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BackgroundWhile numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.ObjectivesThis study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants.MethodsAD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.ResultsGenetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36).ConclusionsThis study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

The incidence of allergic diseases is increasing, and research on their epidemiology, pathophysiology, and the prevention of onset is urgently needed. The onset of allergic disease begins in infancy with atopic dermatitis and food allergy and develops into allergic asthma and allergic rhinitis in childhood; the process is defined as "atopic march ". Atopic march is caused by multiple immunological pathways, including allergen exposure, environmental pollutants, skin barrier dysfunction, type 2 inflammation, and oxidative stress, which promote the progression of atopic march. Using recent evidence, herein, we explain the involvement of allergic inflammatory conditions and oxidative stress in the process of atopic march, its epidemiology, and methods for prevention of onset.

La dermite atopique, une maladie inflammatoire de la peau, est connue pour son implication dans la sensibilisation aux allergènes via la barrière cutanée endommagée. Cette sensibilisation est associée au développement de certaines maladies allergiques, dont la rhinite allergique et l’asthme allergique. La cascade inflammatoire caractéristique de ces maladies inclut le recrutement de cellules pro-inflammatoires dont les éosinophiles qui sont alors augmentés et activés dans le sang. Jusqu’ici, très peu d’études ont analysé le transcriptome de ce type cellulaire et encore moins d’études se sont concentrées sur le profil différentiel des microARN (miARN) qui pourrait réguler la transcription et donc avoir un impact sur le niveau de certaines protéines et subséquemment sur la pathogénèse et la symptomatologie des maladies allergiques. Le but de cette étude était de mesurer les niveaux différentiels de miARN primaires (pri-miARN) dans les éosinophiles isolés de prélèvements sanguins d’individus atteints de maladies allergiques (dermite atopique, d’atopie, de rhinite allergique et d’asthme) et d’individus témoins (sans maladies allergiques). Les comptes différentiels ont également été évalués pour une série d’autres phénotypes liés aux maladies allergiques incluant des données de la fonction respiratoire et des données immunologiques. Dix-huit pri-miARN ont été identifiés comme différemment exprimés dans les éosinophiles d’individus atteints comparativement aux témoins. Ces 18 pri-miARN ont ensuite été groupés à l’aide de l’algorithme de Ward afin de les associer à un phénotype. Les groupes constitués ont été expliqués par le diagnostic d’asthme, l’historique familial de maladies respiratoires, l’historique familial de rhinite allergique et le compte cellulaire des neutrophiles sanguins. Cette étude a donc permis d’identifier 18 pri-=miARN primaires associés aux maladies allergiques ce qui contribue à documenter une part des mécanismes épigénétiques qui sous-tendent ces ma

Background: The atopic march is defined by the increased prevalence of allergic diseases after atopic dermatitis onset. In fact, atopic dermatitis is believed to play an important role in allergen sensitization via the damaged skin barrier, leading to allergic diseases such as allergic asthma and allergic rhinitis. The eosinophil, a pro-inflammatory cell that contributes to epithelial damage, is one of the various cells recruited in the inflammatory reactions characterizing these diseases. Few studies were conducted on the transcriptome of this cell type and even less on their specific microRNA (miRNA) profile, which could modulate pathogenesis of allergic diseases and clinical manifestations post-transcriptionally. Actually, their implication in allergic diseases is not fully understood, but they are believed to play a role in inflammation-related patterns and epithelial cell proliferation. Methods: Next-generation sequencing was performed on RNA samples from eosinophils of individuals with atopic dermatitis, atopy, allergic rhinitis and asthma to obtain differential counts of primary miRNA (pri-miRNA); these were also analyzed for asthma-related phenotypes such as forced expiratory volume in one second (FEV1), immunoglobulin E (IgE) and provocative concentration of methacholine inducing a 20% fall in forced expiratory volume in 1 s (PC20) levels, as well as FEV1 to forced vital capacity (FEV1/FVC) ratio. Results: Eighteen miRNAs from eosinophils were identified to be significantly different between affected individuals and unaffected ones. Based on counts from these miRNAs, individuals were then clustered into groups using Ward’s method on Euclidian distances. Groups were found to be explained by asthma diagnosis, familial history of respiratory diseases and allergic rhinitis as well as neutrophil counts. Conclusions: The 18 differential miRNA counts for the studying phenotypes allow a better understanding of the epigenetic mechanisms underlying the development of

We aimed to explore the association of key clinical characteristics with disease severity in atopic dermatitis (AD) and its relation to components of the atopic march in a large hospital cohort. Outpatients with AD referred to the Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark, between January 2012 and December 2017, were compared based on disease severity (SCORAD); mild (<25), moderate (25-50) and severe (>50). A total of 470AD patients were included: 122 small children (<4years of age), 103 children/adolescents (age 4-15years) and 245 adults (>15years of age). A significant difference between severity groups in small children was observed for FLG mutation carrier status (16.7 vs. 30.2 vs. 60.0% mutation carriers among patients with mild, moderate and severe AD, respectively, p=0.012) and self-rated health (3.2 vs. 2.7 vs. 2.8 with 4 being excellent health, p=0.022). A significant difference between severity groups in adults was observed for male sex (24.4 vs. 39.8 vs. 52.9%, p=0.003), serum total IgE (577 vs. 1269 vs. 2379x10(3)IU/L, p<0.001), blood eosinophil count (0.28 vs. 0.39 vs. 0.61x10(9)/L, p<0.001) and asthma (42.9 vs. 38.8 vs. 72.0%, p<0.001). Early onset of AD (<1year of age) and FLG mutation was associated with more severe disease and high serum total IgE levels. In conclusion, the distribution of key clinical characteristics varies significantly according to the severity of AD measured by SCORAD. Sub-typing of AD patients related to determinants of disease severity may be helpful in establishing prognosis and targeted treatment of AD.

Background: Asthma in early and mid-life, and chronic obstructive pulmonary disease (COPD) in later life, are two very common respiratory disorders that contribute enormously to the burden of disease in developed countries such as Australia. Researchers have investigated the risk factors associated with the onset of these diseases and have conducted many studies exploring treatments that have the potential to provide effective control of disease symptoms. The analysis of family data with appropriate statistical techniques has the potential to ensure the magnitude of the effects of both genetic and environmental risk factors are estimated free from confounding by shared influences. My systematic review on asthma phenotypes on twins and sibship (CHAPTER 3) targeted only those studies that examined the atopic march diseases from infantile eczema to hay fever and asthma. My study was the first review to assess systematically these relationships using studies that generated family data. Most previous studies reported only estimates of prevalence, incidence, heritability, concordance rate and intraclass correlation between asthma and its phenotypes without synthesizing the evidence on associations between asthma phenotypes. Also, although there exist clear sequential and plausible biological mechanisms to explain such associations, previous evidence has been generated from studies featuring only young children. Such studies were not in a position to explore whether these allergic conditions continue to adult life was. My review confirmed the need for more sibship and or twin studies to investigate potential relationships between these phenotypes from childhood to adulthood. For childhood asthma and COPD association, there are, to my knowledge, no previously published analyses that feature sibship data of the type analysed in this thesis. Methods: In CHAPTER 4, I used data from the Tasmanian Longitudinal Health Study (TAHS) on which the research findings presented in this

We aimed to explore the association of key clinical characteristics with disease severity in atopic dermatitis (AD) and its relation to components of the atopic march in a large hospital cohort. Outpatients with AD referred to the Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark, between January 2012 and December 2017, were compared based on disease severity (SCORAD); mild (<25), moderate (25-50) and severe (>50). A total of 470AD patients were included: 122 small children (<4years of age), 103 children/adolescents (age 4-15years) and 245 adults (>15years of age). A significant difference between severity groups in small children was observed for FLG mutation carrier status (16.7 vs. 30.2 vs. 60.0% mutation carriers among patients with mild, moderate and severe AD, respectively, p=0.012) and self-rated health (3.2 vs. 2.7 vs. 2.8 with 4 being excellent health, p=0.022). A significant difference between severity groups in adults was observed for male sex (24.4 vs. 39.8 vs. 52.9%, p=0.003), serum total IgE (577 vs. 1269 vs. 2379x10(3)IU/L, p<0.001), blood eosinophil count (0.28 vs. 0.39 vs. 0.61x10(9)/L, p<0.001) and asthma (42.9 vs. 38.8 vs. 72.0%, p<0.001). Early onset of AD (<1year of age) and FLG mutation was associated with more severe disease and high serum total IgE levels. In conclusion, the distribution of key clinical characteristics varies significantly according to the severity of AD measured by SCORAD. Sub-typing of AD patients related to determinants of disease severity may be helpful in establishing prognosis and targeted treatment of AD.

The review deals with the data of studies covering last 10 years held in populations of different countries concerning the association of atopic diseases, which compose the atopic march in children (atopic eczema, allergic rhinitis, allergic rhinoconjunctivitis, bronchial asthma) with genes pathologic mutations (single nucleotid polymorphisms — SNP), which encode the molecules participating in allergic inflammation in the skin and mucosae. The review has been made using the PubMed as a search tool. There is analysis of studies provided on the candidate gens for allergic inflammation — interleukin-1-like-receptor-1, sphyngolipid synthesis regulator, glucorticoid receptor gene, programmed cell death gene 4. There are also provided the candidate markers for the severity of atopic diseases course, particularly, atopic eczema: vitamin D, thymus and activation regulated chemokine, TARC/CCl17 and cutaneous T-cell attracting chemokine, CTAC/CCL27. There has been proposed conducting the studies of provided SNP and allergic inflammation markers on Ukrainian pediatric population for working out the personalized genotype-associated approach for diagnosing and management of atopic diseases in Ukrainian pediatric population., В обзоре приведены данные исследований за последние 10 лет в популяциях разных стран, касающиеся ассоциации атопических болезней, составляющих атопический марш (атопический дерматит, аллергический ринит, аллергический риноконъюнктивит, бронхиальная астма), и патологических мутаций генов (однонуклеотидные полиморфизмы, single nucleotid poymorphysms — SNP), кодирующих синтез молекул, которые принимают участие в аллергическом воспалении на коже и слизистых оболочках. В качестве поисковой системы использован PubMed. Представлен анализ исследований генов-кандидатов аллергического воспаления — интерлейкин-1-подобного рецептора-1, сфинголипидного регулятора биосинтеза, гена глюкокортикоидных рецепторов, гена запрограммированной клеточной смерти 4. Приведены новые маркеры-кандидаты тяжести течения атопических заболеваний, в частности атопического дерматита: витамин D3, тимус и активацией регулированный хемокин TARC/CCl17, кожный Т-аттрактивный хемокин CTAC/CCL27. Предложено проведение исследований выше­указанных SNP и маркеров аллергического воспаления на украинской педиатрической популяции для разработки персонализированного генотип-ассоциированного подхода к диагностике и лечению атопических болезней у детского населения Украины., В огляді наведені дані досліджень за останні 10 років у популяціях різних країн щодо асоціацій атопічних хвороб, що становлять атопічний марш у дітей (атопічного дерматиту, алергічного риніту, алергічного ринокон’юнктивіту та бронхіальної астми), і патологічних мутацій генів (однонуклеотидних поліморфізмів, single nucleotid poymorphysms — SNP), які кодують синтез молекул, що беруть участь у алергічному запаленні на шкірі та слизових оболонках. Як пошукову систему було застосовано PubMed. Наданий аналіз досліджень генів-кандидатів алергічного запалення — інтерлейкін-1-подібного рецептора-1, сфінголіпідного регулятора біосинтезу, гена глюкокортикостероїдних рецепторів, гена запрограмованої клітинної смерті 4. Наведено нові маркери-кандидати тяжкості перебігу атопічних хвороб, зокрема атопічного дерматиту: вітамін D3, тимус, активацією регульований хемокін TARC/CCl17 та шкірний Т-атрактивний хемокін CTAC/CCL27. Запропоновано проведення досліджень вищенаведених SNP і маркерів алергічного запалення на українській педіатричній популяції для розробки персоналізованого генотип-асоційованого підходу до діагностики та лікування атопічних хвороб у дитячого населення України.

В огляді наведені дані досліджень за останні 10 років у популяціях різних країн щодо асоціацій атопічних хвороб, що становлять атопічний марш у дітей (атопічного дерматиту, алергічного риніту, алергічного ринокон’юнктивіту та бронхіальної астми), і патологічних мутацій генів (однонуклеотидних поліморфізмів, single nucleotid polymorphysms — SNP), які кодують синтез молекул, що беруть участь в алергічному запаленні на шкірі та слизових оболонках. Як пошукову систему використано PubMed. Наданий аналіз досліджень вивчених SNP — філагрину, тол-подібних рецепторів, висвітлено перспективний каскад запалення при бронхіальній астмі — інтерлейкін-1-подібний рецептор 1 та інтерлейкін-33. Запропоновано проведення досліджень наведених SNP на українській педіатричній популяції для розробки персоналізованого генотип-асоційованого підходу до діагностики та лікування атопічних хвороб у дитячого населення України., В обзоре приведены данные исследований за последние 10 лет в популяциях разных стран относительно ассоциаций атопических болезней, составляющих атопический марш у детей (атопического дерматита, аллергического ринита, аллергического риноконъюнктивита, бронхиальной астмы), и патологических мутаций генов (однонуклеотидных полиморфизмов, single nucleotid poymorphysms — SNP), кодирующих синтез молекул, которые принимают участие в аллергическом воспалении на коже и слизистых оболочках. В качестве поисковой системы использован PubMed. Приведен анализ исследований изученных SNP — филаггрина, толл-подобных рецепторов, освещен перспективный каскад воспаления при бронхиальной астме — интерлейкин-1-подобный рецептор 1 и интерлейкин-33. Предложено проведение исследований приведенных SNP на украинской педиатрической популяции для разработки персонализированного генотип-ассоциированного подхода к диагностике и лечению атопических болезней у детского населения Украины., The review deals with the data of studies over last 10 years of populations of different countries on association of atopic diseases being the components of the atopic march in children (atopic eczema, allergic rhinitis, allergic rhinoconjunctivitis, bronchial asthma) with pathologic mutations of genes (single nucleotid polymorphisms — SNP), which encode the molecules participating in allergic inflammation in the skin and mucosa. PubMed had been used as the search tool. There is a review of studies provided on investigated SNPs — filaggrin, receptors, toll-like receptors; the article describes a perspective bronchial asthma inflammation cascade — interleukin-1 receptor-like-1 and interleukin-33. There has been proposed conducting the studies of SNP on Ukrainian pediatric population for working out the personalized genotype-associated approach for diagnosing and management of atopic diseases in Ukrainian children population.

Eczema often precedes the development of asthma in a disease course called the ‘atopic march’. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.