Eosinophilic Esophagitis
Background
Section titled “Background”Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory disease of the esophagus. It is characterized by the presence of a significant number of eosinophils, a type of white blood cell, in the esophageal tissue. This condition can affect individuals of all ages, from infants to adults, and has seen a notable increase in prevalence over recent decades. Clinically, EoE often presents with symptoms such as difficulty swallowing (dysphagia), food impaction, and reflux-like symptoms that do not respond well to standard acid-suppressing medications.
Biological Basis
Section titled “Biological Basis”The biological basis of eosinophilic esophagitis involves a complex interplay of genetic predisposition and environmental triggers, primarily food allergens and aeroallergens. When susceptible individuals are exposed to these allergens, an allergic inflammatory response is mounted in the esophagus. This response leads to the recruitment and accumulation of eosinophils, which release various cytotoxic proteins and inflammatory mediators. The sustained presence and activation of these eosinophils cause inflammation, tissue damage, and remodeling of the esophageal wall, contributing to the characteristic symptoms and structural changes observed in EoE. Genetic studies have indicated a significant hereditary component, with certain genetic variations influencing an individual’s susceptibility to developing the disease and its severity.
Clinical Relevance
Section titled “Clinical Relevance”Eosinophilic esophagitis is clinically relevant due to its impact on a patient’s quality of life and potential for serious complications. Untreated or poorly managed EoE can lead to esophageal dysfunction, including narrowing (strictures) and fibrosis, which can necessitate endoscopic dilation procedures. The persistent inflammation can also cause chronic pain, weight loss, and nutritional deficiencies, particularly in children. Diagnosis typically involves endoscopy with biopsies of the esophagus to identify the characteristic eosinophilic infiltration. Management strategies often include dietary elimination of trigger foods, proton pump inhibitors, and topical corticosteroids to reduce esophageal inflammation.
Social Importance
Section titled “Social Importance”The rising incidence and prevalence of eosinophilic esophagitis highlight its growing social importance. It represents a significant public health concern due to the chronic nature of the disease, the need for long-term management, and its considerable impact on daily life for both patients and their families. The condition can lead to frequent medical visits, diagnostic procedures, and ongoing treatments, contributing to a substantial economic burden on healthcare systems. Increased awareness, improved diagnostic methods, and continued research into its underlying mechanisms are crucial for developing more effective and personalized treatments, ultimately improving patient outcomes and alleviating the societal impact of this condition.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Research into eosinophilic esophagitis (EoE) often faces methodological and statistical challenges that can impact the interpretation and generalizability of findings. Many studies, particularly genome-wide association studies (GWAS), operate with modest sample sizes, especially when investigating relatively rare diseases like EoE, where clinical diagnosis and recruitment can be difficult. This limited power can restrict the ability to detect genetic variants with moderate effect sizes, potentially leading to an underestimation of the genetic architecture of the condition. Consequently, findings from discovery phases often require rigorous replication in independent cohorts to mitigate the risk of spurious associations.[1]Furthermore, the statistical assumptions inherent in many genetic analyses can introduce limitations. For instance, GWAS commonly assume an additive or monogenic effect for identified variants, which may not fully capture the complex, polygenic nature of eosinophilic esophagitis, where multiple genes and intricate interactions likely contribute to disease susceptibility. Variations in cohort characteristics, such as follow-up times, or the presence of non-independent traits and shared controls within study populations, can further complicate analyses and introduce biases. Insufficient correction for genomic inflation of test statistics can also inflate effect sizes, leading to potentially misleading conclusions about the strength of genetic associations.[2]
Phenotypic Definition and Biological Complexity
Section titled “Phenotypic Definition and Biological Complexity”The precise definition and characterization of eosinophilic esophagitis phenotypes present a significant challenge in genetic studies. A reductionist approach, relying on broad clinical criteria or questionnaire-based assessments, may oversimplify the disease by failing to account for distinct endophenotypes, varying disease trajectories, or specific biological subtypes of EoE. This simplification can obscure nuanced genetic signals that might be associated with particular disease manifestations or severities, thereby limiting the depth of understanding of the genetic contributions to the condition.[2]The biological complexity of eosinophilic esophagitis also introduces limitations, particularly concerning tissue-specific gene expression. While studies may utilize readily available tissues like peripheral blood lymphocytes for gene expression profiling, the results might not fully reflect the intricate gene expression patterns or coexpression networks active within the esophageal tissue, which is the primary site of inflammation in EoE. Gene expression profiles can vary significantly between different tissues, meaning that findings from one tissue type may not be directly transferable or fully representative of the disease mechanisms occurring in the target organ, thus impacting the biological interpretation of identified genetic pathways.[3]
Generalizability and Environmental Confounders
Section titled “Generalizability and Environmental Confounders”A significant limitation in genetic research on eosinophilic esophagitis is the potential for restricted generalizability of findings, largely due to biases in population ancestry. Many studies, particularly in their discovery phases, are often conducted in cohorts predominantly composed of individuals from specific ethnic backgrounds, such as European-American populations. Given that gene expression and genetic associations can vary considerably across different ancestries, findings from such cohorts may not be directly applicable or fully representative of the genetic landscape of EoE in more diverse global populations. This lack of ancestral diversity can hinder the identification of universally relevant genetic risk factors and pathways.[3]Furthermore, the influence of environmental factors and complex gene-environment interactions on the development and progression of eosinophilic esophagitis is often challenging to fully capture and account for in studies. While genetic factors are important, environmental exposures play a crucial role, and their interplay with genetic predispositions is complex. Cohorts characterized by highly similar environmental exposures, such as those drawn from a single geographic region, might limit the ability to identify critical gene-environment interactions. This incomplete understanding of environmental contributions, combined with unmeasured genetic factors, contributes to the challenge of explaining the “missing heritability” for complex conditions like EoE, leaving significant knowledge gaps in our understanding of disease etiology.[4]
Variants
Section titled “Variants”Genetic variants play a crucial role in predisposing individuals to complex inflammatory conditions like eosinophilic esophagitis (EoE), often by influencing immune responses, tissue integrity, or cell signaling pathways. TheDDAH1 gene, for example, encodes dimethylarginine dimethylaminohydrolase 1, an enzyme critical for nitric oxide metabolism. Nitric oxide is a key signaling molecule involved in various physiological processes, including inflammation and immune regulation. The variant rs17131726 near DDAH1 may alter its expression or activity, potentially affecting the inflammatory environment of the esophagus and contributing to the accumulation of eosinophils.[5] The WDR36 gene, which is associated with rs1438673 alongside the pseudogene RPS3AP21, codes for a WD repeat-containing protein that is broadly involved in cellular processes, including membrane trafficking and protein degradation. While WDR36 is primarily recognized for its role in glaucoma, its broader cellular functions could indirectly impact cell stress responses or tissue homeostasis in the esophagus, thereby contributing to susceptibility to chronic inflammation.[6] Similarly, the EMSY gene, linked with rs61894547 , is known for its involvement in DNA repair and transcriptional regulation. Alterations in EMSY function could lead to dysregulated gene expression in esophageal cells, potentially impairing their ability to respond to inflammatory stimuli or maintain epithelial barrier integrity, thereby increasing vulnerability to EoE.
Several variants are found within or near CAPN14, a gene encoding calpain-14, which is highly expressed in the esophagus and strongly implicated in EoE pathogenesis. The variants rs143457388 , rs77569859 , and rs149864795 in CAPN14 are thought to influence the gene’s expression or activity. Calpains are calcium-dependent proteases that play roles in cell signaling, cell migration, and tissue remodeling, processes highly relevant to the chronic inflammation and tissue damage observed in EoE.[7] Specifically, increased CAPN14 expression has been associated with the allergic inflammatory response in the esophagus, suggesting that these variants may contribute to EoE by enhancing pro-inflammatory pathways or altering the tissue’s response to allergens.[5] Adjacent to these, the SHANK2 gene, associated with rs182139615 , encodes a scaffolding protein predominantly found in synapses, crucial for neuronal signaling. However, scaffolding proteins like SHANK2 can also be involved in organizing cell adhesion complexes and signaling hubs in non-neuronal tissues, potentially affecting epithelial cell structure and communication in the esophagus, which is vital for maintaining barrier function against environmental triggers.
Further contributing to the genetic landscape of EoE are variants affecting cell structure and signaling. The region encompassing WASF3 and GPR12 contains the variant rs146034499 . WASF3 (Wiskott-Aldrich syndrome protein family member 3) is involved in actin cytoskeleton remodeling, which is essential for cell motility, adhesion, and epithelial barrier function. Disruption of these processes can compromise the esophageal lining, making it more susceptible to allergen penetration and immune activation. GPR12 (G protein-coupled receptor 12) is involved in diverse physiological functions, including immune responses, and its modulation could influence local inflammation.[6] The PRKD3 gene, with variant rs143457389 , encodes protein kinase D3, a serine/threonine kinase involved in cell proliferation, differentiation, and inflammatory signaling pathways. Altered activity of PRKD3 due to this variant could lead to dysregulated cellular responses in the esophagus, contributing to the chronic inflammatory state of EoE.[7] Additionally, the PRKG1 gene and its antisense RNA PRKG1-AS1, associated with rs185811602 , are involved in cGMP-dependent protein kinase signaling, which regulates smooth muscle relaxation, vascular permeability, and immune cell function. Variations here may impact esophageal motility and immune cell recruitment, both of which are relevant to EoE pathophysiology.
Finally, the genetic associations extend to chromatin remodeling and protein modification. The intergenic region between INO80C and GALNT1 includes the variant rs534845465 . INO80C is a component of the INO80 chromatin remodeling complex, which plays a critical role in gene expression by altering chromatin structure. Changes in its function could broadly affect the transcriptional programs of esophageal cells, including those related to inflammation and tissue repair. GALNT1 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 1) is involved in O-linked glycosylation, a post-translational modification crucial for protein function and cell-cell interactions.[5] The URGCP gene, also known as URGCP-MRPS24, is linked with rs188483654 . URGCP(Up-Regulated in General Cancer Protein) is associated with cell proliferation and survival, whileMRPS24 encodes a mitochondrial ribosomal protein. Variants in this region could affect cellular growth, metabolism, or stress responses within the esophageal epithelium, potentially influencing its resilience to chronic inflammation and tissue damage characteristic of EoE.[6]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs17131726 | DDAH1 | eosinophilic esophagitis |
| rs1438673 | WDR36 - RPS3AP21 | asthma, allergic disease allergic disease asthma, seasonal allergic rhinitis eosinophilic esophagitis atopic eczema |
| rs143457388 rs77569859 rs149864795 | CAPN14 | eosinophilic esophagitis |
| rs182139615 | SHANK2 | eosinophilic esophagitis |
| rs146034499 | WASF3 - GPR12 | eosinophilic esophagitis |
| rs143457389 | PRKD3 | eosinophilic esophagitis |
| rs185811602 | PRKG1, PRKG1-AS1 | eosinophilic esophagitis |
| rs61894547 | EMSY | eosinophil percentage of leukocytes eosinophil count eosinophil percentage of granulocytes eosinophilic esophagitis asthma |
| rs534845465 | INO80C - GALNT1 | eosinophilic esophagitis |
| rs188483654 | URGCP-MRPS24, URGCP | eosinophilic esophagitis |
Genetic Predisposition and Immune Pathway Dysregulation
Section titled “Genetic Predisposition and Immune Pathway Dysregulation”The development of allergic and inflammatory conditions often involves a complex interplay of genetic factors. Genome-wide association studies (GWAS) have identified numerous genetic variants that contribute to the risk of various immune-mediated diseases. For instance, a missense variant, rs3763978 , within the TSPAN8gene, which causes a glycine to alanine substitution predicted to be damaging, has been associated with hay fever and eczema.[4] Similarly, variants in genes like CLEC16A have been linked to immune disorders such as common variable immunodeficiency, underscoring the role of specific genetic alterations in immune system function.[8]Furthermore, a polygenic risk model suggests that multiple common genetic variants, rather than a single gene, collectively influence susceptibility to complex immune conditions. Studies on celiac disease, for example, have revealed several common variants that impact immune gene expression, highlighting a broad genetic architecture underlying immune dysregulation.[9]This concept is reinforced by findings of shared susceptibility loci across various autoimmune diseases like Crohn’s disease and psoriasis, and a shared genetic architecture among ten different pediatric autoimmune diseases, indicating common pathways in immune-mediated inflammation.[10] These genetic predispositions can alter immune cell function, epithelial barrier integrity, or inflammatory signaling, contributing to an individual’s susceptibility to chronic inflammatory responses.
Environmental Triggers and Allergic Sensitization
Section titled “Environmental Triggers and Allergic Sensitization”Environmental factors play a crucial role in triggering and exacerbating allergic and inflammatory conditions in genetically predisposed individuals. Exposure to various allergens, including those in diet or inhaled, can initiate immune responses that lead to chronic inflammation. Research on food allergy, for instance, has explored the influence of maternal genetic effects and parent-of-origin effects, suggesting that early life environmental exposures, potentially modulated by parental genetics, can shape the developing immune system and influence allergic sensitization.[11]Beyond specific allergens, broader environmental influences, such as lifestyle and geographic factors, can contribute to the prevalence and severity of allergic conditions. The understanding of other allergic conditions, like asthma and hay fever, points to a general susceptibility where environmental triggers interact with genetic backgrounds to provoke inflammatory responses. A meta-analysis of GWAS for serum total IgE levels, a key marker of allergic sensitization, has identified genetic variants influencing overall allergic propensity, which can be further modulated by environmental exposures.[7]
Gene-Environment Interactions and Comorbidities
Section titled “Gene-Environment Interactions and Comorbidities”The manifestation of allergic inflammatory diseases is often a result of intricate gene-environment interactions, where genetic predispositions are amplified or mitigated by environmental exposures. Individuals carrying specific risk variants for allergic conditions, such as the 11 risk variants associated with asthma with hay fever, may develop more pronounced inflammatory responses when exposed to relevant environmental triggers.[12] This complex interaction can lead to a breakdown of immune tolerance or an exaggerated T-helper 2 (Th2) immune response, characteristic of allergic inflammation.
Moreover, allergic inflammatory conditions frequently co-occur, indicating shared underlying mechanisms and genetic predispositions. The genetic overlap observed between conditions like asthma, hay fever, eczema, and various autoimmune diseases suggests a systemic susceptibility to immune dysregulation. These comorbidities are not merely coincidental but often reflect common pathways affected by both inherited genetic factors and environmental influences, where an individual’s overall allergic or inflammatory load might determine the specific organ system that becomes primarily affected.
Understanding Eosinophilic Esophagitis: An Overview
Section titled “Understanding Eosinophilic Esophagitis: An Overview”Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory condition of the esophagus characterized by the presence of a significant number of eosinophils, a type of white blood cell, in the esophageal lining. This allergic reaction is primarily triggered by certain foods or environmental allergens, leading to impaired esophageal function and symptoms such as difficulty swallowing, heartburn, and food impaction. The disease represents a complex interplay between genetic predispositions, environmental exposures, and a dysregulated immune response that specifically targets the esophageal tissue.
Immune Dysregulation and Allergic Pathways
Section titled “Immune Dysregulation and Allergic Pathways”The core of EoE pathophysiology involves a misdirected immune response heavily reliant on allergic pathways, with immunoglobulin E (IgE) playing a central role. Elevated total serum IgE levels are often observed, and the high-affinity IgE receptor, encoded by the_FCER1A_ gene, is a known susceptibility locus for these levels.[13] Polymorphisms within the _FCER1A_promoter region can influence its transcription activity, potentially contributing to allergic disease development by modulating the sensitivity of immune cells like mast cells and basophils to IgE-mediated activation.[14] This allergic cascade is further supported by the _TH2_ locus control region, which is essential for the expression of _TH2_cytokine genes that drive allergic inflammation, and for facilitating long-range intrachromosomal interactions crucial for robust immune responses.[15] Beyond IgE, other immune regulatory molecules contribute to the inflammatory environment. For instance, the _TNFRSF9_ gene, a member of the tumor necrosis factor (TNF)-receptor superfamily, produces a protein critical for the clonal expansion, survival, and development of T cells.[16] Variants like *rs11121129 * can act as expression quantitative trait loci (eQTLs) for _TNFRSF9_, thereby influencing T cell-mediated immunity.[16] Similarly, _ENO1_, which encodes alpha enolase, has been identified as a putative autoantigen in severe asthma, suggesting shared molecular mechanisms or antigens that might provoke immune responses in various allergic or autoimmune conditions.[16] These intricate molecular and cellular pathways highlight the systemic nature of allergic predisposition that manifests locally in the esophagus.
Genetic Contributions and Regulatory Mechanisms
Section titled “Genetic Contributions and Regulatory Mechanisms”EoE, like many immune-mediated conditions, has a significant genetic component, often sharing a complex genetic architecture with other pediatric autoimmune and inflammatory diseases, such as celiac disease and inflammatory bowel disease.[8] Genetic variants can influence immune gene expression and regulatory networks, predisposing individuals to heightened allergic responses. For example, specific polymorphisms in the promoter of the _FCER1A_ gene can alter its transcriptional activity, impacting the levels of the high-affinity IgE receptor and thus modulating allergic reactivity.[14] Furthermore, genome-wide association studies have identified various loci that contribute to immune dysregulation. Genetic variants acting as eQTLs, such as *rs7548511 * for _ENO1_ and *rs11121129 * for _TNFRSF9_, can alter the expression levels of these key immune-related genes, influencing cellular functions like T cell development or the presentation of potential autoantigens.[16] The _HLA_ region, known for its critical role in immune recognition and antigen presentation, also harbors polymorphisms associated with immune-mediated conditions, further underscoring the genetic predisposition to a dysregulated immune system in EoE.[17] The maternal inheritance patterns of atopic IgE responsiveness on chromosome 11q also indicate a hereditary component to allergic susceptibility.[18]
Esophageal Pathology and Systemic Interconnections
Section titled “Esophageal Pathology and Systemic Interconnections”At the tissue and organ level, EoE is characterized by chronic inflammation and eosinophil infiltration specifically within the esophageal wall, distinguishing it from other gastrointestinal conditions. This persistent inflammation disrupts the normal homeostatic functions of the esophagus, leading to symptoms and potential structural changes like strictures or narrowing over time. The local tissue damage is a direct consequence of the activated immune cells and their released inflammatory mediators, driven by the underlying allergic pathways.
The esophageal pathology in EoE is not isolated but is intricately linked to broader systemic allergic predispositions. Individuals with EoE often have a history of other atopic conditions, such as asthma or elevated total serum IgE levels, suggesting a systemic immune profile prone to allergic reactions.[19] The genetic and molecular pathways involved in EoE, including those related to _FCER1A_ and _TH2_cytokine production, are also fundamental to the pathogenesis of other allergic diseases. Therefore, EoE can be understood as a specific manifestation of a generalized allergic diathesis, where the esophageal tissue becomes a primary target for chronic allergic inflammation due to a complex interplay of genetic susceptibility and environmental triggers.
Frequently Asked Questions About Eosinophilic Esophagitis
Section titled “Frequently Asked Questions About Eosinophilic Esophagitis”These questions address the most important and specific aspects of eosinophilic esophagitis based on current genetic research.
1. Does my family history mean I’ll get EoE?
Section titled “1. Does my family history mean I’ll get EoE?”Yes, there’s a significant hereditary component to EoE. If your parents have it, you have a higher susceptibility due to shared genetic variations that influence disease risk. However, genetics are only part of the picture; environmental triggers also play a crucial role.
2. My sibling has EoE, why don’t I?
Section titled “2. My sibling has EoE, why don’t I?”Even with a strong genetic predisposition, the development of EoE is complex. You and your sibling inherit different combinations of genetic variations, and you also have unique environmental exposures. This interplay of multiple genes and various triggers means that not everyone in a family will develop the condition, even if some are susceptible.
3. Can diet changes really fix my EoE if it’s genetic?
Section titled “3. Can diet changes really fix my EoE if it’s genetic?”Dietary changes are a cornerstone of EoE management, even with a genetic predisposition. While genetics influence your susceptibility, food allergens are key environmental triggers. Eliminating these specific trigger foods can significantly reduce inflammation and symptoms, working withyour genetic makeup to manage the disease.
4. Will my kids inherit my EoE risk?
Section titled “4. Will my kids inherit my EoE risk?”Yes, your children may inherit a genetic predisposition to EoE. The condition has a significant hereditary component, meaning certain genetic variations can increase their susceptibility. However, developing EoE also requires exposure to specific environmental triggers, so inheriting the risk doesn’t guarantee they will develop the disease.
5. Does my background affect my EoE risk?
Section titled “5. Does my background affect my EoE risk?”Yes, your ethnic background can influence your EoE risk and how the disease presents. Genetic associations and gene expression patterns can vary significantly across different ancestries. This means research primarily focused on one population might not fully capture the genetic landscape or risk factors relevant to your specific background.
6. Why is my EoE worse than my friend’s?
Section titled “6. Why is my EoE worse than my friend’s?”The severity of EoE can vary greatly among individuals due to a complex interplay of genetic factors and environmental exposures. Your specific combination of genetic variations might predispose you to a more intense inflammatory response or greater tissue damage. Additionally, differences in your personal allergen exposures or how your body responds to treatment can also play a role.
7. Can my environment trigger my EoE symptoms?
Section titled “7. Can my environment trigger my EoE symptoms?”Absolutely, environmental factors are crucial triggers for EoE symptoms, especially in genetically susceptible individuals. These can include not just food allergens but also aeroallergens like pollen or dust mites. Exposure to these triggers mounts an allergic inflammatory response in your esophagus, leading to the characteristic symptoms.
8. Why don’t my treatments always work for me?
Section titled “8. Why don’t my treatments always work for me?”EoE is a complex condition, and treatment effectiveness can vary due to individual genetic differences and specific disease subtypes. Your unique genetic makeup might influence how you respond to certain medications or dietary interventions. Also, the disease’s “polygenic” nature, involving many genes, means a single treatment might not fully address all contributing factors.
9. Is a DNA test useful for my EoE?
Section titled “9. Is a DNA test useful for my EoE?”Currently, routine DNA tests aren’t typically used to diagnose or predict EoE for individuals. While genetic research has identified many contributing variations, the disease is complex and polygenic, meaning many genes are involved. Future research may lead to more personalized genetic insights, but for now, diagnosis relies on endoscopy and biopsies.
10. Besides food, can anything else trigger my EoE?
Section titled “10. Besides food, can anything else trigger my EoE?”Yes, beyond specific food allergens, other environmental factors can trigger or worsen your EoE. Aeroallergens, such as pollen, dust mites, or pet dander, are significant contributors, especially in genetically predisposed individuals. The interplay between these environmental exposures and your genetic background can collectively drive the inflammatory response in your esophagus.
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
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[4] Johansson A et al. Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema. Hum Mol Genet. 2019;28(20):3472-3481.
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[9] Dubois, P. C., et al. “Multiple common variants for celiac disease influencing immune gene expression.”Nat Genet, vol. 42, no. 4, 2010, pp. 295-300.
[10] Ellinghaus, D., et al. “Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.”Am J Hum Genet, vol. 90, no. 4, 2012, pp. 636-47.
[11] Liu, X., et al. “Genome-wide association study of maternal genetic effects and parent-of-origin effects on food allergy.”Medicine (Baltimore), vol. 97, no. 8, 2018, p. e9771.
[12] Ferreira MA et al. Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. J Allergy Clin Immunol. 2013;133(2):494-503.e5.
[13] Weidinger, S., et al. “Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus.” PLoS Genetics, vol. 4, no. 10, 2008, e1000202.
[14] Hasegawa, M., et al. “A novel -66T/C polymorphism in Fc epsilon RI alpha-chain promoter affecting the transcription activity: possible relationship to allergic diseases.” The Journal of Immunology, vol. 171, no. 4, 2003, pp. 1927-1933.
[15] Lee, G. R., et al. “Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions.”Nature Immunology, vol. 6, no. 1, 2005, pp. 42-48.
[16] Tian, C., et al. “Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections.” Nature Communications, vol. 8, no. 1, 2017, p. 574.
[17] Nicoletti, P., et al. “Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.” Gastroenterology, vol. 152, no. 1, 2017, pp. 103-116.e4.
[18] Cookson, W. O. C., et al. “Maternal inheritance of atopic IgE responsiveness on chromosome 11q.” The Lancet, vol. 340, no. 8816, 1992, pp. 381-384.
[19] Yao, T. C., et al. “Genome-wide association study of lung function phenotypes in a founder population.” Journal of Allergy and Clinical Immunology, vol. 133, no. 4, 2013, pp. 1184-1192.e10.