Adult Onset Asthma
Adult onset asthma is a chronic inflammatory respiratory condition that develops for the first time in adulthood, typically after the age of 20. It is characterized by airway hyperresponsiveness, reversible airflow obstruction, and symptoms such as wheezing, shortness of breath, chest tightness, and coughing. Unlike childhood-onset asthma, which often has a strong allergic component, adult onset asthma is thought to have a minor atopic component.[1]It is considered a complex disease arising from the interplay of genetic predispositions and environmental factors.[2]
Biological Basis
Section titled “Biological Basis”The underlying biological mechanisms of adult onset asthma are diverse, reflecting the heterogeneous nature of the disease.[1]Asthma involves type 2 helper T-cell (Th2) inflammation in response to epithelial damage.[1]Genetic studies have revealed that later-onset asthma cases are influenced more by the Major Histocompatibility Complex (MHC) region compared to childhood-onset cases.[1]For instance, a highly significant association with adult asthma has been observed atrs404860 within the MHC region in Japanese populations. [2] This SNP is located near rs2070600 in the AGERgene, which has been associated with lung function measures such as forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio. [2] The HLA-DQgene, also within the MHC region, may play a role in adult-onset asthma by restricting the immune response to bacterial or other antigens that are not classical allergens.[1]
Genome-wide association studies (GWAS) have identified several other susceptibility loci for adult asthma. These include theUSP38/GAB1 locus on chromosome 4q31, a region on chromosome 10p14, and a gene-rich region on chromosome 12q13. [2] Genes such as SLC22A5 and RORA have also been suggestively implicated. [1] Some genetic variants, like those in ORMDL3/GSDMB and IL18R1/IL1RL1, suggest shared biological mechanisms with other inflammatory conditions such as Crohn’s disease, possibly involving modulation of microbial interactions with the mucosa.[1]
Clinical Relevance
Section titled “Clinical Relevance”Understanding the genetic architecture of adult onset asthma is clinically relevant for several reasons. The reduction of theFEV1/FVCratio is a characteristic feature of obstructive lung diseases, including asthma.[2]Furthermore, lower pulmonary function is often indicative of more severe asthma.[2]Identifying specific genetic markers can aid in distinguishing adult onset asthma from other respiratory conditions, predicting disease progression, and potentially guiding personalized treatment strategies, given the disease’s heterogeneity.
Social Importance
Section titled “Social Importance”Adult onset asthma significantly impacts public health and individual quality of life. As a common inflammatory disease[2]it contributes to a substantial healthcare burden due to chronic management, emergency visits, and potential hospitalizations. For affected individuals, it can lead to limitations in physical activity, reduced productivity, and impaired overall well-being. Genetic research into adult onset asthma offers the promise of a better understanding of its pathophysiology, which could lead to improved diagnostic tools, more effective therapies, and ultimately, better outcomes for patients.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Many genome-wide association studies (GWAS) for asthma have faced significant methodological and statistical limitations that impact the interpretability and generalizability of their findings. Foremost among these are issues related to sample size, with several studies acknowledging that their cohorts were relatively small for detecting associations with complex diseases[3], [4]. [5]This often results in inadequate statistical power, increasing the risk of false negative results and preventing single nucleotide polymorphisms (SNPs) from reaching genome-wide significance after stringent multiple testing corrections, such as Bonferroni adjustment[4]. [5] Consequently, while suggestive associations may be observed, their definitive confirmation often requires larger meta-analyses or extensive replication efforts.
Replication of initial GWAS findings has also proven challenging, with some associations failing to replicate in independent cohorts, particularly across diverse ancestral groups [3], [6]. [5] This lack of consistent replication can stem from several factors, including modest effect sizes of associated alleles, differences in study design, or even ‘winner’s bias’ where initial positive findings might be overemphasized or due to loose replication standards [7]. [4] Furthermore, technical variables such as array batch effects have been identified as potential confounders that can lead to false-positive results if not carefully controlled, especially when cases and controls are genotyped separately. [3]These factors collectively underscore the need for larger, well-powered studies and robust replication strategies to solidify genetic associations with asthma.
Phenotypic Complexity and Measurement Inconsistencies
Section titled “Phenotypic Complexity and Measurement Inconsistencies”The heterogeneous nature of asthma presents substantial challenges for genetic studies, leading to inconsistencies in phenotype definition and measurement that can obscure true genetic signals. Many studies relied on self-reported lifetime asthma status, which can be a “loose” definition based on varying survey questions and often does not exclude co-morbid conditions like Chronic Obstructive Pulmonary Disease (COPD).[3] This variability in diagnostic criteria and reporting can lead to phenotypic misclassification, reducing the power to detect genetic associations and making comparisons across different cohorts difficult. [7]
Moreover, asthma is recognized as a heterogeneous disease with diverse severities and natural histories, implying that different genetic factors may contribute to distinct subphenotypes[2]. [7]While some studies have begun to explore associations with specific asthma subphenotypes, such as atopic versus non-atopic asthma, the sample sizes for these secondary analyses are often modest, necessitating further independent confirmation.[3]Additionally, control groups in some studies have been significantly younger than cases, posing a limitation as some controls might eventually develop asthma, potentially rendering the observed genetic associations conservative.[4]These phenotypic complexities highlight the need for more precise and consistent asthma characterization in future genetic research.
Ancestry Bias and Environmental Confounding
Section titled “Ancestry Bias and Environmental Confounding”Genetic studies of asthma frequently encounter limitations related to ancestry bias, generalizability, and the influence of unmeasured environmental factors. Many GWAS have been conducted predominantly in populations of European descent, or specific admixed groups such as Hispanic white and non-Hispanic white individuals, or Japanese populations, leading to an under-representation of other ancestral groups[3], [6]. [2] This bias raises concerns about the generalizability of findings, as genetic associations identified in one population may not translate to others due to differences in allele frequencies, linkage disequilibrium patterns, or varying gene-environment interactions [7]. [5]For example, some findings have failed to replicate in black populations, suggesting that specific genetic variants may not directly modify the asthma phenotype across all ancestries.[6]
Population stratification, even when minimized by methods like ancestry-informative markers, can still be a concern, potentially leading to spurious associations or masking true ones. [4]Furthermore, complex diseases like asthma are significantly influenced by a multitude of environmental exposures, which are often difficult to measure comprehensively in genetic studies.[7] The absence of detailed environmental data, such as lifetime smoking status for a large proportion of controls, represents a significant knowledge gap. [3]This missing information on environmental or gene-environment confounders contributes to the ‘missing heritability’ phenomenon, where identified genetic variants explain only a fraction of the observed familial aggregation of asthma, suggesting that unmeasured genetic factors, gene-environment interactions, or epigenetic mechanisms play a substantial, yet uncharacterized, role.
Variants
Section titled “Variants”Genetic variations play a critical role in an individual’s susceptibility to adult-onset asthma, influencing immune responses, inflammatory pathways, and airway remodeling. Genome-wide association studies (GWAS) have identified several key regions and specific single nucleotide polymorphisms (SNPs) associated with this complex respiratory condition. These variants often affect genes involved in immune regulation, cytokine signaling, and cellular development, contributing to the diverse clinical presentations of asthma.
The Major Histocompatibility Complex (MHC) region, particularly genes within the HLA-DQ and HLA-DRloci, consistently shows strong associations with asthma. Genes likeHLA-DQA1 and HLA-DQB1 encode subunits of MHC Class II molecules, which are essential for presenting antigens to T-cells and initiating adaptive immune responses. Variants such as rs9272346 , rs9272426 , rs3104369 , and rs28407950 in this region may alter antigen presentation efficiency or T-cell activation, thereby shaping the immune system’s response to allergens and pathogens. The HLA-DQregion, in particular, has demonstrated a slightly stronger association with later-onset asthma, highlighting its relevance to the adult form of the disease.[1]Such genetic differences can lead to a heightened or dysregulated immune response in the airways, contributing to chronic inflammation characteristic of asthma.
Another crucial set of variants resides in genes encoding interleukin receptors and cytokines, central to allergic inflammation. The IL1RL1 gene, also known as ST2, encodes a receptor for IL33, an alarmin cytokine released by stressed or damaged cells that drives Type 2 immune responses. Variants likers60227565 , rs12470864 , rs12479210 , rs59185885 , and rs10208293 in IL1RL1 and its closely linked gene IL18R1(Interleukin 18 Receptor 1) are significantly associated with asthma.[1] These variants can influence the sensitivity to IL33, leading to exaggerated inflammatory responses in the lungs. Similarly, variants rs992969 and rs928413 near the IL33gene itself are implicated in asthma risk, potentially by altering the production or activity of this key inflammatory mediator.[7]Dysregulation of these pathways promotes the characteristic airway hyperresponsiveness and eosinophilic inflammation seen in asthma.
The SMAD3 gene, located on chromosome 15, is a vital component of the Transforming Growth Factor-beta (TGF-beta) signaling pathway, which is crucial for cell growth, differentiation, and immune regulation. Variants such as rs72743461 , rs10152595 , and rs56062135 near or within SMAD3are associated with asthma, withrs744910 specifically showing significant association. [1] Alterations in SMAD3function can impact airway remodeling, fibrosis, and the resolution of inflammation, all of which are critical processes in the pathogenesis of adult-onset asthma. These variants may lead to persistent inflammation and structural changes in the airways, exacerbating disease severity.[3]
Less understood but potentially significant are variants in long intergenic non-coding RNA (lincRNA) genes such as LINC02676, LINC00709, and LINC02757, as well as genes like CFAP144P2, EMSY, D2HGDH, EIF2S2P3, and HHEX. While specific functional details for variants like rs1775554 , rs962992 , rs12413578 , rs60227565 , rs12470864 , rs7936312 , rs7936070 , rs55646091 , rs34290285 , and rs2185756 are still being investigated, these genomic regions have been broadly implicated in genetic susceptibility to asthma.[1] LincRNAs are known to regulate gene expression, potentially affecting immune cell development or function, while HHEX plays a role in hematopoietic development, which could influence immune cell populations. Other genes like EMSY (involved in DNA repair and transcription) and D2HGDH(involved in metabolism) might indirectly contribute to cellular stress or inflammatory responses in the airways. These less characterized variants highlight the complex and polygenic nature of asthma, where many genes with subtle effects collectively contribute to disease risk.[4]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs1775554 rs962992 rs12413578 | LINC02676 - LINC00709 | childhood onset asthma adult onset asthma eosinophil percentage of leukocytes asthma |
| rs9272346 rs9272426 rs3104369 | HLA-DQA1 | type 1 diabetes mellitus asthma childhood onset asthma adult onset asthma asthma, age at onset |
| rs60227565 rs12470864 | CFAP144P2 - IL1RL1 | asthma adult onset asthma asthma, age at onset |
| rs7936312 rs7936070 rs55646091 | EMSY - LINC02757 | asthma eosinophil count childhood onset asthma adult onset asthma atopic asthma |
| rs12479210 rs59185885 rs10208293 | IL18R1, IL1RL1 | asthma Nasal Cavity Polyp adult onset asthma eosinophil count |
| rs28407950 | HLA-DQA1 - HLA-DQB1 | adult onset asthma childhood onset asthma Eczematoid dermatitis, allergic rhinitis asthma, Eczematoid dermatitis, allergic rhinitis Antihistamine use measurement |
| rs992969 rs928413 | GTF3AP1 - IL33 | asthma childhood onset asthma adult onset asthma PHF-tau measurement asthma, age at onset |
| rs34290285 | D2HGDH | eosinophil percentage of leukocytes eosinophil count eosinophil percentage of granulocytes asthma, allergic disease basophil count, eosinophil count |
| rs2185756 | EIF2S2P3 - HHEX | adult onset asthma body mass index diabetic neuropathy |
| rs72743461 rs10152595 rs56062135 | SMAD3 | myocardial infarction coronary artery disease asthma asthma, Eczematoid dermatitis, allergic rhinitis childhood onset asthma |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Definition and Distinctive Features of Adult-Onset Asthma
Section titled “Definition and Distinctive Features of Adult-Onset Asthma”Adult-onset asthma refers to asthma that develops and is diagnosed during adulthood, distinguishing it from cases that manifest in childhood. While the median age of asthma onset in some populations can be as early as 5-8 years, the disease can present across a broad age range, extending into late adulthood, with reported onset ages up to 66 years.[7] This late presentation suggests potentially different etiological pathways or triggers compared to early-onset forms.
Conceptually, adult-onset asthma shares the fundamental characteristics of asthma, including airway hyperresponsiveness, inflammation, tissue remodeling, and airflow obstruction.[8]However, a key distinguishing feature is its often-minor atopic component compared to childhood-onset asthma. The immune response in adult-onset cases may involve theHLA-DQ locus, potentially restricting reactions to bacterial or other antigens that do not function as classical allergens. [1]This suggests a unique immunological profile and varying environmental interactions compared to asthma that begins in earlier life stages.
Classification and Heterogeneity
Section titled “Classification and Heterogeneity”Asthma is widely recognized as a heterogeneous disease, encompassing various clinical subtypes that differ in their severity, natural history, and underlying mechanisms.[2]This heterogeneity is notably observed when classifying asthma by age of onset, as genetic influences can vary significantly; for instance, later-onset cases show a greater influence from the Major Histocompatibility Complex (MHC) region compared to childhood-onset cases.[1]This distinction underscores a categorical approach to classification based on the age of disease presentation.
Beyond age of onset, asthma is also classified by severity, ranging from mild to moderate to severe, particularly in pediatric populations.[5]This dimensional classification is crucial for guiding treatment and understanding disease progression, as lower pulmonary function, specifically a reduced forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio, is a hallmark of obstructive lung diseases like asthma and is a feature of severe asthma.[2]The disease is further characterized as a T helper (Th) type 2 immune disease, given the critical role of Th2 cytokines and inflammatory cell infiltration in orchestrating its inflammatory responses.[8]
Diagnostic and Measurement Criteria
Section titled “Diagnostic and Measurement Criteria”For the purpose of clinical diagnosis and research, asthmatic subjects are often defined by a documented history of asthma alongside a physician-diagnosed history of the condition, either past or current.[6]This operational definition ensures consistency in identifying affected individuals, while control subjects are typically confirmed to have no history of asthma.[6] Such precise criteria are essential for accurate phenotypic characterization in genetic studies.
Key measurement approaches in asthma involve assessing lung function, most notably through the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), where a reduced FEV1/FVC ratio is indicative of obstructive lung disease.[2]Airway hyperresponsiveness, another characteristic of asthma, can be quantitatively measured by determining the methacholine dose that causes a 20% decrease in FEV1.[6]Additionally, atopy, a common comorbidity, is diagnosed by a positive skin prick test to at least one aeroallergen[5] providing further diagnostic context.
Terminology and Genetic Nomenclature
Section titled “Terminology and Genetic Nomenclature”The condition is broadly referred to as “bronchial asthma,” highlighting its inflammatory nature and interaction of genetic and environmental factors.[2]Specifically, “adult-onset asthma” denotes its manifestation in adulthood. Asthma is officially recognized with the OMIM number 600807, providing a standardized identifier in medical genetics databases.[5]Its classification as a Th2-type immune disease reflects the central role of T helper type 2 cytokines and eosinophilic inflammation in its pathophysiology.[8]
Genetic research employs precise nomenclature for genes, such as AGER, HLA-DQ, USP38, GAB1, TSLP, PDE4D, ORMDL3, IL1RL1, IL18R1, DENND1B, SLC22A5, RORA, CHI3L1, DPP10, GPR154 (NPSR1), ADAM33, PHF11, OPN3, IRAK3, PCDH1, and HLA-G, which are implicated in general asthma susceptibility or specifically in adult asthma.[2] Specific genetic variants are identified by unique reference SNP cluster IDs (rsIDs), such as rs2070600 , rs404860 , rs1063355 , and rs9273349 . [2] This standardized terminology is crucial for unambiguous communication and data integration in the scientific community.
Signs and Symptoms
Section titled “Signs and Symptoms”Core Clinical Manifestations and Symptom Patterns
Section titled “Core Clinical Manifestations and Symptom Patterns”Adult onset asthma is characterized by a range of respiratory symptoms that often include wheezing, coughing, shortness of breath, and tightness in the chest. These symptoms can present in various patterns, sometimes occurring without an upper-respiratory infection (URI), or in conjunction with a URI.[6]A documented history of physician-diagnosed asthma, alongside a self-reported history of the condition, forms a key aspect of its clinical presentation.[3]The severity of these manifestations can vary significantly, with lower pulmonary function often indicating a more severe disease course.[2]
Diagnostic Approaches and Objective Measures
Section titled “Diagnostic Approaches and Objective Measures”Diagnosis of adult onset asthma relies on a combination of objective physiological assessments and subjective symptom reports. Key objective measures include the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), with a reduction in the FEV1/FVC ratio being a characteristic indicator of obstructive lung disease.[2]Airway hyperresponsiveness can be assessed by measuring the methacholine dose required to cause a 20% decrease in FEV1.[6]Additional quantitative traits, such as total serum IgE levels, are also utilized in evaluating asthma-related characteristics.[4] For identifying atopic phenotypes, a positive skin prick test to common allergens serves as a crucial diagnostic tool. [3]
Phenotypic Diversity and Age-Related Patterns
Section titled “Phenotypic Diversity and Age-Related Patterns”Adult onset asthma is a heterogeneous condition, displaying wide variations in its severity and natural history.[2] The age of onset itself is highly variable, with studies reporting median onset ages ranging from approximately 3 to over 60 years in diverse populations. [7]This variability contributes to distinct phenotypic subtypes, such as atopic asthma, which is characterized by a positive skin prick test to common allergens.[3]Genetic factors also play a role in this diversity, as later-onset cases of asthma are notably influenced more by the Major Histocompatibility Complex (MHC) region compared to childhood-onset cases.[1] Furthermore, specific genetic variants, such as the rs7130588 :G variant on chromosome 11q13.5, have been observed to be more prevalent in atopic asthmatic patients, highlighting the genetic underpinnings of phenotypic differences. [3]
Causes of Adult Onset Asthma
Section titled “Causes of Adult Onset Asthma”Genetic Predisposition and Heterogeneity
Section titled “Genetic Predisposition and Heterogeneity”Asthma is fundamentally a complex disease, with genetic factors playing a significant role in determining an individual’s susceptibility, particularly in later-onset cases.[2]Numerous genetic variants contribute to this risk, indicating a polygenic nature where multiple genes, each with a modest effect, collectively increase the likelihood of developing the condition. Studies have identified several candidate loci across the genome, highlighting the heterogeneity of asthma and suggesting different genetic underpinnings depending on the age of onset.[1]
The Major Histocompatibility Complex (MHC) region on chromosome 6p21, specifically variants like rs404860 and those near HLA-DQ, shows a strong association with adult-onset asthma, suggesting its importance in immune responses to various antigens, potentially including bacterial or other non-classical allergens.[2] Other genes, such as USP38/GAB1on chromosome 4q31, a locus on chromosome 10p14, and a gene-rich region on chromosome 12q13, have also been identified as susceptibility loci for adult asthma in diverse populations.[2] These findings underscore that while some common alleles may confer risk across all ages, specific genetic influences, like those at the ORMDL3/GSDMBlocus on chromosome 17q21, are associated only with childhood-onset disease.[1]
Immune System Pathways and Epithelial Barrier Function
Section titled “Immune System Pathways and Epithelial Barrier Function”Genetic studies have illuminated key biological pathways involved in adult-onset asthma, particularly those related to the initiation and regulation of airway inflammation. Many identified candidate genes are implicated in Type 2 helper T-cell (Th2) inflammatory responses, which are triggered by epithelial damage.[1] For instance, variants in genes such as IL13, IL6R, and those within the HLA region, are associated with asthma and play roles in immune signaling and inflammatory processes.[3]
Furthermore, genes involved in epithelial barrier integrity and innate immune defense mechanisms appear to be critical. RORA, a nuclear hormone receptor, is highly expressed in keratinocytes and associated with a cluster of genes that form the structural and innate immune defenses of the epithelial barrier.[1] Another gene, SLC22A5, which encodes a carnitine transporter, shares variants with Crohn’s disease, suggesting common mechanisms that might involve the modulation of microbial interactions with the mucosa and thereby influence airway health.[1] These genetic insights point to the importance of how the body’s initial defenses respond to environmental challenges and regulate subsequent inflammatory cascades.
Interplay of Genetics and Environmental Triggers
Section titled “Interplay of Genetics and Environmental Triggers”Adult-onset asthma is understood to arise from a complex interaction between an individual’s genetic makeup and various environmental factors.[2]This means that genetic predispositions can modify an individual’s susceptibility or response to environmental exposures. Certain genetic variants may render an individual more vulnerable to developing asthma when exposed to particular environmental agents, or conversely, offer a degree of protection.
The interplay emphasizes that genetics alone do not determine disease risk, nor do environmental factors in isolation. Instead, the combination and timing of these influences shape an individual’s likelihood of developing adult-onset asthma. Although the exact mechanisms of these gene-environment interactions are still being elucidated, the overarching concept is fundamental to understanding the multifactorial etiology of the disease.[1]
Shared Mechanisms with Related Conditions and Age-Related Aspects
Section titled “Shared Mechanisms with Related Conditions and Age-Related Aspects”The development of adult-onset asthma can also be influenced by shared biological mechanisms with other chronic conditions, suggesting common pathways or genetic predispositions. For example, variants in genes likeSLC22A5, and those similar to variants found in ORMDL3/GSDMB and IL1RL1, are associated with both asthma and Crohn’s disease.[1] This overlap indicates that shared mechanisms, possibly involving the modulation of microbial interactions at mucosal surfaces, could contribute to the pathogenesis of both diseases.
Furthermore, the distinction between childhood-onset and later-onset asthma underscores the role of age-related factors in disease manifestation. Later-onset cases are observed to have a minor atopic component compared to childhood-onset asthma, and are influenced more by specific genetic regions like the MHC.[1]This suggests that the immune system’s response to antigens and the overall disease phenotype can evolve or be initiated differently depending on the age of onset, highlighting the dynamic nature of asthma development across the lifespan.
Biological Background for Adult Onset Asthma
Section titled “Biological Background for Adult Onset Asthma”Defining Adult-Onset Asthma and its Clinical Manifestations
Section titled “Defining Adult-Onset Asthma and its Clinical Manifestations”Adult-onset asthma is a chronic respiratory condition characterized by inflammation and narrowing of the airways, leading to symptoms such as cough, wheeze, and shortness of breath.[9]This diagnosis is typically established based on a combination of self-reported symptoms, a physician’s assessment, and the current use of asthma-specific medications.[9]The presence of these persistent respiratory issues distinguishes asthma from transient breathing difficulties, necessitating ongoing management to control symptoms and prevent exacerbations.
A critical objective measure in diagnosing asthma, including adult-onset forms, is the assessment of lung function and bronchial hyperresponsiveness (BHR).[9]BHR refers to an exaggerated narrowing of the airways in response to various triggers, which can be objectively demonstrated by a significant decrease in forced expiratory volume in 1 second (FEV1).[9]Specifically, a 15% reduction from baseline FEV1 following exposure to agents like histamine or during physical exertion, such as 6 minutes of exercise, is a key indicator of BHR and helps confirm an asthma diagnosis.[9]
Pathophysiological Mechanisms of Airway Dysfunction
Section titled “Pathophysiological Mechanisms of Airway Dysfunction”The core pathophysiological process in asthma involves the disruption of normal respiratory homeostasis, primarily manifested as bronchial hyperresponsiveness. This condition causes the airways to constrict excessively and rapidly in response to stimuli that would typically have little effect on healthy individuals.[9]This heightened reactivity contributes significantly to the characteristic symptoms of asthma, including episodic wheezing and dyspnea, as the airways struggle to maintain adequate airflow.
At a molecular and cellular level, the response to specific triggers like histamine highlights underlying signaling pathways critical to asthma pathogenesis.[9]Histamine, an inflammatory mediator, binds to receptors on airway smooth muscle cells, initiating a cascade of events that leads to bronchoconstriction and a measurable decrease in FEV1.[9] This response is indicative of an underlying inflammatory state within the bronchial tissues, where various cellular functions and regulatory networks contribute to chronic airway remodeling and sustained hyperreactivity.
Molecular and Cellular Underpinnings
Section titled “Molecular and Cellular Underpinnings”The acute bronchoconstriction observed in asthma is often mediated by key biomolecules such as histamine. Upon exposure to allergens or irritants, mast cells and other immune cells in the airway release histamine, which then acts on H1 receptors on airway smooth muscle cells, triggering their contraction and subsequent airway narrowing.[9]This molecular interaction represents a rapid cellular pathway that directly impacts lung function and contributes to the immediate symptoms of an asthma attack.
Beyond acute responses, chronic asthma involves complex cellular functions and regulatory networks that perpetuate inflammation and structural changes in the airways. These processes include the recruitment and activation of various immune cells, the release of cytokines and chemokines, and changes in the extracellular matrix, all contributing to airway remodeling.[9]These integrated cellular and molecular mechanisms lead to sustained BHR and the long-term progression of the disease, affecting tissue integrity and organ-level respiratory function.
Genetic and Biomarker Contributions
Section titled “Genetic and Biomarker Contributions”Genetic mechanisms play a significant role in an individual’s susceptibility to developing asthma, including adult-onset forms. Research investigates specific gene functions and regulatory elements that may influence asthma risk and lung function, with variations in genes such asCHI3L1 being of particular interest. [9] These genetic predispositions can affect how an individual’s immune system responds to environmental triggers or how their airways develop and maintain homeostasis.
In addition to genetic factors, specific biomolecules can serve as indicators or mediators of asthma. For instance, serum YKL-40, a chitinase-like protein, is a key biomolecule whose levels have been studied in relation to variations in theCHI3L1gene and their association with asthma risk and lung function.[9]Elevated levels of such biomarkers may reflect ongoing inflammatory processes or tissue remodeling, offering insights into disease activity and potentially guiding personalized treatment strategies.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Immune Activation and Inflammatory Cascade Dysregulation
Section titled “Immune Activation and Inflammatory Cascade Dysregulation”Adult-onset asthma involves complex immune signaling pathways that drive inflammatory responses, often distinct from childhood asthma’s atopic component. TheHLA-DQlocus, fundamental to later-onset disease, may restrict the immune system’s response to bacterial or other antigens that do not typically act as classical allergens.[1] This restriction influences specific allergen sensitization and the production of tumor necrosis factor and related gene products. Epithelial damage can initiate type 2 helper T-cell (Th2) inflammation through IL33, which activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases, leading to the production of Th2-associated cytokines like interleukin-4, interleukin-5, and interleukin-13. [1]
Further contributing to inflammatory modulation, the locus implicating IL1RL1 (the receptor for IL33) and IL18R1 on chromosome 2 may modify the inflammatory response to epithelial damage. [1] IL18, closely related to IL33, synergizes with IL12 to induce interferon-γproduction and promote Th1 responses, highlighting a potential balance between Th1 and Th2 pathways in disease pathogenesis.[1] Regulatory T-cell function and effector T-cell subgroup differentiation (Th1, Th2, Th17, and memory CD8+ T cells) are controlled by IL2, while SMAD3, a transcriptional modulator activated by transforming growth factor β, regulates proliferation and differentiation in various cell types, including regulatory T cells. [1] Dysregulation of SMAD3 is suggested by increased proinflammatory cytokines in the lungs of Smad3 deficient mice, indicating its role in down-regulating airway inflammation. [1] The interleukin-2 receptor β chain (IL2RB), a signal-transduction element, may also regulate homeostatic and healing pathways, suggesting mechanisms for resolving or perpetuating inflammation. [1]
Epithelial Barrier Function and Metabolic Interplay
Section titled “Epithelial Barrier Function and Metabolic Interplay”The integrity of the epithelial barrier and its interaction with the environment are critical in adult-onset asthma, involving specific genetic and metabolic pathways. TheRORAgene, encoding a nuclear hormone receptor of the NR1 subfamily, is highly expressed in keratinocytes and functions alongside a cluster of genes that form the structural and innate immune defenses of the epithelial barrier.[1] This suggests a role for RORA in maintaining epithelial health and mediating early immune responses to environmental stimuli. Furthermore, variants in SLC22A5, which encodes a carnitine transporter, are associated with adult-onset asthma.[1] The shared association of SLC22A5variants with Crohn’s disease points to common mechanisms potentially involving the modulation of microbial interactions with the mucosa, highlighting a systems-level integration between gut and airway immunity.[1]
The chromosome 17q21 locus, containing ORMDL3 and GSDMB, also plays a significant role, with single nucleotide polymorphisms (SNPs) in this region strongly associated with variation in the expression of both genes.[1] Evidence from yeast studies indicates that changes in the homologous ORM gene lead to dysregulation of sphingolipid metabolism. [1] If similar pathways are involved in humans, this suggests a potential mechanism for modulating airway inflammation through metabolic pathways, where altered sphingolipid biosynthesis or catabolism could impact cell membrane integrity, signaling, and inflammatory mediator production, offering a potential therapeutic target. [1]
Cellular Signaling and Airway Smooth Muscle Regulation
Section titled “Cellular Signaling and Airway Smooth Muscle Regulation”Specific intracellular signaling cascades and regulatory mechanisms profoundly influence airway function and contribute to asthma pathophysiology. ThePDE4Dgene, encoding phosphodiesterase 4D, is implicated as an asthma-susceptibility gene.[6] PDE4Dplays a critical role in the control of airway smooth muscle contraction.[6]This enzyme regulates cyclic AMP (cAMP) levels, and its dysregulation can lead to altered smooth muscle tone and bronchial hyperresponsiveness, a hallmark of asthma. Such metabolic regulation of second messenger systems, controlling flux of cellular signals, impacts the physiological responses of the airways.
Beyond smooth muscle contraction, other genes contribute to the overall cellular environment of the airways. For instance,ADAM33has been associated with asthma and bronchial hyperresponsiveness, suggesting its involvement in airway remodeling processes.[10] These mechanisms highlight how specific enzyme activities and protein functions, often regulated at the post-translational level or through allosteric control, can collectively contribute to the emergent properties of asthmatic airways, including increased contractility and structural changes.
Systems-Level Integration and Homeostatic Control
Section titled “Systems-Level Integration and Homeostatic Control”The development and progression of adult-onset asthma involve a complex interplay of various pathways, demonstrating extensive pathway crosstalk and hierarchical regulation. The initial identification ofHLA-DQas an asthma-susceptibility locus underscores the role of major histocompatibility complex genes in modulating immune responses to antigens.[1]While IgE levels are often considered in asthma, studies suggest that elevation of IgE is an inconsistent secondary effect rather than a primary cause, except for specific genes likeIL13 and the HLA region, which affect both phenotypes. [1]This indicates a nuanced relationship where certain genetic predispositions can influence multiple facets of the disease.
Mechanisms regulating homeostatic and healing pathways are also crucial. For example, SMAD3 and IL2RBare implicated in these regulatory processes, suggesting that proper resolution of inflammation and tissue repair are essential for preventing chronic airway disease.[1] Furthermore, genetic determinants of lung function, such as the nonsynonymous coding SNP rs2070600 in AGER(associated with forced expiratory volume in one second (FEV1)/forced vital capacity (FVC)), contribute to the overall susceptibility and severity of asthma.[2] The reduction of FEV1/FVC is a characteristic of obstructive lung diseases, indicating that the genetic landscape influences not just the inflammatory response but also the fundamental mechanics of respiration, integrating immune, structural, and functional aspects of the lung.
Clinical Relevance of Adult Onset Asthma
Section titled “Clinical Relevance of Adult Onset Asthma”Diagnostic Utility and Risk Stratification
Section titled “Diagnostic Utility and Risk Stratification”Genetic studies on adult onset asthma currently offer limited direct diagnostic utility for individual patients, as multi-SNP scores, despite their association with disease risk, demonstrate low sensitivity and specificity in discriminating disease status.[3] However, ongoing research aims to improve the precision of SNP effect estimates through larger genome-wide association studies (GWAS), which could enhance the accuracy of genome-wide SNP scores and potentially contribute to future diagnostic tools. [3] For instance, the rs7130588 :Gvariant on chromosome 11q13.5 has been observed to be more prevalent in atopic asthmatic patients compared to non-atopic individuals, suggesting a potential avenue for stratifying patients based on specific asthma subphenotypes.[3] Such findings highlight the potential for genetic markers to inform risk assessment and guide personalized medicine approaches, particularly as our understanding of the complex interplay between genetic factors and environmental triggers deepens.
Phenotypic Heterogeneity and Prognostic Insights
Section titled “Phenotypic Heterogeneity and Prognostic Insights”Genetic factors influencing asthma susceptibility and progression vary significantly with the age of onset, underscoring the heterogeneous nature of the disease. Research indicates that later-onset asthma cases are more strongly influenced by the major histocompatibility complex (MHC) region compared to childhood-onset cases, which are more distinctly linked to the chromosome 17q locus.[1]This distinction suggests different underlying pathophysiological mechanisms, with adult-onset asthma potentially having a minor atopic component andHLA-DQ genes restricting responses to non-classical antigens. [1] Furthermore, specific genetic variants, such as a nonsynonymous coding SNP in AGER (rs2070600 ) on chromosome 6p21, have been associated with lung function parameters like FEV1/FVC, a characteristic marker of obstructive lung diseases and a feature of severe asthma.[2]These genetic insights are crucial for predicting disease progression, identifying individuals prone to severe asthma, and potentially guiding treatment selection, as they highlight the important role ofTH2cytokine and antigen presentation genes in asthma development.[4]
Shared Genetic Mechanisms and Comorbidities
Section titled “Shared Genetic Mechanisms and Comorbidities”The genetic landscape of adult onset asthma reveals shared susceptibility loci with other inflammatory conditions, implying common underlying biological pathways. For example, SNPs at the chromosome 17q21 locus, associated with asthma, are also strongly linked to Crohn’s disease.[1] Additionally, genes like SLC22A5, a carnitine transporter, and theORMDL3/GSDMB and IL18R1/IL1RL1regions, which include genes replicated as asthma risk loci, also harbor variants associated with Crohn’s disease[1], [3](Lancet). This genetic overlap suggests that asthma and Crohn’s disease may share mechanisms, possibly involving the modulation of microbial interactions with mucosal barriers.[1] While IL13and the HLA region show some association with total serum IgE levels, genetic studies largely indicate little overlap between the principal loci for asthma susceptibility and those regulating IgE, suggesting that elevated IgE levels are often a secondary effect rather than a primary cause of asthma.[1]
Frequently Asked Questions About Adult Onset Asthma
Section titled “Frequently Asked Questions About Adult Onset Asthma”These questions address the most important and specific aspects of adult onset asthma based on current genetic research.
1. Could my kids inherit my adult asthma?
Section titled “1. Could my kids inherit my adult asthma?”Yes, there’s a genetic component to adult onset asthma, so your children could have a predisposition. It’s considered a complex disease, meaning both inherited genetic factors and environmental exposures play a role in whether someone develops it. So, while genetics increase risk, it’s not a guarantee.
2. Why do new things suddenly trigger my breathing?
Section titled “2. Why do new things suddenly trigger my breathing?”Your immune system might be reacting to environmental factors or even certain bacteria or antigens that aren’t typical allergens. Genes within the Major Histocompatibility Complex (MHC) region, like HLA-DQ, are particularly influential in adult-onset asthma and can restrict your immune response to these non-classical triggers, leading to new symptoms.
3. Can I still exercise safely with my adult asthma?
Section titled “3. Can I still exercise safely with my adult asthma?”Exercise can be challenging with adult onset asthma due to potential limitations in physical activity. However, understanding your specific triggers and managing your condition with your doctor’s guidance is key. Lower pulmonary function, which can be influenced by genetic factors like those near theAGERgene, often indicates more severe asthma and might require careful exercise planning.
4. Will my asthma get worse as I get older?
Section titled “4. Will my asthma get worse as I get older?”It’s possible, as lower pulmonary function, a characteristic feature of obstructive lung diseases like asthma, is often indicative of more severe asthma. Genetic markers can help predict disease progression. Regular monitoring and personalized management can help mitigate worsening symptoms.
5. Does what I eat impact my asthma symptoms?
Section titled “5. Does what I eat impact my asthma symptoms?”Your diet might indirectly influence your asthma, especially through its impact on your immune system and gut microbiome. Genes likeORMDL3/GSDMB and IL18R1/IL1RL1are implicated in modulating microbial interactions, suggesting a link between your body’s internal environment and inflammatory conditions like asthma. Maintaining a healthy gut could potentially support better asthma management.
6. Why is my asthma experience different from others?
Section titled “6. Why is my asthma experience different from others?”Adult onset asthma is a highly heterogeneous disease, meaning it manifests differently in various people due to diverse underlying biological mechanisms. Your unique combination of genetic predispositions and environmental exposures shapes your specific symptoms and disease course. This is why personalized treatment strategies are so important.
7. Are my other health issues connected to my asthma?
Section titled “7. Are my other health issues connected to my asthma?”Yes, some genetic variants suggest shared biological mechanisms between adult onset asthma and other inflammatory conditions, such as Crohn’s disease. These connections often involve how your body interacts with microbes in your system. Discussing all your health conditions with your doctor can help identify potential links and inform comprehensive care.
8. How can doctors be sure it’s mytype of asthma?
Section titled “8. How can doctors be sure it’s mytype of asthma?”Doctors look at several factors, including your symptoms, medical history, and lung function tests, particularly the FEV1/FVCratio. Genetic markers are also being explored to help distinguish adult onset asthma from other respiratory conditions, aiding in a more precise diagnosis for your specific case.
9. Why don’t my asthma meds always work well for me?
Section titled “9. Why don’t my asthma meds always work well for me?”Because adult onset asthma is a very diverse disease with varied biological mechanisms, a “one-size-fits-all” approach to medication isn’t always effective. Your unique genetic profile and the specific pathways involved in your asthma might require a more personalized treatment strategy to find what works best for you.
10. Would a DNA test help manage my asthma?
Section titled “10. Would a DNA test help manage my asthma?”A DNA test could potentially be useful in the future. Identifying specific genetic markers can help doctors distinguish your asthma from other conditions, predict how your disease might progress, and eventually guide personalized treatment strategies tailored to your unique genetic makeup. While research is ongoing, this offers promise for more targeted care.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Moffatt MF, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363(13):1211-21.
[2] Hirota T, et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet. 2011;43(9):893-6.
[3] Ferreira MA, et al. Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. Eur J Hum Genet. 2011;19(1):103-6.
[4] Li X, et al. Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol. 2010;125(2):326-33.e11.
[5] Hancock, D. B., et al. “Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children.”PLoS Genetics, 2009.
[6] Himes, B. E., et al. “Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene.”American Journal of Human Genetics, 2009.
[7] Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, et al. “Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.”Nat Genet, vol. 43, no. 9, 2011, pp. 887–892.
[8] Noguchi, E. et al. “Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.”PLoS Genet, vol. 7, no. 7, 2011, p. e1002170.
[9] Ober, C., et al. “Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function.”N Engl J Med, vol. 358, no. 16, 2008, pp. 1682-1691.
[10] Van Eerdewegh, P. et al. “Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.”Nature, vol. 418, no. 6896, 2002, pp. 426-430.