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Lawson LP, Parameswaran S, Panganiban RA, Constantine GM, Weirauch MT, Kottyan LC. Update on the genetics of allergic diseases. J Allergy Clin Immunol 2025; 155:1738-1752. [PMID: 40139464 PMCID: PMC12145254 DOI: 10.1016/j.jaci.2025.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 02/24/2025] [Accepted: 03/09/2025] [Indexed: 03/29/2025]
Abstract
The field of genetic etiology of allergic diseases has advanced significantly in recent years. Shared risk loci reflect the contribution of genetic factors to the sequential development of allergic conditions across the atopic march, while unique risk loci provide opportunities to understand tissue specific manifestations of allergic disease. Most identified risk variants are noncoding, indicating that they likely influence gene expression through gene regulatory mechanisms. Despite recent advances, challenges persist, particularly regarding the need for increased ancestral diversity in research populations. Further, while polygenic risk scores show promise for identifying individuals at higher genetic risk for allergic diseases, their predictive accuracy varies across different ancestries and can be difficult to translate to an individual's absolute risk of developing a disease. Methodologies, including "nearest gene," 3D chromatin interaction analysis, expression quantitative trait locus analysis, experimental screens, and integrative bioinformatic models, have established connections between genetic variants and their regulatory targets, enhancing our understanding of disease risk and phenotypic variability. In this review, we focus on the state of knowledge of allergic sensitization and 5 allergic diseases: asthma, atopic dermatitis, allergic rhinitis, food allergy, and eosinophilic esophagitis. We summarize recent progress and highlight opportunities for advancing our understanding of their genetic etiology.
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Affiliation(s)
- Lucinda P Lawson
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Sreeja Parameswaran
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ronald A Panganiban
- Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Gregory M Constantine
- Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, Md
| | - Matthew T Weirauch
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Leah C Kottyan
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
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Kim JW, Kim MJ, Paik K, Kim BR, Choi CW, Na JI. Genome-wide Association Study of Susceptibility Loci for Self-Reported Atopic Dermatitis and Allergic Rhinitis in the Korean Population. Ann Dermatol 2024; 36:74-80. [PMID: 38576245 PMCID: PMC10995615 DOI: 10.5021/ad.22.160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 11/19/2023] [Accepted: 12/27/2023] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Allergic diseases include atopic dermatitis (AD) and allergic rhinitis (AR), which are chronic, relapsing inflammatory disorders of the skin or mucosa that usually accompany immunoglobulin E-mediated immune responses. They are complex, multifactorial diseases with an etiology involving interactions between genetic and environmental factors. OBJECTIVE We performed a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with allergic diseases in the Korean population. METHODS A total of 8,840 samples were obtained from the Korean Association Resource Consortium dataset of the Korean Genome and Epidemiology Study Ansan-Anseong cohort. The allergic disease phenotype was determined based on self-reported physician diagnoses. After quality control, 8,823 subjects with 877,242 variants remained for the final analysis. The GWAS was performed using logistic regression analysis in an additive model adjusted for age and sex. RESULTS A total of 636 patients with allergic disease and 8,176 controls were analyzed. Three SNPs were associated with allergic disease at a level of genome-wide suggestive significance (p<1.0×10-5) in the Korean population: rs7275360, located in neural cell adhesion molecule 2; rs698195; and rs3750552, located in family with sequence similarity 189, member A2. These polymorphisms were on chromosomes 21q21.1, 7q31.1, and 9q21.12, respectively. CONCLUSION We identified 3 novel SNPs significantly associated with allergic diseases in the Korean population. Further research is required to confirm the association between these novel SNPs and allergic disease in the Korean population and in other ethnicities.
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Affiliation(s)
- Jee Woo Kim
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Min Jae Kim
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kyungho Paik
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Bo Ri Kim
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Chong Won Choi
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jung-Im Na
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Korea.
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Brar T, Marino MJ, Lal D. Unified Airway Disease: Genetics and Epigenetics. Otolaryngol Clin North Am 2023; 56:23-38. [DOI: 10.1016/j.otc.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Kang NJ, Han SC, Yoon SH, Sim JY, Maeng YH, Kang HK, Yoo ES. Cinnamomum camphora Leaves Alleviate Allergic Skin Inflammatory Responses In Vitro and In Vivo. Toxicol Res 2019; 35:279-285. [PMID: 31341557 PMCID: PMC6629446 DOI: 10.5487/tr.2019.35.3.279] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 12/24/2018] [Accepted: 01/16/2019] [Indexed: 11/23/2022] Open
Abstract
In this study, we investigated the therapeutic potential of Cinnamomum camphora leaves on allergic skin inflammation such as atopic dermatitis. We evaluated the effects of C. camphora leaves on human adult low-calcium high-temperature keratinocytes and atopic dermatitis mice. C. camphora leaves inhibited Macrophage-derived chemokine (an inflammatory chemokine) production in interferon-γ (10 ng/mL) stimulated Human adult low-calcium high-temperature keratinocytes in a dose dependent manner. C. camphora leaves suppressed the phosphorylation of janus kinase signal transducer and activator of transcription 1. C. camphora leaves also suppressed the phosphorylation of extracellular signal-regulated kinase 1/2, a central signaling molecule in the inflammation process. These results suggest that C. camphora leaves exhibits anti-inflammatory effect via the phosphorylation of signal transducer and activator of transcription 1 and extracellular signal-regulated kinase 1/2. To study the advanced effects of C. camphora leaves on atopic dermatitis, we induced experimental atopic dermatitis in mice by applying 2,4-dinitrochlorobenzene. The group treated with C. camphora leaves (100 mg/kg) showed remarkable improvement of atopic dermatitis symptoms: reduced serum immunoglobulin E levels, smaller lymph nodes with reduced thickness and length, decreased ear edema, and reduced levels of inflammatory cell infiltration in the ears. Interestingly, the effects of C. camphora leaves on atopic dermatitis symptoms were stronger than those of hydrocort cream, a positive control. Taken together, C. camphora leaves showed alleviating effects on the inflammatory chemokine production in vitro and atopic dermatitis symptoms in vivo. These results suggest that C. camphora leaves help in the treatment of allergic inflammation such as atopic dermatitis.
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Affiliation(s)
- Na-Jin Kang
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Sang-Chul Han
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Seok-Hyun Yoon
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Jae-Yeop Sim
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Young Hee Maeng
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Hee-Kyoung Kang
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Eun-Sook Yoo
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
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Kelly K, Ratliff S, Mezuk B. Allergies, asthma, and psychopathology in a nationally-representative US sample. J Affect Disord 2019; 251:130-135. [PMID: 30921596 PMCID: PMC7671678 DOI: 10.1016/j.jad.2019.03.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/20/2019] [Accepted: 03/04/2019] [Indexed: 11/16/2022]
Abstract
BACKGROUND Symptoms of depressed mood and anxiety have been associated with immune dysregulation and atopic disorders, however it is unclear whether this relationship spans other forms of psychopathology. The objective of this study was to use a large, population-based sample to examine the association between several common psychiatric conditions and two atopic disorders: seasonal allergies and asthma. This study also examined whether comorbidity between psychiatric disorders confounded the relationship between atopy and each psychiatric disorder. METHODS Data come from the Comprehensive Psychiatric Epidemiology Surveys, a nationally-representative sample of US adults (N = 10,309). Lifetime history of major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder (PD), and post-traumatic stress disorder (PTSD) was assessed using the Composite International Diagnostic Inventory. History of seasonal allergies and asthma were assessed by self-report. Weighted logistic regression was used to evaluate the association between allergies and asthma and psychopathology. Psychiatric comorbidities were also examined as potential confounders. RESULTS Approximately 36.6% had a history of allergies and 11.5% a history of asthma. Seasonal allergies were positively associated with odds of MDD (Odds ratio (OR): 1.24, 95% Confidence Interval (CI): 1.06-1.46), GAD (OR: 1.54 (1.28-1.84)), PD (OR: 1.54 (1.24-1.91)), and PTSD (OR: 1.32 (1.09-1.59)). Asthma was not significantly associated with any psychiatric disorder. All significant associations persisted after adjustment for psychiatric comorbidities. LIMITATIONS Limitations include self-reporting of atopic disorder status and of all disorder ages of onset. CONCLUSIONS This study confirms the association between MDD and PD and seasonal allergies, and extends this relationship to GAD and PTSD.
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Affiliation(s)
- Kristen Kelly
- Department of Epidemiology, School of Public Health, University of Michigan, United States.
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Sallustio F, Gesualdo L, Gallone A. New findings showing how DNA methylation influences diseases. World J Biol Chem 2019; 10:1-6. [PMID: 30622680 PMCID: PMC6314879 DOI: 10.4331/wjbc.v10.i1.1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/01/2018] [Accepted: 12/05/2018] [Indexed: 02/05/2023] Open
Abstract
In 1975, Holliday and Pugh as well as Riggs independently hypothesized that DNA methylation in eukaryotes could act as a hereditary regulation mechanism that influences gene expression and cell differentiation. Interest in the study of epigenetic processes has been inspired by their reversibility as well as their potentially preventable or treatable consequences. Recently, we have begun to understand that the features of DNA methylation are not the same for all cells. Major differences have been found between differentiated cells and stem cells. Methylation influences various pathologies, and it is very important to improve the understanding of the pathogenic mechanisms. Epigenetic modifications may take place throughout life and have been related to cancer, brain aging, memory disturbances, changes in synaptic plasticity, and neurodegenerative diseases, such as Parkinson's disease and Huntington's disease. DNA methylation also has a very important role in tumor biology. Many oncogenes are activated by mutations in carcinogenesis. However, many genes with tumor-suppressor functions are "silenced" by the methylation of CpG sites in some of their regions. Moreover, the role of epigenetic alterations has been demonstrated in neurological diseases. In neuronal precursors, many genes associated with development and differentiation are silenced by CpG methylation. In addition, recent studies show that DNA methylation can also influence diseases that do not appear to be related to the environment, such as IgA nephropathy, thus affecting the expression of some genes involved in the T-cell receptor signaling. In conclusion, DNA methylation provides a whole series of fundamental information for the cell to regulate gene expression, including how and when the genes are read, and it does not depend on the DNA sequence.
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Affiliation(s)
- Fabio Sallustio
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari 70121, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari “Aldo Moro”, Bari 70121, Italy
| | - Anna Gallone
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari 70121, Italy
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Abstract
PURPOSE OF REVIEW Although asthma is a common disease worldwide, its pathogenesis remains to be fully elucidated. There is increasing evidence of the interaction between epigenetics, DNA-damage, and environmental allergens in the development of asthma. In this review, we will focus on the role of epigenetics and DNA-damage in asthma. RECENT FINDINGS There is growing evidence of environmental allergens, particularly house dust mite, stimulating oxidative DNA damage in airway epithelial cells. The repair of this DNA damage has been implicated in the secretion of Th2 cytokines and the induction of allergic inflammation. SUMMARY Studies of the role of epigenetics, DNA-damage, and environmental allergens have begun to reveal the their complex interactions and their roles in the development of asthma. Further study in these areas may lead to novel prevention and treatment approaches.
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Piler P, Švancara J, Kukla L, Pikhart H. Role of combined prenatal and postnatal paracetamol exposure on asthma development: the Czech ELSPAC study. J Epidemiol Community Health 2018; 72:349-355. [PMID: 29371328 DOI: 10.1136/jech-2017-209960] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 12/22/2017] [Accepted: 01/02/2018] [Indexed: 02/02/2023]
Abstract
BACKGROUND Prenatal and postnatal paracetamol exposure has been previously associated with asthma development in childhood in Western populations. We explore the association between prenatal and postnatal paracetamol exposure and asthma development in a Central European sample of Czech children, suggesting possible additive effect of the both exposures. Furthermore, since aspirin had been used more widely during study data collection in Central Europe, we also compared asthma development for those exposed to paracetamol and aspirin. METHODS We used data from 3329 children born in the 1990s as members of the prospective Czech European Longitudinal Study of Pregnancy and Childhood. Data about prenatal and postnatal paracetamol and aspirin exposure, and potential covariates were obtained from questionnaires completed by mothers. Data about incident asthma were obtained from paediatrician health records. RESULTS 60.9% of children received paracetamol only postnatally, 1.5% only prenatally and 4.9% of children were exposed both during pregnancy and infancy. Prevalence of asthma in following population was 5% at 11 years. Being exposed to paracetamol both in prenatal and postnatal period was associated with asthma development (unadjusted OR 1.98, 95% CI 1.02 to 3.87). Being exposed only in the postnatal period was also significantly associated with increased risk of asthma. No association between prenatal exposure only and outcome was found. A higher but non-significant risk of asthma was observed for those whose mothers used paracetamol during pregnancy compared with those who used aspirin. CONCLUSIONS The main findings of this prospective birth cohort study add to previous observations linking prenatal and early postnatal paracetamol exposure to asthma development. However, the magnitude of effect is relatively modest, and therefore, we recommend paracetamol to remain the analgesic and antipyretic of choice throughout pregnancy and early childhood.
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Affiliation(s)
- Pavel Piler
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jan Švancara
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic.,Institute of Biostatistics and Analyses, Faculty of Medicine and Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Lubomír Kukla
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Hynek Pikhart
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic.,Department of Epidemiology and Public Health, University College London, London, UK
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Khan SJ, Dharmage SC, Matheson MC, Gurrin LC. Is the atopic march related to confounding by genetics and early-life environment? A systematic review of sibship and twin data. Allergy 2018; 73:17-28. [PMID: 28618023 DOI: 10.1111/all.13228] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2017] [Indexed: 01/14/2023]
Abstract
A popular hypothesis known as the atopic march proposes a set of sequential allergy and respiratory disorders in early childhood contributes enormously to the burden of disease in developed countries. Although the concept of the atopic march has been refined and strengthened by many cross-sectional and longitudinal studies linking eczema as the initial manifestation with progression to hay fever and then asthma, there is yet no definitive proof that the atopic march is the primary causal factor in childhood allergic disease. This debate is mainly related to the controversy around potential confounding of these associations by genetic and environmental factors. Family studies are ideally suited to unravelling the role of these factors. While multiple reviews have synthesized evidence from studies investigating this question, no review to date has explored specific evidence generated by twin and sibling studies to understand the aetiology of atopic march diseases. Our aim was to conduct a systematic review of twin and sibling studies that examine the allergic phenotypes that form the atopic march, to determine whether such analyses of data from these studies attempt to control for the effect confounding by shared factors, and to report estimates of the magnitude of associations between multiple phenotypes. Our review suggests that (1) genetics play a bigger role predisposing eczema to hay fever and eczema to asthma than environmental factors, and (2) the link between eczema and asthma and hay fever is independent of shared early-life environmental factors.
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Affiliation(s)
- S. J. Khan
- Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Vic Australia
| | - S. C. Dharmage
- Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Vic Australia
- Murdoch Childrens Research Institute Melbourne Vic Australia
| | - M. C. Matheson
- Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Vic Australia
- Murdoch Childrens Research Institute Melbourne Vic Australia
| | - L. C. Gurrin
- Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Vic Australia
- Murdoch Childrens Research Institute Melbourne Vic Australia
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Han SC, Kang NJ, Yoon WJ, Kim S, Na MC, Koh YS, Hyun JW, Lee NH, Ko MH, Kang HK, Yoo ES. External Application of Apo-9'-fucoxanthinone, Isolated from Sargassum muticum, Suppresses Inflammatory Responses in a Mouse Model of Atopic Dermatitis. Toxicol Res 2016; 32:109-14. [PMID: 27123161 PMCID: PMC4843979 DOI: 10.5487/tr.2016.32.2.109] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/15/2015] [Accepted: 01/27/2016] [Indexed: 11/20/2022] Open
Abstract
Allergic skin inflammation such as atopic dermatitis is characterized by skin barrier dysfunction, edema, and infiltration with various inflammatory cells. The anti-inflammatory effects of Apo-9′-fucoxanthinone, isolated from Sargassum muticum, have been described in many diseases, but the mechanism by which it modulates the immune system is poorly understood. In this study, the ability of Apo-9′-fucoxanthinone to suppress allergic reactions was investigated using a mouse model of atopic dermatitis. The Apo-9′-fucoxanthinone-treated group showed significantly decreased immunoglobulin E in serum. Also, Apo-9′-fucoxanthinone treatment resulted in a smaller lymph node size with reduced the thickness and length compared to the induction group. In addition, Apo-9′-fucoxanthinone inhibited the expression of interleukin-4, interferon-gamma and tumor necrosis factor-alpha by phorbol 12-myristate 13-acetate and ionomycin-stimulated lymphocytes. These results suggest that Apo-9′-fucoxanthinone may be a useful therapeutic strategy for treating chronic inflammatory diseases.
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Affiliation(s)
- Sang-Chul Han
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Na-Jin Kang
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Weon-Jong Yoon
- Jeju Biodiversity Research Institute (JBRI), Jeju Technopark (JTP), Jeju, Korea
| | - Sejin Kim
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Min-Chull Na
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Young-Sang Koh
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Jin-Won Hyun
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Nam-Ho Lee
- Department of Chemistry, College of Natural Science, Jeju National University, Jeju, Korea
| | - Mi-Hee Ko
- Jeju Biodiversity Research Institute (JBRI), Jeju Technopark (JTP), Jeju, Korea
| | - Hee-Kyoung Kang
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Eun-Sook Yoo
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
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Ullemar V, Magnusson PKE, Lundholm C, Zettergren A, Melén E, Lichtenstein P, Almqvist C. Heritability and confirmation of genetic association studies for childhood asthma in twins. Allergy 2016; 71:230-8. [PMID: 26786172 DOI: 10.1111/all.12783] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Although the genetics of asthma has been extensively studied using both quantitative and molecular genetic analysis methods, both approaches lack studies specific to the childhood phenotype and including other allergic diseases. This study aimed to give specific estimates for the heritability of childhood asthma and other allergic diseases, to attempt to replicate findings from genomewide association studies (GWAS) for childhood asthma and to test the same variants against other allergic diseases. METHODS In a cohort of 25 306 Swedish twins aged 9 or 12 years, data on asthma were available from parental interviews and population-based registers. The interviews also inquired about wheeze, hay fever, eczema, and food allergy. Through structural equation modeling, the heritability of all phenotypes was calculated. A subset of 10 075 twins was genotyped for 16 single nucleotide polymorphisms (SNPs) selected from previous GWAS; these were first tested for association with asthma and significant findings also against the other allergic diseases. RESULTS The heritability of any childhood asthma was 0.82 (95% CI 0.79-0.85). For the other allergic diseases, the range was approximately 0.60-0.80. Associations for six SNPs with asthma were replicated, including rs2305480 in the GSDMB gene (OR 0.80, 95% CI 0.74-0.86, P = 1.5*10(-8) ; other significant associations all below P = 3.5*10(-4) ). Of these, only rs3771180 in IL1RL1 was associated with any other allergic disease (for hay fever, OR 0.64, 95% CI 0.53-0.77, P = 2.5*10(-6) ). CONCLUSION Asthma and allergic diseases of childhood are highly heritable, and these high-risk genetic variants associated specifically with childhood asthma, except for one SNP shared with hay fever.
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Affiliation(s)
- V. Ullemar
- Department of Medical Epidemiology and Biostatistics; Karolinska Institutet; Stockholm Sweden
| | - P. K. E. Magnusson
- Department of Medical Epidemiology and Biostatistics; Karolinska Institutet; Stockholm Sweden
| | - C. Lundholm
- Department of Medical Epidemiology and Biostatistics; Karolinska Institutet; Stockholm Sweden
| | - A. Zettergren
- Department of Pharmacology; Institute of Neuroscience and Physiology at the Sahlgrenska Academy; University of Gothenburg; Gothenburg Sweden
- Department of Psychiatry and Neurochemistry; Institute of Neuroscience and Physiology; The Sahlgrenska Academy at University of Gothenburg; Gothenburg Sweden
| | - E. Melén
- Institute of Environmental Medicine; Karolinska Institutet; Stockholm Sweden
- Sachs' Children's Hospital; Stockholm Sweden
| | - P. Lichtenstein
- Department of Medical Epidemiology and Biostatistics; Karolinska Institutet; Stockholm Sweden
| | - C. Almqvist
- Department of Medical Epidemiology and Biostatistics; Karolinska Institutet; Stockholm Sweden
- Astrid Lindgren Children's Hospital; Lung and Allergy Unit; Karolinska University Hospital; Stockholm Sweden
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Kang NJ, Han SC, Kang HJ, Ko G, Yoon WJ, Kang HK, Yoo ES. Anti-Inflammatory Effect of 3-Bromo-4,5-Dihydroxybenzaldehyde, a Component of Polysiphonia morrowii, In Vivo and In Vitro. Toxicol Res 2015; 33:325-332. [PMID: 29071017 PMCID: PMC5654201 DOI: 10.5487/tr.2017.33.4.325] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 08/21/2017] [Accepted: 09/14/2017] [Indexed: 12/18/2022] Open
Abstract
3-Bromo-4,5-dihydroxybenzaldehyde (BDB) is a natural bromophenol compound that is most commonly isolated from red algae. The present study was designed to investigate the anti-inflammatory properties of BDB on atopic dermatitis (AD) in mice induced by 2,4-dinitrochlorobenzene (DNCB) and on lipopolysaccharide (LPS)-stimulated murine macrophages. BDB treatment (100 mg/kg) resulted in suppression of the development of AD symptoms compared with the control treatment (induction-only), as demonstrated by reduced immunoglobulin E levels in serum, smaller lymph nodes with reduced thickness and length, a decrease in ear edema, and reduced levels of inflammatory cell infiltration in the ears. In RAW 264.7 murine macrophages, BDB (12.5, 25, 50, and 100 μM) suppressed the production of interleukin-6, a proinflammatory cytokine, in a dose-dependent manner. BDB also had an inhibitory effect on the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 1 (STAT1; Tyr 701), two major signaling molecules involved in cellular inflammation. Taken together, the results show that BDB treatment alleviates inflammatory responses in an atopic dermatitis mouse model and RAW 264.7 macrophages. These results suggest that BDB may be a useful therapeutic strategy for treating conditions involving allergic inflammation such as atopic dermatitis.
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Affiliation(s)
- Na-Jin Kang
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Sang-Chul Han
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Hyun-Jae Kang
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Geum Ko
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Weon-Jong Yoon
- Jeju Biodiversity Research Institute (JBRI), Jeju Technopark (JTP), Jeju, Korea
| | - Hee-Kyoung Kang
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
| | - Eun-Sook Yoo
- Department of Medicine, School of Medicine, Jeju National University, Jeju, Korea
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Thomsen SF. The contribution of twin studies to the understanding of the aetiology of asthma and atopic diseases. Eur Clin Respir J 2015; 2:27803. [PMID: 26672957 PMCID: PMC4653279 DOI: 10.3402/ecrj.v2.27803] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 08/11/2015] [Indexed: 01/17/2023] Open
Abstract
The prevalence of asthma and other atopic diseases has increased markedly during the past decades and the reasons for this are not fully understood. Asthma is still increasing in many parts of the world, notably in developing countries, and this emphasizes the importance of continuing research aimed at studying the aetiological factors of the disease and the causes of its increase in prevalence. Twin studies enable investigations into the genetic and environmental causes of individual variation in multifactorial diseases such as asthma. Thorough insight into these causes is important as this will ultimately guide the development of preventive strategies and targeted therapies. This review explores the contribution of twin studies to the understanding of the aetiology of asthma and atopic diseases.
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Affiliation(s)
- Simon F Thomsen
- Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark;
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Twin Studies of Atopic Dermatitis: Interpretations and Applications in the Filaggrin Era. J Allergy (Cairo) 2015; 2015:902359. [PMID: 26448767 PMCID: PMC4581550 DOI: 10.1155/2015/902359] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 09/02/2015] [Indexed: 12/31/2022] Open
Abstract
Aim. The aim of this study was to conduct a systematic review of population-based twin studies of (a) the concordance and heritability of AD and (b) the relationship between AD and asthma and, furthermore, to reinterpret findings from previous twin studies in the light of the emerging knowledge about filaggrin and its role in the atopic march and provide suggestions for future research in this area. Methods. We identified all twin studies (published after 1970) that have calculated the concordance rate and/or the heritability of AD, or the genetic and environmental correlations between AD and asthma. Results. Reported concordance rates for AD ranged, respectively. From 0.15 to 0.86 for MZ and from 0.05 to 0.41 for DZ twins, with an overall ratio of MZ : DZ twins of approximately three. The heritability of AD was estimated to be approximately 75%, and the association between AD and asthma was around 85% explained by genetic pleiotropy. Conclusions. Genetic factors account for most of the variability in AD susceptibility and for the association between AD and asthma. Controversy remains as to whether the atopic diseases are causally related or whether they are diverse clinical manifestations of a common, underlying (genetic) disease trait. Future twin studies may help solve this enigma.
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Bathing Effects of Various Seawaters on Allergic (Atopic) Dermatitis-Like Skin Lesions Induced by 2,4-Dinitrochlorobenzene in Hairless Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015. [PMID: 26221169 PMCID: PMC4488017 DOI: 10.1155/2015/179185] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
We evaluated the preventive effects of four types of seawater collected in Republic of Korea on hairless mice with 2,4-dinitrochlorobenzene- (DNCB-) induced allergic/atopic dermatitis (AD). The anti-inflammatory effects were evaluated by measuring tumor necrosis factor- (TNF-) α and interleukins (ILs). Glutathione (GSH), malondialdehyde (MDA), superoxide anion, and inducible nitric oxide synthase (iNOS) were measured to evaluate the antioxidant effects. Caspase-3 and poly (ADP-ribose) polymerase (PARP) were observed to measure the antiapoptotic effects; matrix metalloproteinase- (MMP-) 9 levels were also evaluated. Mice with AD had markedly higher clinical skin severity scores and scratching behaviors; higher TNF-α and ILs (1β, 10, 4, 5, and 13) levels; higher MDA, superoxide anion, caspase-3, PARP, and MMP-9 levels; and greater iNOS activity. However, the severity of AD was significantly decreased by bathing in seawaters, but it did not influence the dermal collagen depositions and skin tissue antioxidant defense systems. These results suggest that bathing in all four seawaters has protective effects against DNCB-induced AD through their favorable systemic and local immunomodulatory effects, active cytoprotective antiapoptotic effects, inhibitory effects of MMP activity and anti-inflammatory and antioxidative effects.
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Kim KW, Myers RA, Lee JH, Igartua C, Lee KE, Kim YH, Kim EJ, Yoon D, Lee JS, Hirota T, Tamari M, Takahashi A, Kubo M, Choi JM, Kim KE, Nicolae DL, Ober C, Sohn MH. Genome-wide association study of recalcitrant atopic dermatitis in Korean children. J Allergy Clin Immunol 2015; 136:678-684.e4. [PMID: 25935106 DOI: 10.1016/j.jaci.2015.03.030] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 03/05/2015] [Accepted: 03/13/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Atopic dermatitis (AD) is a heterogeneous chronic inflammatory skin disease. Most AD during infancy resolves during childhood, but moderate-to-severe AD with allergic sensitization is more likely to persist into adulthood and more often occurs with other allergic diseases. OBJECTIVE We sought to find susceptibility loci by performing the first genome-wide association study (GWAS) of AD in Korean children with recalcitrant AD, which was defined as moderate-to-severe AD with allergic sensitization. METHODS Our study included 246 children with recalcitrant AD and 551 adult control subjects with a negative history of both allergic disease and allergic sensitization. DNA from these subjects was genotyped; sets of common single nucleotide polymorphisms (SNPs) were imputed and used in the GWAS after quality control checks. RESULTS SNPs at a region on 13q21.31 were associated with recalcitrant AD at a genome-wide threshold of significance (P < 2.0 × 10(-8)). These associated SNPs are more than 1 Mb from the closest gene, protocadherin (PCDH)9. SNPs at 4 additional loci had P values of less than 1 × 10(-6), including SNPs at or near the neuroblastoma amplified sequence (NBAS; 2p24.3), thymus-expressed molecule involved in selection (THEMIS; 6q22.33), GATA3 (10p14), and S-phase cyclin A-associated protein in the ER (SCAPER; 15q24.3) genes. Further analysis of total serum IgE levels suggested 13q21.31 might be primarily an IgE locus, and analyses of published data demonstrated that SNPs at the 15q24.3 region are expression quantitative trait loci for 2 nearby genes, ISL2 and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), in immune cells. CONCLUSION Our GWAS of recalcitrant AD identified new susceptibility regions containing genes involved in epithelial cell function and immune dysregulation, 2 key features of AD, and potentially extend our understanding of their role in pathogenesis.
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Affiliation(s)
- Kyung Won Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Human Genetics, University of Chicago, Chicago, Ill
| | - Rachel A Myers
- Department of Human Genetics, University of Chicago, Chicago, Ill
| | - Ji Hyun Lee
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea
| | | | - Kyung Eun Lee
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Hee Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Eun-Jin Kim
- Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Korea
| | - Dankyu Yoon
- Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Korea
| | - Joo-Shil Lee
- Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Korea
| | - Tomomitsu Hirota
- Laboratory for Respiratory and Allergic Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
| | - Mayumi Tamari
- Laboratory for Respiratory and Allergic Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
| | - Atsushi Takahashi
- Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan
| | - Michiaki Kubo
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
| | - Je-Min Choi
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Kyu-Earn Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Dan L Nicolae
- Department of Human Genetics, University of Chicago, Chicago, Ill; Department of Medicine and Statistics, University of Chicago, Chicago, Ill
| | - Carole Ober
- Department of Human Genetics, University of Chicago, Chicago, Ill
| | - Myung Hyun Sohn
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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Tarnoki DL, Medda E, Tarnoki AD, Bikov A, Lazar Z, Fagnani C, Stazi MA, Karlinger K, Garami Z, Berczi V, Horvath I. Modest genetic influence on bronchodilator response: a study in healthy twins. Croat Med J 2015; 56:152-8. [PMID: 25891875 PMCID: PMC4410177 DOI: 10.3325/cmj.2015.56.152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Aim To determine the reasons for large standard deviation of bronchodilator response (BDR) and establish whether there is a potential heritable component in healthy subjects. Methods 67 monozygotic and 42 dizygotic adult twin pairs were assessed for bronchodilator response (%change in FEV1 after inhaling 400 µg salbutamol). Univariate quantitative genetic modeling was performed. Results Multiple regression modeling showed a significant association between BDR and sex and baseline FEV1 (P < 0.05), while no association was found with smoking habits, body mass index, or age. Within pair correlation in monozygotic twins was modest (0.332), but higher than in dizygotic twins (0.258). Age-, sex-, and baseline FEV1-adjusted genetic effect accounted for 14.9% (95% confidence interval, CI 0%-53.1%) of the variance of BDR, shared environmental effect for 18.4% (95% CI 0%-46.8%), and unshared environmental effect for 66.8% (95% CI 46.8%-88.7%). Conclusion Our twin study showed that individual differences in BDR can be mostly explained by unshared environmental effects. In addition, it is the first study to show low, insignificant hereditary influences, independently from sex, age, and baseline FEV1.
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Affiliation(s)
- David Laszlo Tarnoki
- David Laszlo Tarnoki, Department of Radiology and Oncotherapy, Semmelweis University, 78/A Ulloi street, 1082 Budapest, Hungary,
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Abstract
Genome-wide association studies (GWAS) have been employed in the field of allergic disease, and significant associations have been published for nearly 100 asthma genes/loci. An outcome of GWAS in allergic disease has been the formation of national and international collaborations leading to consortia meta-analyses, and an appreciation for the specificity of genetic associations to sub-phenotypes of allergic disease. Molecular genetics has undergone a technological revolution, leading to next-generation sequencing strategies that are increasingly employed to hone in on the causal variants associated with allergic diseases. Unmet needs include the inclusion of diverse cohorts and strategies for managing big data.
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Affiliation(s)
- Romina A Ortiz
- Department of Medicine, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 3A.62, Baltimore, MD 21224, USA
| | - Kathleen C Barnes
- Department of Medicine, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 3A.62, Baltimore, MD 21224, USA.
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Abstract
This thesis explores the contribution of twin studies, particularly those studies originating from the Danish Twin Registry, to the understanding of the aetiology of asthma. First, it is explored how twin studies have established the contribution of genetic and environmental factors to the variation in the susceptibility to asthma, and to the variation in several aspects of the clinical expression of the disease such as its age at onset, its symptomatology, its intermediate phenotypes, and its relationship with other atopic diseases. Next, it is explored how twin studies have corroborated theories explaining asthma's recent increase in prevalence, and last, how these fit with the explanations of the epidemiological trends in other common chronic diseases of modernity.
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Mathias RA. Introduction to genetics and genomics in asthma: genetics of asthma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 795:125-55. [PMID: 24162907 DOI: 10.1007/978-1-4614-8603-9_9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
While asthma is a heterogeneous disease, a strong genetic basis has been firmly established. Rather than being a single disease entity, asthma consists of related, overlapping syndromes [Barnes (Proc Am Thor Soc 8:143-148, 2011)] including three general domains: variable airway obstruction, airway hyper-responsiveness, and airway inflammation with a considerable proportion, but not all, of asthma being IgE-mediated further adding to its heterogeneity. This chapter reviews the approaches to the elucidation of genetics of asthma from the early evidence of familial clustering to the current state of knowledge with genome-wide approaches. The conclusion is that research efforts have led to a tremendous repository of genetic determinants of asthma, most of which fall into the above phenotypic domains of the syndrome. We now look to future integrative approaches of genetics, genomics (Chap. 10), and epigenetics (Chap. 11) to better understand the causal mechanism through which, these genetic loci act in manifesting asthma.
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Affiliation(s)
- Rasika Ann Mathias
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, 3B.79, Baltimore, MD, 21224, USA,
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Asthma and Microbes: A New Paradigm. THE ROLE OF MICROBES IN COMMON NON-INFECTIOUS DISEASES 2014. [PMCID: PMC7120979 DOI: 10.1007/978-1-4939-1670-2_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Asthma is worldwide at pandemic levels for the past 30 years but is increasing at a greater rate in more affluent societies. It is a heterogeneous disorder caused by interaction between genetic predisposition, atopy, and environmental factors, including allergens, air pollution, and respiratory infections. The pathological aspects and pathophysiological mechanisms are reviewed in this chapter. Allergens or infectious agents may stimulate Th-2 inflammation which causes activation of IL-13, eosinophils, and increase IgE levels, subsequently leading to bronchial smooth muscle hypercontraction. Respiratory viral infections are well-known causes of precipitation of acute asthma exacerbations in 50–60 % of attacks. There is also increasing evidence that bacterial infections, Chlamydia pneumoniae, and Mycoplasma pneumoniae, may contribute to the onset and course of asthma. The two main hypothesis of microbial genesis of asthma that has arisen in the past 20–30 years appears to be incongruous, but are not, are the hygiene hypothesis of asthma, and the virus-related asthma, early onset of viral bronchiolitis in the susceptible hosts being responsible for later development of asthma. The clinical and experimental evidences to support these contentions are reviewed and critiqued.
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Han SC, Kang GJ, Ko YJ, Kang HK, Moon SW, Ann YS, Yoo ES. External Application of Fermented Olive Flounder (Paralichthys olivaceus) Oil Alleviates Inflammatory Responses in 2,4-Dinitrochlorobenzeneinduced Atopic Dermatitis Mouse Model. Toxicol Res 2013; 28:159-64. [PMID: 24278605 PMCID: PMC3834415 DOI: 10.5487/tr.2012.28.3.159] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2012] [Revised: 08/23/2012] [Accepted: 08/24/2012] [Indexed: 11/23/2022] Open
Abstract
Allergic skin inflammation such as atopic dermatitis (AD) is characterized by edema and infiltration with various inflammatory cells such as mast cells, basophils, eosinophils and T cells. Thymic stromal lymphopoietin (TSLP) is produced mainly by epidermal keratinocytes, as well as dermal fibroblasts and mast cells in the skin lesions of AD. Omega-3 polyunsaturated fatty acids in fish oil can reduce inflammation in allergic patients. Fermentation has a tremendous capacity to transform chemical structures. The antiinflammatory effects of fish oil have been described in many diseases, but the beneficial effects by which fermented olive flounder oil (FOF) modulates the allergic response is poorly understood. In this study, we produced FOF and tested its ability to suppress the various allergic inflammatory responses. The ability of FOF to modulate the immune system was investigated using a mouse model of AD. The FOF-treated group showed significantly decreased immunoglobulin E (IgE) and histamine in serum. Also, the increased TSLP expression was significantly inhibited in the FOF group; the FOF-treated group was not appreciably different from the hydrocort cream treatment group. In addition, FOF treatment resulted in a smaller spleen size with reduced the thickness and length compared to the induction group. Splenocytes from mice treated with FOF produced significantly less IFN-γ, IL-4, T-box transcription factor (T-bet) and GATA binding protein 3 (GATA3) expression compared with the induction group. These results suggest that FOF may be effective in treating the allergic symptoms of AD. 5.
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Affiliation(s)
- Sang-Chul Han
- Department of Pharmacology, School of Medicine, Jeju National University, , Jeju 690-756, Korea
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Bunyavanich S, Silberg JL, Lasky-Su J, Gillespie NA, Lange NE, Canino G, Celedón JC. A twin study of early-childhood asthma in Puerto Ricans. PLoS One 2013; 8:e68473. [PMID: 23844206 PMCID: PMC3700929 DOI: 10.1371/journal.pone.0068473] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 06/05/2013] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The relative contributions of genetics and environment to asthma in Hispanics or to asthma in children younger than 3 years are not well understood. OBJECTIVE To examine the relative contributions of genetics and environment to early-childhood asthma by performing a longitudinal twin study of asthma in Puerto Rican children ≤ 3 years old. METHODS 678 twin infants from the Puerto Rico Neo-Natal Twin Registry were assessed for asthma at age 1 year, with follow-up data obtained for 624 twins at age 3 years. Zygosity was determined by DNA microsatellite profiling. Structural equation modeling was performed for three phenotypes at ages 1 and 3 years: physician-diagnosed asthma, asthma medication use in the past year, and ≥ 1 hospitalization for asthma in the past year. Models were additionally adjusted for early-life environmental tobacco smoke exposure, sex, and age. RESULTS The prevalences of physician-diagnosed asthma, asthma medication use, and hospitalization for asthma were 11.6%, 10.8%, 4.9% at age 1 year, and 34.1%, 40.1%, and 8.5% at 3 years, respectively. Shared environmental effects contributed to the majority of variance in susceptibility to physician-diagnosed asthma and asthma medication use in the first year of life (84%-86%), while genetic effects drove variance in all phenotypes (45%-65%) at age 3 years. Early-life environmental tobacco smoke, sex, and age contributed to variance in susceptibility. CONCLUSION Our longitudinal study in Puerto Rican twins demonstrates a changing contribution of shared environmental effects to liability for physician-diagnosed asthma and asthma medication use between ages 1 and 3 years. Early-life environmental tobacco smoke reduction could markedly reduce asthma morbidity in young Puerto Rican children.
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Affiliation(s)
- Supinda Bunyavanich
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
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Fermented fish oil suppresses T helper 1/2 cell response in a mouse model of atopic dermatitis via generation of CD4+CD25+Foxp3+ T cells. BMC Immunol 2012; 13:44. [PMID: 22873180 PMCID: PMC3537649 DOI: 10.1186/1471-2172-13-44] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 07/26/2012] [Indexed: 11/21/2022] Open
Abstract
Background Allergic skin inflammation such as atopic dermatitis (AD), which is characterized by pruritus and inflammation, is regulated partly through the activity of regulatory T cells (Tregs). Tregs play key roles in the immune response by preventing or suppressing the differentiation, proliferation and function of various immune cells, including CD4+ T cells. Recent studies report that fermentation has a tremendous capacity to transform chemical structures or create new substances, and the omega-3 polyunsaturated fatty acids (n-3 PUFAs) in fish oil can reduce inflammation in allergic patients. The beneficial effects of natural fish oil (NFO) have been described in many diseases, but the mechanism by which fermented fish oil (FFO) modulates the immune system and the allergic response is poorly understood. In this study, we produced FFO and tested its ability to suppress the allergic inflammatory response and to activate CD4+CD25+Foxp3+ Tregs. Results The ability of FFO and NFO to modulate the immune system was investigated using a mouse model of AD. Administration of FFO or NFO in the drinking water alleviated the allergic inflammation in the skin, and FFO was more effective than NFO. FFO treatment did increase the expression of the immune-suppressive cytokines TGF-β and IL-10. In addition, ingestion of FFO increased Foxp3 expression and the number of CD4+CD25+Foxp3+ Tregs compared with NFO. Conclusions These results suggest that the anti-allergic effect of FFO is associated with enrichment of CD4+CD25+ Foxp3+ T cells at the inflamed sites and that FFO may be effective in treating the allergic symptoms of AD.
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Abstract
Somatic mosaicism is the result of postzygotic de novo mutation occurring in a portion of the cells making up an organism. Structural genetic variation is a very heterogeneous group of changes, in terms of numerous types of aberrations that are included in this category, involvement of many mechanisms behind the generation of structural variants, and because structural variation can encompass genomic regions highly variable in size. Structural variation rapidly evolved as the dominating type of changes behind human genetic diversity, and the importance of this variation in biology and medicine is continuously increasing. In this review, we combine the evidence of structural variation in the context of somatic cells. We discuss the normal and disease-related somatic structural variation. We review the recent advances in the field of monozygotic twins and other models that have been studied for somatic mutations, including other vertebrates. We also discuss chromosomal mosaicism in a few prime examples of disease genes that contributed to understanding of the importance of somatic heterogeneity. We further highlight challenges and opportunities related to this field, including methodological and practical aspects of detection of somatic mosaicism. The literature devoted to interindividual variation versus papers reporting on somatic variation suggests that the latter is understudied and underestimated. It is important to increase our awareness about somatic mosaicism, in particular, related to structural variation. We believe that further research of somatic mosaicism will prove beneficial for better understanding of common sporadic disorders.
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Abstract
AbstractThe South Korean Twin Registry (SKTR), previously called the Seoul Twin Family Study, is a nationwide volunteer registry of South Korean twins and their families. Since 2002, the SKTR has been updated in 4 important ways. First, continued sampling led to an increase in the number of twins. Second, the target area, Seoul, was enlarged to include other cities and rural areas in the country. Third, the target population was extended from school-aged twins to preschool and adult twins. Fourth, the research focus was expanded to include psychiatric and physical disease phenotypes. The present article describes a brief history of the SKTR, goals and current research highlights, recent major accomplishments, and future directions.
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Harris JR, Magnus P, Tambs K. The Norwegian Institute of Public Health Twin Program of Research: An Update. Twin Res Hum Genet 2012. [DOI: 10.1375/twin.9.6.858] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
AbstractThe population-based twin program of research at the Norwegian Institute of Public Health (NIPH) was begun in 1992. It consists of a number of questionnaire and clinical interview projects exploring a broad array of mental and physical health outcomes. This article provides a brief update summarizing our research activities, some research highlights, new developments and potentials for further developing the program of twin research. In the most recent years a large effort has concentrated on completing a mental health interview study of Axis I psychiatric and substance use disorders and Axis II personality disorders. Although still in the early planning phases, one of the most significant developments is that an agreement is now in place to centralize the Norwegian twin data into a national Norwegian Twin Registry. This new registry will include twin cohorts born from 1905 onwards. Other resources for building twin projects are described. Nationally, there is great potential for linking the NIPH twin data with other health registries and with information in a number of Norway's large population-based biobank studies. Internationally, platforms such as those developed within GenomEUtwin, for data standards and data sharing and access are greatly facilitating international collaborations in twin research.
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Bataille V, Lens M, Spector T. The use of the twin model to investigate the genetics and epigenetics of skin diseases with genomic, transcriptomic and methylation data. J Eur Acad Dermatol Venereol 2012; 26:1067-73. [DOI: 10.1111/j.1468-3083.2011.04444.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits.
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Affiliation(s)
- Carole Ober
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
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Gerez IFA, Lee BW, van Bever HP, Shek LP. Allergies in Asia: differences in prevalence and management compared with western populations. Expert Rev Clin Immunol 2010; 6:279-89. [PMID: 20402390 DOI: 10.1586/eci.09.82] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
There is wide variability in the epidemiology and management of childhood asthma and related atopic diseases globally. Urbanized, affluent Western countries tend to have a higher prevalence of these diseases compared with Asian nations. However, recent studies have shown that the prevalence in Asia is increasing, although the rate of increase has slowed in the more developed Asian cities. Some possible causes for these differences are socioeconomic status, degree of urbanization, rates of infection, healthcare practices and genetic factors. Importantly, there are significant differences in the way asthma and allergic diseases are managed within Asia. This is of great concern because of the health implications, as these diseases are some of the most common chronic conditions that affect both adults and children. This review compares the differences in prevalence and management between Asia and the West, and discusses some of the possible reasons behind these variations.
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Kaminuma O, Suko M, Mori A. Genetic factors in the treatment of bronchial asthma. Expert Rev Clin Immunol 2010; 2:727-35. [PMID: 20477628 DOI: 10.1586/1744666x.2.5.727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Owing to the recent vast progress in analytical tools and procedures to elucidate the relationship between genes and diseases, many candidate genes leading to the development of bronchial asthma have been reported. However, the quantitative phenotypes of asthma, such as decrease in forced expiratory volume in the first second, serum hyper-IgE, bronchial hyperresponsiveness and blood hyper-eosinophilia, do not represent this disease completely. On the other hand, eosinophilic inflammation of the bronchial mucosa represents accurately the feature of bronchial asthma, although accurate quantification of its status is difficult. While the production of interleukin (IL)-5 in peripheral CD4(+) T cells probably correlates with eosinophilic inflammation of the airway, the effectiveness of anti-IL-5 antibody for the treatment of bronchial asthma is controversial. Since intervention with asthma-causing gene products may not be sufficient for the treatment of this disease, identification of therapy-responsive genes should become more important in the near future.
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Affiliation(s)
- Osamu Kaminuma
- The Tokyo Metropolitan Institute of Medical Science, Department of Allergy and Immunology, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
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Kawai T, Takeshita S, Imoto Y, Matsumoto Y, Sakashita M, Suzuki D, Shibasaki M, Tamari M, Hirota T, Arinami T, Fujieda S, Noguchi E. Associations between decay-accelerating factor polymorphisms and allergic respiratory diseases. Clin Exp Allergy 2009; 39:1508-14. [PMID: 19681921 DOI: 10.1111/j.1365-2222.2009.03316.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Allergic diseases such as asthma and allergic rhinitis are major causes of morbidity in developed countries. The pathology underlying allergic respiratory diseases is considered to be IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. They are common diseases involving a complex inheritance. Complement systems are known to play an important role in allergic diseases. Decay-accelerating factor (DAF) is important for the regulation of the complement system and is a good candidate for determining the susceptibility to allergic diseases. OBJECTIVE The present study aimed to investigate whether polymorphisms in the DAF gene are associated with allergic respiratory diseases in the Japanese population. METHODS We performed mutation screenings of DAF and conducted a tag single-nucleotide polymorphisms (SNP) association analysis for 684 unrelated adult individuals with seasonal allergic rhinitis (SAR) with Japanese ceder pollen, 188 mite-sensitive adults with asthma, and 346 unrelated non-allergic healthy controls. RESULTS DAF is located in the tight linkage disequilibrium (LD) block spanning 62 kb. The tag SNP analysis revealed that rs10746463 was significantly associated with SAR (P=0.00033) and mite-sensitive adult asthma (P=0.044). The rs2564978 and rs3841376 haplotypes, which are located in the promoter region of DAF, were in complete LD with rs10746463 (r2=1). Luciferase reporter assays with constructs containing the 5' flanking regions of DAF showed that the plasmid with rs2564978 C/rs3841376 deletion (the risk haplotype) had a statistically significantly lower transcriptional activity than that containing the rs2564978 T/rs3841376 insertion. CONCLUSIONS Our results suggest that DAF is one of the genes involved in conferring susceptibility to allergic respiratory diseases and show that decreased levels of DAF may be associated with the enhanced specific IgE responses occurring in allergic diseases in the Japanese population.
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Affiliation(s)
- T Kawai
- Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Imada Y, Fujimoto M, Hirata K, Hirota T, Suzuki Y, Saito H, Matsumoto K, Akazawa A, Katsunuma T, Yoshihara S, Ebisawa M, Shibasaki M, Arinami T, Tamari M, Noguchi E. Large scale genotyping study for asthma in the Japanese population. BMC Res Notes 2009; 2:54. [PMID: 19335888 PMCID: PMC2674055 DOI: 10.1186/1756-0500-2-54] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Accepted: 03/31/2009] [Indexed: 11/10/2022] Open
Abstract
Background Asthma is a complex phenotype that is influenced by both genetic and environmental factors. Genome-wide linkage and association studies have been performed to identify susceptibility genes for asthma. These studies identified new genes and pathways implicated in this disease, many of which were previously unknown. Objective To perform a large-scale genotyping study to identify asthma-susceptibility genes in the Japanese population. Methods We performed a large-scale, three-stage association study on 288 atopic asthmatics and 1032 controls, by using multiplex PCR-Invader assay methods at 82,935 single nucleotide polymorphisms (SNPs) (1st stage). SNPs that were strongly associated with asthma were further genotyped in samples from asthmatic families (216 families, 762 members, 2nd stage), 541 independent patients, and 744 controls (3rd stage). Results SNPs located in the 5' region of PEX19 (rs2820421) were significantly associated with P < 0.05 through the 1st to the 3rd stage analyses; however, the P values did not reach statistically significant levels (combined, P = 3.8 × 10-5; statistically significant levels with Bonferroni correction, P = 6.57 × 10-7). SNPs on HPCAL1 (rs3771140) and on IL18R1 (rs3213733) were associated with asthma in the 1st and 2nd stage analyses, but the associations were not observed in the 3rd stage analysis. Conclusion No association attained genome-wide significance, but several loci for possible association emerged. Future studies are required to validate these results for the prevention and treatment of asthma.
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Affiliation(s)
- Yoshiko Imada
- Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8577 Japan.
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Giwercman C, Lerbaek A, Bisgaard H, Menné T. Classification of atopic hand eczema and the filaggrin mutations. Contact Dermatitis 2009; 59:257-60. [PMID: 18976374 DOI: 10.1111/j.1600-0536.2008.01426.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hand eczema is a common disease with various risk factors of which atopic dermatitis is known to be one of the most important. Recently, two mutations in the gene coding for filaggrin, a protein important for the skin barrier, have repeatedly been shown to be associated with atopic dermatitis. Moreover, one study point towards an association between the filaggrin null alleles and the subgroup of patients having both hand eczema and atopic dermatitis. For the remainder of hand eczema patients, still unknown genetic risk factors exist. We propose that in future, classification of atopic hand eczema should distinguish between patients with and without the filaggrin null alleles and to further differentiate between associations with type I allergy, type IV allergy and exposure to irritants, respectively. Furthermore, we suggest future studies of atopic hand eczema to analyse for the filaggrin mutations. We believe this will increase the possibility of subgrouping this otherwise heterogenic disease and thereby enable a better phenotype-genotype characterization of hand eczema. This could improve the preventive initiatives, secure better information of patients about the prognosis for their disease, and possibly enable targeted treatment.
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Affiliation(s)
- Charlotte Giwercman
- Department of Dermatology, Copenhagen University Hospital Gentofte, DK-2900 Hellerup, Denmark.
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Shah A, Kala J, Sahay S, Panjabi C. Frequency of familial occurrence in 164 patients with allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol 2008; 101:363-9. [PMID: 18939723 DOI: 10.1016/s1081-1206(10)60311-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Asthma is known to run in families. Allergic bronchopulmonary aspergillosis (ABPA) occurs predominantly in patients with asthma. However, there are only 6 reports of familial occurrence over a period of 35 years. OBJECTIVE To determine the frequency of familial occurrence in 164 patients with ABPA diagnosed over a period of 22 years in one unit. METHODS The 164 patients with ABPA were reviewed for the occurrence of familial ABPA. Symptomatic family members were evaluated for the presence of ABPA as well as allergic Aspergillus sinusitis (AAS). Allergic bronchopulmonary aspergillosis and AAS were diagnosed as per criteria established. RESULTS Of the 164 patients with ABPA, familial occurrence was detected in 4 pairs of first degree relatives, 2 of whom were parent-child while the other 2 were siblings. Familial ABPA was seen in 4.9% of the total patients. Of these 8 patients seven had symptoms of rhinitis while 4 had sinusitis confirmed on computed tomography of paranasal sinuses. Allergic Aspergillus sinusitis was detected in 3 of these 4 patients. The fourth patient with sinusitis did not consent to surgery required to confirm the diagnosis. Five of our 8 patients, prior to referral, had received antituberculous therapy. All patients responded favourably to oral prednisolone. CONCLUSION Familial occurrence was documented in 4.9% of the 164 patients with ABPA.
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Affiliation(s)
- Ashok Shah
- Department of Respiratory Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India.
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Thomsen SF, Kyvik KO, Backer V. Etiological relationships in atopy: a review of twin studies. Twin Res Hum Genet 2008; 11:112-20. [PMID: 18361711 DOI: 10.1375/twin.11.2.112] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The genetics of asthma and atopy has been studied frequently in twin populations from various parts of the world. However, emphasis has been put on univariate analysis of questionnaire data, whereas clinical and intermediate traits only sporadically have been studied, especially in multivariate settings. This review focuses on multivariate twin studies of atopy and related traits. We conclude that the genetic liability to most atopic traits is significantly correlated but that trait-specific genes also play a role. Previous studies have estimated the genetic correlation between upper and lower respiratory allergic symptoms, that is, asthma and hay fever, to be between .47 and .95. Furthermore, atopic traits share a portion of their genetic determinants with other complex disorders like obesity and behavioral traits. A correlation of about .3 and .34 has been reported between genes associated with asthma and obesity, and between genes associated with asthma and depression, respectively. We emphasize that multivariate methods applied to twin studies, especially when genetic marker information is available, provide a valuable framework within which complex etiological mechanisms underlying atopy can be disentangled.
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Thomsen SF, Kyvik KO, Backer V. A note on twin-singleton differences in asthma. Twin Res Hum Genet 2008; 11:161-4. [PMID: 18361717 DOI: 10.1375/twin.11.2.161] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Twins constitute a valuable resource for genetic studies of asthma. However, critics argue that twins are 'special' in terms of prenatal environment and upbringing and therefore nonrepresentative. In respect to asthma a small range of studies report differential morbidity in twins compared with singletons. We review some of the possible explanations for these findings and conclude that results from twin studies of asthma can be extrapolated to the general population.
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van Beijsterveldt TCEM, Boomsma DI. An exploration of gene-environment interaction and asthma in a large sample of 5-year-old Dutch twins. Twin Res Hum Genet 2008; 11:143-9. [PMID: 18361714 DOI: 10.1375/twin.11.2.143] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
A consistent finding from twin studies is that the environment shared by family members does not contribute to the variation in susceptibility to asthma. At the same time, it is known that environmental risk factors that are shared by family members are associated with the liability for asthma. We hypothesize that the absence of a main effect of shared environmental factors in twin studies can be explained by gene-environment interaction, that is, that the effect of an environmental factor shared by family members depends on the genotype of the individual. We explore this hypothesis by modeling the resemblance in asthma liability in twin pairs as a function of various environmental risk factors and test for gene-environment interaction. Asthma data were obtained by parental report for nearly 12,000 5-year-old twin pairs. A series of environmental risk factors was examined: birth cohort, gestational age, time spent in incubator, breastfeeding, maternal educational level, maternal smoking during pregnancy, current smoking of parents, having older siblings, and amount of child care outside home. Results revealed that being a boy, born in the 1990s, premature birth, longer incubator time, and child care outside home increased the risk for asthma. With the exception of premature birth, however, none of these factors modified the genetic effects on asthma. In very premature children shared environmental influences were important. In children born after a gestation of 32 weeks or more only genetic factors were important to explain familial resemblance for asthma.
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Willemsen G, van Beijsterveldt TCEM, van Baal CGCM, Postma D, Boomsma DI. Heritability of self-reported asthma and allergy: a study in adult Dutch twins, siblings and parents. Twin Res Hum Genet 2008; 11:132-42. [PMID: 18361713 DOI: 10.1375/twin.11.2.132] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The present study assessed the prevalence of asthma and allergy, and estimated the importance of genetic and environmental influences on asthma and allergy liability and their association. Longitudinal data on self-reported, doctor-diagnosed asthma and allergy were collected in over 14,000 individuals registered with the Netherlands Twin Register. Structural equation modeling was used for univariate and bivariate genetic analyses on data from twins, their siblings, and parents. Results showed no sex, age, and minimal birth cohort effects for asthma prevalence (11.8%). For allergy, prevalence was higher in women (19.8%) than in men (13.9%). Allergy prevalence at ages 22, 23, and 24 years increased from the 1970 to the 1980 birth cohort. The prevalence of allergy, but not of asthma, was higher in nontwin siblings than in twins. No assortative mating was observed. High (broad-sense) heritabilities were found for asthma (75%) and allergy (66%), with evidence for nonadditive genetic effects in asthma. The association between asthma and allergy (correlation=.65) was largely due to common genes (70%). No sex differences in genetic architecture were found. In conclusion, the prevalence of allergy but not of asthma increased in recent years. Individual differences in the liability to asthma, allergy and their co-occurrence are for a large part accounted for by differences in genetic background. Nonadditive gene action is important, which may have consequences for gene hunting strategies.
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Affiliation(s)
- Gonneke Willemsen
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
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40
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Newacheck PW, Kim SE, Blumberg SJ, Rising JP. Who is at risk for special health care needs: findings from the National Survey of Children's Health. Pediatrics 2008; 122:347-59. [PMID: 18676553 DOI: 10.1542/peds.2007-1406] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE A conceptual model of risk factors for special health care needs in childhood was presented previously. This article uses that conceptual model to identify candidate variables for an exploratory empirical examination of the effects of factors that may increase or decrease the risk of developing a special health care need. METHODS The National Survey of Children's Health was used for our analysis (N = 102 353). We used multilevel and multivariate analysis methods. We examined risk factors for special health care needs generally and for specific physical, developmental, behavioral, and emotional conditions cooccurring with special health care needs. Risk factors were grouped into 6 major domains, namely, predisposing characteristics, genetic endowment, physical environment, social environment, health-influencing behavior, and health care system characteristics. We examined preschool-aged and school-aged children separately. RESULTS Significant associations were found in 5 of 6 domains studied (no variables in the health care systems characteristics were significant). Individual variables found to decrease or to increase significantly the odds of experiencing special health care needs were expressed at the child level (eg, age and gender), family level (eg, family structure and family conflict), and neighborhood level (eg, perception of supportiveness of the neighborhood). CONCLUSIONS This analysis is the first to consider empirically a range of risk factors for special health care needs, using a population health model. Although provisional, the results of our analysis can help us to begin thinking about which characteristics of the child, family, and community are worthy of further exploration. Some of the variables we found to be significantly associated with special health care needs, such as age and ethnicity, are immutable. However, we found a number of significant correlates (ie, possible risk factors) that may be amenable to public health interventions, including breastfeeding practices, exposure to secondhand smoke, family closeness, and neighborhood cohesion.
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Affiliation(s)
- Paul W Newacheck
- Institute for Health Policy Studies, University of California, San Francisco, 3333 California St, Suite 265, San Francisco, CA 94118, USA.
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Filaggrin null mutations are associated with atopic dermatitis and elevated levels of IgE in the Japanese population: a family and case-control study. J Hum Genet 2008; 53:615. [PMID: 18521703 DOI: 10.1007/s10038-008-0293-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2007] [Accepted: 03/17/2008] [Indexed: 02/06/2023]
Abstract
Filaggrin (FLG) plays an important role in the barrier function of the skin. Several loss-of-function mutations in the FLG gene have been identified in patients with ichthyosis vulgaris, and these null mutations are associated with atopic dermatitis (AD) development. In this study, we examined tag single nucleotide polymorphisms (tSNPs) and null mutations in FLG for possible associations with AD and atopic phenotypes in a Japanese population. Transmission disequilibrium test of 105 AD families showed that the null allele of the S2554X variant of FLG tended to be overtransmitted to AD-affected offspring; however, the P value did not reach statistical significance. In a case-control comparison of 376 AD cases and 923 nonallergic controls, the null allele of S2554X was significantly associated with AD (P = 0.0012), and the association was strengthened in subjects with AD alone (P = 0.000024). We found that 3321delA and S2554X were also associated with elevated levels of immunoglobulin E (IgE). Combined null mutation carriers were observed more in AD patients and in subjects with high IgE than in control subjects. The combined P value for the family and case-control data was significant for the S2554X and combined null mutations. Our data further support the importance of FLG in AD development.
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Linet MS, Schubauer-Berigan MK, Weisenburger DD, Richardson DB, Landgren O, Blair A, Silver S, Field RW, Caldwell G, Hatch M, Dores GM. Chronic lymphocytic leukaemia: an overview of aetiology in light of recent developments in classification and pathogenesis. Br J Haematol 2008; 139:672-86. [PMID: 18021081 DOI: 10.1111/j.1365-2141.2007.06847.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This overview of the epidemiology of chronic lymphocytic leukaemia (CLL) summarizes the evolution of classification and coding systems and describes the intersection of pathogenesis and aetiology. The role of the putative precursor to CLL, monoclonal B-cell lymphocytosis (MBL), is considered, and ideas for future investigations of the MBL-CLL relationship are outlined. We discuss the epidemiology of CLL, focusing on descriptive patterns and methodological considerations. Postulated risk factors are reviewed including the role of ionizing and non-ionizing radiation, occupational and environmental chemical exposures, medical conditions and treatments, and lifestyle and genetic factors. We conclude by raising key questions that need to be addressed to advance our understanding of CLL aetiology. Recommendations for future epidemiological studies are given, including the standardization of reporting of CLL across cancer registries, the clarification of the natural history of MBL, and the circumvention of the methodological shortcomings of prior epidemiological investigations in relation to radiation, chemical exposures and infectious agents.
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Affiliation(s)
- Martha S Linet
- DCEG/Radiation Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA.
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Familial risks for common diseases: etiologic clues and guidance to gene identification. Mutat Res 2008; 658:247-58. [PMID: 18282736 DOI: 10.1016/j.mrrev.2008.01.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2007] [Revised: 12/21/2007] [Accepted: 01/03/2008] [Indexed: 12/20/2022]
Abstract
Familial clustering of a disease is a direct indicator of a possible heritable cause, provided that environmental sharing can be excluded. If the familial clustering is lacking, the likelihood of a heritable influence is also small. In the era of genome scans, the consideration of data on heritability should be important in the assessment of the likely success of the genome scan. The availability of a Multigeneration Register in Sweden provides a reliable access to families throughout the last century. This Register has been extensively used to study a number of different diseases through linkage to the Hospital Discharge Register. In the present article we review the obtained and some unpublished results for nine main disease classes. For each of these, familial risks are given for four disease subtypes. As measures of familial clustering we use risks between siblings, twins and spouses. Disease correlation between spouses suggests environmental sharing and a higher correlation between siblings and particularly twins shows heritable effects. We will also comment on the established susceptibility genes and the risks conferred by them. The data suggest high heritabilities for chronic obstructive pulmonary disease, asthma, noninfective enteritis and colitis, cerebral palsy and endocrine and metabolic diseases. Among the performed first-generation genome scans on various diseases, the success appears to be related to the a priori heritability estimates. To our knowledge this is a first attempt to summarize familial risks for a large number of diseases using data from a single population on which reasonable uniform diagnostic criteria have been applied.
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Hemminki K, Li X, Sundquist K, Sundquist J. Familial risks for asthma among twins and other siblings based on hospitalizations in Sweden. Clin Exp Allergy 2007; 37:1320-5. [PMID: 17845412 DOI: 10.1111/j.1365-2222.2007.02737.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Asthma is a common disabling condition, with known environmental and familial risk factors and with their assumed interactions. We wanted to carry out a family study on asthma to address gene-environment interactions at a population level. METHODS We conducted a nation-wide study on familial risks for asthma. An asthma database was constructed by linking the Multigeneration Register on 0-72-year-old subjects to the Hospital Discharge Register for diagnosed asthma cases in Sweden from years 1987 to 2004. Standardized incidence ratios (SIRs) were calculated for affected singleton siblings, twins and spouses by comparing with those whose siblings or spouses had no asthma. RESULTS A total of 67 370 hospitalized cases and 5638 affected siblings were identified with a familial SIR of 3.70, which was independent of sex, diagnostic age and age differences between the siblings. The SIR for different-sex twins was 5.17 and for same-sex twins it was 13.38. There was a low correlation between spouses for asthma. CONCLUSIONS Asthma shows a higher familial risk than many common diseases. The higher difference in familial excess risk between singleton siblings and different-sex twins provides strong genetic epidemiological evidence for gene-environment interactions in asthma. The concept of gene-environment interactions needs to be accommodated in future aetiological studies on asthma. Data on environmental factors and family history are important for clinical risk estimation.
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Affiliation(s)
- K Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Enomoto H, Noguchi E, Iijima S, Takahashi T, Hayakawa K, Ito M, Kano T, Aoki T, Suzuki Y, Koga M, Tamari M, Shiohara T, Otsuka F, Arinami T. Single nucleotide polymorphism-based genome-wide linkage analysis in Japanese atopic dermatitis families. BMC DERMATOLOGY 2007; 7:5. [PMID: 17900373 PMCID: PMC2082241 DOI: 10.1186/1471-5945-7-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2007] [Accepted: 09/28/2007] [Indexed: 01/26/2023]
Abstract
Background Atopic dermatitis develops as a result of complex interactions between several genetic and environmental factors. To date, 4 genome-wide linkage studies of atopic dermatitis have been performed in Caucasian populations, however, similar studies have not been done in Asian populations. The aim of this study was to identify chromosome regions linked to atopic dermatitis in a Japanese population. Methods We used a high-density, single nucleotide polymorphism genotyping assay, the Illumina BeadArray Linkage Mapping Panel (version 4) comprising 5,861 single nucleotide polymorphisms, to perform a genome-wide linkage analysis of 77 Japanese families with 111 affected sib-pairs with atopic dermatitis. Results We found suggestive evidence for linkage with 15q21 (LOD = 2.01, NPL = 2.87, P = .0012) and weak linkage to 1q24 (LOD = 1.26, NPL = 2.44, P = .008). Conclusion We report the first genome-wide linkage study of atopic dermatitis in an Asian population, and novel loci on chromosomes 15q21 and 1q24 linked to atopic dermatitis. Identification of novel causative genes for atopic dermatitis will advance our understanding of the pathogenesis of atopic dermatitis.
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Affiliation(s)
- Hisako Enomoto
- Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
- Department of Dermatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
| | - Emiko Noguchi
- Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
| | | | - Takenori Takahashi
- Department of Dermatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
| | - Kazuhito Hayakawa
- Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan
| | | | | | - Takeshi Aoki
- Department of Pediatrics, Tsukuba Medical Center Hospital, Japan
| | - Yoichi Suzuki
- Department of Public Health, Chiba University Graduate School of Medicine, Japan
| | - Minori Koga
- Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
| | - Mayumi Tamari
- Laboratory of Genetics of Allergic Disease, RIKEN SNP Research Center, Yokohama, Japan
| | - Tetsuo Shiohara
- Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Fujio Otsuka
- Department of Dermatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
| | - Tadao Arinami
- Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
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Le Souëf PN. Using twin studies to determine genetic and environmental components of allergy and asthma. Clin Exp Allergy 2006; 36:1353-4. [PMID: 17083343 DOI: 10.1111/j.1365-2222.2006.02608.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Thomsen SF, Ulrik CS, Kyvik KO, von Bornemann Hjelmborg J, Skadhauge LR, Steffensen I, Backer V. Genetic and environmental contributions to hay fever among young adult twins. Respir Med 2006; 100:2177-82. [PMID: 16650971 DOI: 10.1016/j.rmed.2006.03.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2005] [Revised: 03/03/2006] [Accepted: 03/14/2006] [Indexed: 11/19/2022]
Abstract
BACKGROUND The susceptibility to develop hay fever is putatively the result both of genetic and environmental causes. We estimated the significance and magnitude of genetic and environmental contributions to hay fever among young adult twins. METHODS From the birth cohorts 1953-82 of The Danish Twin Registry 11,750 twin pairs were identified through a nationwide questionnaire survey. Subjects were regarded hay fever cases when responding affirmatively to the question 'Do you have, or have you ever had hay fever?' Latent factor models of genetic and environmental effects were fitted to the observed data using maximum likelihood methods. RESULTS The overall cumulative prevalence of hay fever was 12.6%. Identical twins were significantly more likely to be concordant for hay fever than were fraternal twins (P<0.001). Additive genetic effects accounted for 71% and non-shared environmental effects accounted for 29% of the individual susceptibility to hay fever. The same genes contributed to the susceptibility to hay fever both in males and in females. In families with asthma, the susceptibility to develop hay fever was, in addition to genes, to a great extent ascribable to family environment, whereas the aetiology of 'sporadic' hay fever was mainly genetic. CONCLUSIONS The susceptibility to develop hay fever is attributable to major genetic influences. However, effects of family environment and upbringing are also of importance in families where asthma is present. These results indicate that different sub-forms of hay fever may have different aetiologies.
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Affiliation(s)
- Simon Francis Thomsen
- Department of Respiratory Medicine, Bispebjerg Hospital, DK-2400 Copenhagen NV, and The Danish Twin Registry, University of Southern Denmark, Odense, Denmark.
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