollution (TRAP) on childhood asthma and allergic diseases documented during early-life persist into later childhood. This longitudinal study examined whether TRAP is associated with the prevalence of asthma, allergic rhinitis and aeroallergen sensitization in two German cohorts followed from birth to 10 years.
Materials. Questionnaire-derived annual reports of doctor diagnosed asthma and allergic rhinitis, as well as eye and nose symptoms, were collected from 6,604 children. Aeroallergen sensitization was assessed for 3,655 children who provided blood samples. Associations between these health outcomes and nitrogen dioxide (NO2), particles with aerodynamic diameters less than 2.5 µg/m3 (PM2.5) mass, PM2.5 absorbance and ozone, individually estimated for each child at the birth, six and 10 year home addresses, were assessed using generalized estimation equations including adjustments for relevant covariates. Odds ratios [95% confidence intervals] per increase in interquartile range of pollutant are presented for the total population and per geographical area (GINI/LISA South, GINI/LISA North and LISA East, Germany).
Results. The risk estimates for the total population were generally null across outcomes and pollutants. The area-specific results were heterogeneous. In GINI/LISA North, all associations were null. In LISA East, associations with ozone were elevated for all outcomes, and those for allergic rhinitis and eyes and nose symptom prevalence reached statistical significance (1.30 [1.02, 1.64] and 1.35 [1.16, 1.59], respectively). For GINI/LISA South, two associations with aeroallergen sensitization were significant (0.84 [0.73, 0.97] for NO2 and 0.87 [0.78, 0.97] for PM2.5 absorbance), as well as the association between allergic rhinitis and PM2.5 absorbance (0.83 [0.72, 0.96]).
Conclusions. This study did not find consistent evidence that TRAP increases the prevalence of childhood asthma, allergic rhinitis or aeroallergen sensitization in later childhood using data from birth cohort participants followed for 10 years in three locations in Germany. Results were heterogeneous across the three areas investigated.
doi:10.7717/peerj.193
PMCID: PMC3828611  PMID: 24255809
Asthma; Allergies; Air pollution; Birth cohort; Children; Long-term exposure; Traffic
14.  The -590C/TIL4 single-nucleotide polymorphism as a genetic factor of atopic allergy 
Elevated IgE levels in individuals with asthma, allergic rhinitis, and atopic dermatitis represents a situation in that increased IL4 production seems to occur because of the genetic component of the disease. In this study, one-hundred two matched-pairs of allergic and non-allergic individuals were phenotyped for total serum IgE level using enzyme-linked immunosorbent assay (ELISA). Atopic status was defined by serum IgE concentration ≥100 IU/mL The -590C/T IL4 (rs2243250) was screened by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis. An association between the IL4 -590 TT genotype and levels of IgE was confirmed in the study population (ANOVA p=0.017). Furthermore, the IL4 T allele was significantly increased in allergic (0.299) compared with non-allergic subjects (0.172) (OR=2.060, 95% 01 = 1.285-3.301, χ2 uncorrected p=0.002) at total serum IgE cut-off of 100 IU/mL. A significant relationship between IL4 -590 TT genotype and very high IgE levels (>1000 IU/mL) (OR=3.968, 95% CI = 1.499-10.5, χ2 uncorrected p=0.01624) was also established. The -590C/T IL4 polymorphism is a potential risk factor to and correlates with atopic allergy.
PMCID: PMC3076745  PMID: 21537454
Atopy; allergy; IL-4; single-nucleotide polymorphism; SNP; total IgE
15.  Association of ADAM33 gene polymorphisms with adult allergic asthma and rhinitis in a Chinese Han population 
BMC Medical Genetics  2008;9:82.
Background
Rhinitis and asthma are very common diseases involving genetic and environmental factors. Most patients with asthma also have rhinitis, which suggests the concept of 'one airway, one disease.' A disintegrin and metalloproteinase 33 (ADAM33) is the first asthma-susceptible gene to be discovered by positional cloning. To evaluate the potential influence of ADAM33 gene polymorphisms on allergic rhinitis (AR) and allergic asthma (AS), a case-control study was conducted on the Han population of northeast China.
Methods
Six polymorphic sites (V4, T+1, T2, T1, S1, and Q-1) were genotyped in 128 patients with AR, 181 patients with AS, and 151 healthy controls (CTR). Genotypes were determined by the polymerase chain restriction fragment length polymorphism (PCR-RFLP) method. Data were analyzed using the chi-square test with Haploview software.
Results
The single nucleotide polymorphisms (SNPs), V4 G/C, T+1 A/G, and T1 G/A, of the ADAM33 gene may be the causal variants in AR, whereas ADAM33 V4 G/C, T2 A/G, T1 G/A, and Q-1A/G may participate in the susceptibility of AS.
Conclusion
These results suggest that polymorphisms of the ADAM33 gene may modify individual susceptibility to AR and AS in a Chinese Han population.
doi:10.1186/1471-2350-9-82
PMCID: PMC2553063  PMID: 18778489
16.  Association between Polymorphisms of the IL-23R Gene and Allergic Rhinitis in a Chinese Han Population 
PLoS ONE  2013;8(5):e63858.
Objective
Polymorphism of the interleukin-23 receptor gene corresponds with susceptibility to several immune-related diseases. For the terminal differentiation of IL-17-producing effector T-helper cells in vivo, the interleukin-23 receptor gene is of vital importance. As shown recently, Th17 cells probably have a great influence on the pathogenesis of allergic airway diseases. Our intention was to establish an association between polymorphisms in the IL-23R gene and allergic rhinitis (AR) in the Chinese Han population.
Methods
We included 358 AR patients and 407 control Chinese subjects in a case-control comparison. The study involved obtaining blood samples for DNA extraction genotyping and determination of 4 selected single-nucleotide polymorphisms in IL-23R by performing PCR restriction fragment length polymorphism analysis (PCR-RFLP).
Results
A substantially growing prevalence of the homozygous rs7517847 GG genotype and G allele appeared in the AR patients unlike that observed in the control individuals (P<0.001). In addition, substantially high frequencies of the GGCA and GGCG haplotypes were observed in the AR patients, unlike that observed in the control individuals (P<0.05). The results suggest that the AGTG haplotype may provide protection against AR (P<0.001).
Conclusions
To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IL-23R and AR in the Chinese Han population. A strong association between rs7517847 in a SNP of IL-23R, and AR was identified.
doi:10.1371/journal.pone.0063858
PMCID: PMC3655942  PMID: 23696856
17.  Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis 
BMC Medical Genomics  2014;7:48.
Background
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
Methods
We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
Results
GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).
Conclusions
Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
doi:10.1186/1755-8794-7-48
PMCID: PMC4127082  PMID: 25085501
Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy
18.  Genetic predisposition for atopy and allergic rhinitis in the Singapore Chinese population 
Asia Pacific Allergy  2011;1(3):152-156.
The prevalence of allergic diseases is high globally, but especially in developed countries, with one in five to one in four individuals affected worldwide. The World Health Organization's "Allergic Rhinitis and its Impact on Asthma 2008 Update" guidelines stated explicitly that over 600 million patients from all countries, all ethnic groups and all ages suffer from allergic rhinitis (AR). There are clear evidences to support the concept that allergic diseases are influenced by genetic predisposition and environmental factors. The genetic basis of AR has been evaluated more intensively in the recent 10-20 years. Advances in technology and statistical methods, such as genome-wide association studies (GWAS) have enabled millions of single nucleotide polymorphisms (SNPs) to be genotyped at rapid pace and for less cost. However these studies have not yet answered the entire heritability profile of the disease. Additionally, environmental influences on these genetic variants cannot be discounted. Hence these allergic diseases must be evaluated as a complex interplay between genetic and environmental factors. This review focuses on the genetic basis of AR, with special emphasis on studies performed in Singapore. Candidate gene based studies and GWAS performed in Singapore cohorts have been discussed to suggest how these diseases could be understood better in a Singapore context which is still applicable to research in AR globally.
doi:10.5415/apallergy.2011.1.3.152
PMCID: PMC3206245  PMID: 22053312
Allergic rhinitis; Atopy; Genetic predisposition; Singapore Chinese
19.  Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis 
Objective To investigate whether filaggrin gene defects, present in up to one in 10 western Europeans and North Americans, increase the risk of developing allergic sensitisation and allergic disorders.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, ISI Science Citation Index, BIOSIS, ISI Web of Knowledge, UK National Research Register, clinical trials.gov, the Index to Theses and Digital dissertations, and grey literature using OpenSIGLE.
Study selection Genetic epidemiological studies (family, case-control) of the association between filaggrin gene defects and allergic sensitisation or allergic disorders.
Data extraction Atopic eczema or dermatitis, food allergy, asthma, allergic rhinitis, and anaphylaxis, along with relevant immunological variables relating to the risk of allergic sensitisation as assessed by either positive skin prick testing or increased levels of allergen specific IgE.
Data synthesis 24 studies were included. The odds of developing allergic sensitisation was 1.91 (95% confidence interval 1.44 to 2.54) in the family studies and 1.57 (1.20 to 2.07) in the case-control studies. The odds of developing atopic eczema was 1.99 (1.72 to 2.31) in the family studies and 4.78 (3.31 to 6.92) in the case-control studies. Three studies investigated the association between filaggrin gene mutations and allergic rhinitis in people without atopic eczema: overall odds ratio 1.78 (1.16 to 2.73). The four studies that investigated the association between filaggrin gene mutations and allergic rhinitis in people with atopic eczema reported a significant association: pooled odds ratio from case-control studies 2.84 (2.08 to 3.88). An overall odds ratio for the association between filaggrin gene mutations and asthma in people with atopic eczema was 2.79 (1.77 to 4.41) in case-control studies and 2.30 (1.66 to 3.18) in family studies. None of the studies that investigated filaggrin gene mutations and asthma in people without atopic eczema reported a significant association; overall odds ratio was 1.30 (0.7 to 2.30) in the case-control studies. The funnel plots suggested that publication bias was unlikely to be an explanation for these findings. No studies investigated the association between filaggrin gene mutations and food allergy or anaphylaxis.
Conclusions Filaggrin gene defects increase the risk of developing allergic sensitisation, atopic eczema, and allergic rhinitis. Evidence of the relation between filaggrin gene mutations and atopic eczema was strong, with people manifesting increased severity and persistence of disease. Filaggrin gene mutations also increased the risk of asthma in people with atopic eczema. Restoring skin barrier function in filaggrin deficient people in early life may help prevent the development of sensitisation and halt the development and progression of allergic disease.
doi:10.1136/bmj.b2433
PMCID: PMC2714678  PMID: 19589816
20.  The Impact of Allergic Rhinitis and Asthma on Human Nasal and Bronchial Epithelial Gene Expression 
PLoS ONE  2013;8(11):e80257.
Background
The link between upper and lower airways in patients with both asthma and allergic rhinitis is still poorly understood. As the biological complexity of these disorders can be captured by gene expression profiling we hypothesized that the clinical expression of rhinitis and/or asthma is related to differential gene expression between upper and lower airways epithelium.
Objective
Defining gene expression profiles of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles.
Methods
This cross-sectional study included 18 subjects (6 allergic asthma and allergic rhinitis; 6 allergic rhinitis; 6 healthy controls). The estimated false discovery rate comparing 6 subjects per group was approximately 5%. RNA was extracted from isolated and cultured epithelial cells from bronchial brushings and nasal biopsies, and analyzed by microarray (Affymetrix U133+ PM Genechip Array). Data were analysed using R and Bioconductor Limma package. For gene ontology GeneSpring GX12 was used.
Results
The study was successfully completed by 17 subjects (6 allergic asthma and allergic rhinitis; 5 allergic rhinitis; 6 healthy controls). Using correction for multiple testing, 1988 genes were differentially expressed between healthy lower and upper airway epithelium, whereas in allergic rhinitis with or without asthma this was only 40 and 301 genes, respectively. Genes influenced by allergic rhinitis with or without asthma were linked to lung development, remodeling, regulation of peptidases and normal epithelial barrier functions.
Conclusions
Differences in epithelial gene expression between the upper and lower airway epithelium, as observed in healthy subjects, largely disappear in patients with allergic rhinitis with or without asthma, whilst new differences emerge. The present data identify several pathways and genes that might be potential targets for future drug development.
doi:10.1371/journal.pone.0080257
PMCID: PMC3839950  PMID: 24282527
21.  Association of the Histamine N-methyltransferase C314T (Thr105Ile) Polymorphism with Atopic Dermatitis in Caucasian Children 
Pharmacotherapy  2008;28(12):1495-1501.
Study Objective
To investigate potential associations between the histamine N-methyltransferase (HNMT) C314T (Thr105Ile) polymorphism and atopic dermatitis (AD) in a cohort of Caucasian children.
Design
Prospective, multi-center (n=4) genotype/association study.
Setting
Four academic, tertiary care, medical centers within the Pediatric Pharmacology Research Unit (PPRU) network
Patients or Participants
Caucasian children ages 6 months – 5 years with (n=129) and without (n=127) AD. All subjects completed the study although data from 6 subjects (n=2 AD and n=4 control) were excluded due to violations in inclusion/exclusion criteria (n=5) and the informed consent process (n=1).
Interventions
Information was collected regarding severity of AD, oral antihistamine treatment and treatment response via parental report. Buccal swabs (n=1 per cheek) were also performed to obtain epithelial cells for extraction of genomic DNA.
Measurements and Main results
HMNT genotypes were successfully obtained in 116 and 122 control and AD subjects, respectively. Frequencies of the T314 variant allele (0.12, p=0.04) and combined CT/TT genotype (0.24, p=0.02) were significantly higher in children with AD compared with controls (allele and genotype frequencies = 0.06 and 0.12). Children with genotypes conferring reduced HNMT activity were two times more likely to have AD than those who were homozygous for the C314 reference allele.
Conclusions
Increased histamine levels in patients with AD may result, at least in part, from reduced inactivation via HNMT. Genetically-associated reduction in histamine biotransformation may therefore contribute to the pathogenesis, persistence and progression of AD. If confirmed, these data indicate that HNMT might represent a common risk factor for development of AD, asthma and allergic rhinitis and may be useful in identifying individuals who are candidates for early preventative pharmacotherapeutic intervention. Additional longitudinal studies will be required in order to assess the relationship between genotype, disease severity and antihistamine response.
doi:10.1592/phco.28.12.1495
PMCID: PMC2642612  PMID: 19025430
atopic dermatitis; histamine N-methyltransferase; pediatric; pharmacogenetics
22.  Breast feeding and allergic diseases in infants—a prospective birth cohort study 
Archives of Disease in Childhood  2002;87(6):478-481.
Aims: To investigate the effect of breast feeding on allergic disease in infants up to 2 years of age.
Methods: A birth cohort of 4089 infants was followed prospectively in Stockholm, Sweden. Information about various exposures was obtained by parental questionnaires when the infants were 2 months old, and about allergic symptoms and feeding at 1 and 2 years of age. Duration of exclusive and partial breast feeding was assessed separately. Symptom related definitions of various allergic diseases were used. Odds ratios (OR) and 95% confidence intervals (CI) were estimated in a multiple logistic regression model. Adjustments were made for potential confounders.
Results: Children exclusively breast fed during four months or more exhibited less asthma (7.7% v 12%, ORadj = 0.7, 95% CI 0.5 to 0.8), less atopic dermatitis (24% v 27%, ORadj = 0.8, 95% CI 0.7 to 1.0), and less suspected allergic rhinitis (6.5% v 9%, ORadj = 0.7, 95% CI 0.5 to 1.0) by 2 years of age. There was a significant risk reduction for asthma related to partial breast feeding during six months or more (ORadj = 0.7, 95% CI 0.5 to 0.9). Three or more of five possible allergic disorders—asthma, suspected allergic rhinitis, atopic dermatitis, food allergy related symptoms, and suspected allergic respiratory symptoms after exposure to pets or pollen—were found in 6.5% of the children. Exclusive breast feeding prevented children from having multiple allergic disease (ORadj = 0.7, 95% CI 0.5 to 0.9) during the first two years of life.
Conclusion: Exclusive breast feeding seems to have a preventive effect on the early development of allergic disease—that is, asthma, atopic dermatitis, and suspected allergic rhinitis, up to 2 years of age. This protective effect was also evident for multiple allergic disease.
doi:10.1136/adc.87.6.478
PMCID: PMC1755833  PMID: 12456543
23.  FCRL3 Gene Polymorphisms Confer Autoimmunity Risk for Allergic Rhinitis in a Chinese Han Population 
PLoS ONE  2015;10(1):e0116419.
Background
Heredity and environmental exposures may contribute to a predisposition to allergic rhinitis (AR). Autoimmunity may also involve into this pathologic process. FCRL3 (Fc receptor-like 3 gene), a novel immunoregulatory gene, has recently been reported to play a role in autoimmune diseases.
Objective
This study was performed to evaluate the potential association of FCRL3 polymorphisms with AR in a Chinese Han population.
Methods
Five single-nucleotide polymorphisms of FCRL3, rs945635, rs3761959, rs7522061, rs10489678 and rs7528684 were genotyped in 540 AR patients and 600 healthy controls using a PCR-restriction fragment length polymorphism assay. Allele, genotype and haplotype frequencies were compared between patients and controls using the χ2 test. The online software platform SHEsis was used to analyze their haplotypes.
Results
This study identified three strong risk SNPs rs7528684, rs10489678, rs7522061 and one weak risk SNP rs945635 of FCRL3 in Chinese Han AR patients. For rs7528684, a significantly increased prevalence of the AA genotype and A allele in AR patients was recorded. The frequency of the GG genotype and G allele of rs10489678 was markedly higher in AR patients than those in controls. For rs7522061, a higher frequency of the TT genotype, and a lower frequency of the CT genotype were found in AR patients. Concerning rs945635, a lower frequency of the CC genotype, and a higher frequency of G allele were observed in AR patients. According to the analysis of the three strong positive SNPs, the haplotype of AGT increased significantly in AR cases (AR = 38.8%, Controls = 24.3%, P = 8.29×10-14, OR [95% CI] 1.978 [1.652~2.368]).
Conclusions
This study found a significant association between the SNPs in FCRL3 gene and AR in Chinese Han patients. The results suggest these gene polymorphisms might be the autoimmunity risk for AR.
doi:10.1371/journal.pone.0116419
PMCID: PMC4296936  PMID: 25594855
24.  Toll-like receptor gene polymorphisms are associated with allergic rhinitis: a case control study 
BMC Medical Genetics  2012;13:66.
Background
The Toll-like receptor proteins are important in host defense and initiation of the innate and adaptive immune responses. A number of studies have identified associations between genetic variation in the Toll-like receptor genes and allergic disorders such as asthma and allergic rhinitis. The present study aim to search for genetic variation associated with allergic rhinitis in the Toll-like receptor genes.
Methods
A first association analysis genotyped 73 SNPs in 182 cases and 378 controls from a Swedish population. Based on these results an additional 24 SNPs were analyzed in one Swedish population with 352 cases and 709 controls and one Chinese population with 948 cases and 580 controls.
Results
The first association analysis identified 4 allergic rhinitis-associated SNPs in the TLR7-TLR8 gene region. Subsequent analysis of 24 SNPs from this region identified 7 and 5 significant SNPs from the Swedish and Chinese populations, respectively. The corresponding risk-associated haplotypes are significant after Bonferroni correction and are the most common haplotypes in both populations. The associations are primarily detected in females in the Swedish population, whereas it is seen in males in the Chinese population. Further independent support for the involvement of this region in allergic rhinitis was obtained from quantitative skin prick test data generated in both populations.
Conclusions
Haplotypes in the TLR7-TLR8 gene region were associated with allergic rhinitis in one Swedish and one Chinese population. Since this region has earlier been associated with asthma and allergic rhinitis in a Danish linkage study this speaks strongly in favour of this region being truly involved in the development of this disease.
doi:10.1186/1471-2350-13-66
PMCID: PMC3459792  PMID: 22857391
Allergic rhinitis; Toll-like receptor; Polymorphism; Genetics; Haplotype; Case–control
25.  Association Study on IL4, IL13 and IL4RA Polymorphisms in Mite-Sensitized Persistent Allergic Rhinitis in a Chinese Population 
PLoS ONE  2011;6(11):e27363.
Background
The IL4, IL13, and IL4 receptor α chain (IL4RA) genes are candidate genes for atopic diseases. We hypothesized that the polymorphisms in these genes are associated with persistent allergic rhinitis (PER).
Objective
To investigate the association of the potential functional polymorphisms in IL4, IL13, and IL4RA with PER induced by house dust mites in a Chinese population.
Methods
Using the TaqMan method, we genotyped six single nucleotide polymorphisms (SNPs) including C-590T in IL4, C-1055T and Arg130Gln in IL13, and Ile50Val, Ser478Pro and Gln551Arg in IL4RA, in a case-control study of 265 patients with PER and 275 healthy controls.
Results
We found that the CT/CC genotypes in IL4 C-590T were associated with a significantly decreased risk of mite-sensitized PER [adjusted odds ratio (OR)  = 0.64, 95% confidence interval (CI) 0.45–0.92], compared to the TT genotype. Furthermore, PER patients with CT/CC genotypes had significantly lower serum levels of total IgE than those with TT genotype (P = 0.001). However, there was no significant association of the IL13 and IL4RA polymorphisms with mite-sensitized PER (P>0.05).
Conclusions
Our results suggest that the C-590T polymorphism in IL4 may contribute to the susceptibility to mite-sensitized PER in a Chinese population.
doi:10.1371/journal.pone.0027363
PMCID: PMC3210163  PMID: 22087298

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