Allergic Rhinitis And Genetic Risk Factors
Overview
With the rise in atopic conditions like allergic rhinitis and the “hygiene hypothesis” in mind, numerous studies have explored whether birth order and the size of one’s sibling group could act as protective factors. However, these investigations have yielded conflicting results. This study aimed to comprehensively analyze the global literature connecting birth order and the number of siblings to the susceptibility of allergic rhinitis. The research involved systematically searching fifteen databases, without limitations on publication date or language. Eligible studies were observational in nature, with defined sibship composition as exposure and allergic rhinitis or allergic rhino-conjunctivitis as the outcome, whether self-reported or clinically diagnosed. Study selection, data extraction, and quality assessment were conducted by pairs of independent researchers. Through meta-analysis employing robust variance estimation (RVE), comparable numerical data were examined.
Seventy-six reports encompassing over two million subjects were identified. The analysis indicated that being the second-born or later child was linked to a protective effect against both current (pooled risk ratio [RR] 0.79, 95% CI 0.73–0.86) and ever (RR 0.77, 95% CI 0.68–0.88) allergic rhinitis. Moreover, having siblings, regardless of their birth order, was associated with a reduced risk of developing current allergic rhinitis (RR 0.89, 95% CI 0.83–0.95) and allergic rhino-conjunctivitis (RR 0.92, 95% CI 0.86–0.98). Importantly, these effects remained consistent across various factors including age, time period, and geographical regions. In essence, the study’s findings suggest that higher birth order, and to a lesser extent, having a greater number of siblings, is linked with a diminished risk of allergic rhinitis development.
Introduction
Allergic rhinitis, characterized by chronic upper airway inflammation triggered by immunoglobulin E (IgE) response to environmental allergens, leads to symptoms like nasal congestion, itching, sneezing, and ocular issues. Although not fatal, allergic rhinitis significantly impacts individuals’ quality of life, sleep, mental well-being, and work productivity. Its prevalence has surged in recent years, emerging as a common noncommunicable ailment worldwide among both children and adults. The multifaceted nature of its origins, influenced by genetics, epigenetics, lifestyle, and environmental exposures, complicates the understanding of its cause. Sibship composition, specifically the number and order of siblings, has garnered attention as a potential early-life environmental factor influencing allergic rhinitis, tracing back to Strachan’s findings in the 1980s. However, subsequent research has yielded conflicting outcomes, leaving the role of sibship composition in allergic rhinitis causation unclear.
To bridge this gap, a systematic review was conducted to consolidate global literature on the connection between birth order, sibship size, and allergic rhinitis risk. Furthermore, the study assessed whether changes in hygiene practices and lifestyle have impacted the hypothesized influence of sibship composition on allergic rhinitis development. This was achieved by categorizing studies published before and after the millennium shift and by utilizing the World Bank’s country income classification. The objective was to shed light on the intricate interplay between sibship composition and allergic rhinitis, while accounting for evolving societal factors that might influence the relationship.
Method
This study was conducted following a pre-defined protocol that was registered with the International prospective register of systematic reviews (PROSPERO; CRD42020207905) and adhered to reporting guidelines such as Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) and Meta-analysis of Observational Studies in Epidemiology (MOOSE). The search was comprehensive, spanning databases including AMED, CABI, CINAHL, Embase, Google Scholar, OAIster, Open Access Theses and Dissertations, Open Gray, ProQuest Dissertations & Theses Global, PsycINFO, PubMed, SciELO, Scopus, Web of Science, and WHO Global Index Medicus from inception until September 30, 2020, with a subsequent follow-up search on October 20, 2021. Google Scholar results were screened up to the first 300, and non-English articles were translated using Google Translate. Additionally, reference lists of included articles were reviewed manually for relevant studies.
The records were managed in EndNote X9 for de-duplication, following the methodology proposed by Bramer et al. The screening process involved independent assessment of retrieved records by two reviewers and evaluation of full-text reports that potentially met the exclusion criteria. Data extraction was conducted in pairs using a predefined and piloted form. Any discrepancies were resolved through discussion or by a third reviewer’s (BIN) intervention.
Various details were extracted from the included reports, encompassing first author, publication year, study design, subject source (e.g., general population or pregnant women), subject demographics (number, age, and country), exposure and outcome definitions/assessments, point estimates, and 95% confidence intervals.
Quality and bias assessment were performed independently by pairs of reviewers using the Effective Public Health Practice Project (EPHPP) tool, adapted based on previous systematic reviews. Six domains, such as study design, selection bias, confounding, blinding, data collection, and withdrawals/dropouts, were rated as “strong,” “moderate,” or “weak.” The overall rating was determined by the count of “weak” domain ratings: “weak” if more than one, “moderate” if one, and “strong” if none. In cases of discrepancy, a third reviewer (BIN) acted as an arbiter.
Statistical Analysis
To combine comparable numerical data from two or more distinct studies, random-effects meta-analysis with robust variance estimation (RVE) was employed. RVE techniques allow the incorporation of correlated estimates—commonly encountered when multiple factors are tested against the same reference group—within a single model. In the meta-analyses, the correlated effects model with small sample correction was used, with a default rho value of 0.8 to define within-study effect size correlation. The results were visually represented using forest plots. Separate meta-analyses were conducted for each exposure type (birth order and sibship size) concerning various outcomes: (a) current allergic rhinitis (within the last year), (b) ever allergic rhinitis, (c) current allergic rhino-conjunctivitis (within the last year), and (d) ever allergic rhino-conjunctivitis.
Distinct reference groups were established for birth order (with the first-born as reference) and sibship size (with only-child as reference). In instances where the reference group exhibited a higher cardinality, reciprocal values of point estimates and lower and upper bounds of 95% CI were computed. Risk ratios (RR) were adopted as the effect measure for their intuitive interpretation. Prevalence ratios (PR) were used as-is, as they are mathematically equivalent to RR, while odds ratio (OR) and hazard ratio (HR) data were converted to RR when outcomes reached ≥15% prevalence using appropriate formulae.
Subgroup analyses were performed when ≥4 comparable studies were available in ≥2 subgroups, evaluating associations based on factors such as overall rating, study design, exposure cardinality, data collection year(s) categorized into pre-2000 and post-2000, country’s economy classification (high income, upper middle income, lower-middle income, and low income), and subject age groups (≤12 and ≥13 years).
Sensitivity analysis was conducted by varying the rho value in the meta-analyses from 0 to 1 with 0.2 increments. Heterogeneity between studies was quantified using the I-squared (I²) statistic, while inter-study variance was measured using Tau-squared (τ²). Findings from meta-analyses with Satterwhite degrees of freedom (df) <4 were seen as less reliable.
To assess publication bias in exposure-outcome pairs with ≥10 studies, asymmetry in funnel plots was visually examined. Furthermore, the Egger’s regression test and Begg and Mazumdar rank correlation test were applied, considering p<0.05 as statistically significant. Additionally, the trim-and-fill method was employed to estimate the number of studies required to rectify asymmetric funnel plots.
Inclusion Criteria
The eligible studies were required to meet specific criteria, including:
- Study Design: The studies needed to be observational in nature, encompassing cohort studies, case-control studies, and cross-sectional studies.
- Exposure: The studies should have focused on a well-defined sibship composition, either birth order or sibship size (number of siblings).
- Outcome: The target outcomes were allergic rhinitis or allergic rhino-conjunctivitis. These outcomes could be established through various means, such as self-reported symptoms (including symptom-based definitions), clinical examinations, or medical records indicating diagnosis. There were no limitations on sample size or the subjects’ medical or sociodemographic background.
Exclusion Criteria
To ensure the reliability of our results, we conducted a sensitivity analysis involving the reiteration of the meta-analyses with certain exclusions. Specifically, we excluded studies that did not confirm the outcome through clinical means (such as medical records or clinical assessments). Additionally, studies with an overall rating categorized as “low” were also excluded. This thorough analysis aimed to verify the consistency and robustness of our findings while upholding rigorous standards of research integrity.
Result
From a comprehensive search encompassing 17,466 records and subsequent screening, a total of 76 reports based on 66 studies were included in this study. These reports encompassed a diverse range of study designs, including 49 cross-sectional studies, 26 cohort studies, and one case-control study. The studies collectively represented over 2 million individuals across 70 countries.
The analysis revealed significant associations between birth order and sibship size with the risk of allergic rhinitis and allergic rhino conjunctivitis. Specifically, being the second-born or later was linked to a 21% reduced risk of current allergic rhinitis and a 23% reduced risk of ever allergic rhinitis. Having siblings, regardless of birth order, correlated with an 11% lower risk of current allergic rhinitis and an 8% reduced risk of current allergic rhino conjunctivitis. The analyses also indicated possible dose-dependent effects in relation to the number of siblings.
Heterogeneity in the findings varied across outcomes, ranging from high for birth order to low for sibship size. Sensitivity analyses reinforced the robustness of the results in terms of study quality, with no substantial impact from the exclusion of studies with “weak” ratings. However, when analyzing only studies with clinically assessed outcomes, wider confidence intervals were observed.
While some funnel plots suggested modest asymmetry, publication bias was unlikely to notably influence the results. Furthermore, the variation in the value of rho did not significantly affect the pooled effect size estimates or their confidence intervals. Overall, this synthesis provided valuable insights into the complex relationship between birth order, sibship size, and the risk of allergic rhinitis and allergic rhino conjunctivitis, contributing to a deeper understanding of these conditions.
Conclusion
This comprehensive review meticulously analyzed global literature to discern the relationship between birth order, sibship size, and the risk of allergic rhinitis. The study revealed significant associations with reduced risk, particularly in the presence of older siblings. Both birth order and the number of siblings exhibited a protective effect, albeit with varying strengths for different outcomes. The protection was more pronounced for allergic rhinitis with ocular involvement and for lifetime prevalence of the disease. Although the exact mechanistic factors remain unclear, this protective association aligns with the “hygiene hypothesis,” suggesting that early exposure to infections from older siblings could influence immune development and subsequent allergic disease risk.
The review encompassed an extensive search across 15 databases, employing robust methodologies to ensure accuracy and precision. While the findings reinforced the hygiene hypothesis, highlighting the complex nature of allergic diseases, the conclusions differed from previous reviews on asthma. The study underscores the intricate pathophysiology of these conditions and contributes to a deeper understanding of their underlying mechanisms.
In summary, the research underscores that having siblings, especially older ones, is linked to a reduced risk of current allergic rhinitis. This protective effect remains consistent across various age groups and time periods. The presence of older siblings emerges as a crucial factor, potentially influencing immune responses and lowering the risk of allergic rhinitis.
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