Eight novel susceptibility loci and putative causal variants in atopic dermatitis

Tanaka, Nao; Koido, Masaru; Suzuki, Akari; Otomo, Nao; Suetsugu, Hiroyuki; Kochi, Yuta; Tomizuka, Kouhei; Momozawa, Yukihide; Kamatani, Yoichiro; Ikegawa, Shiro; Yamamoto, Kazuhiko; Terao, Chikashi

doi:10.1016/j.jaci.2021.04.019

Cited by 50 publications

(32 citation statements)

References 57 publications

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“…AD is a complex disease whose etiology has not yet been fully deciphered due to its heterogeneity resulting from patient age, ethnicity, and lifestyle factors [7][8][9]. Moreover, although a genetic predisposition is undeniable in AD pathogenesis, the relative contribution of (epi)genetic [10][11][12][13] versus environmental factors [14][15][16] remains unknown. Heterogeneity of AD due to genetic polymorphism extends beyond filaggrin (FLG) loss-of-function mutations, since patients with serine peptidase inhibitor Kazal-type 5 (SPINK5) mutations also exhibit a severe AD-like phenotype, as do other patients with inherited disorders [17,18].…”

Section: Atopic Dermatitismentioning

confidence: 99%

Atopic Dermatitis: The Fate of the Fat

Pavel

Blunder

Moosbrugger‐Martinz

et al. 2022

IJMS

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Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component, as children from parents with AD have a twofold increased chance of developing the disease. Genetic risk loci and epigenetic modifications reported in AD mainly locate to genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors since environmental triggers such as stress, pollution, microbiota, climate, and allergens also play a crucial role. Alterations of the epidermal barrier in AD, observed at all stages of the disease and which precede the development of overt skin inflammation, manifest as: dry skin; epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system; and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, such as ceramides and free fatty acids. Thus, a compelling question is whether AD is primarily a lipid disorder evolving into a chronic inflammatory disease due to genetic susceptibility loci in immunogenic genes. In this review, we focus on lipid abnormalities observed in the epidermis and blood of AD patients and evaluate their primary role in eliciting an inflammatory response.

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Section: Atopic Dermatitismentioning

confidence: 99%

Atopic Dermatitis: The Fate of the Fat

Pavel

Blunder

Moosbrugger‐Martinz

et al. 2022

IJMS

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“…TRAF3 serves as a constitutive negative regulator of the alternative nuclear factor-κB (NF-κB) pathway and has a potential role in many immune cell types, but defects in it have only been studied in detail in cell lines and mouse models ( 3 ). Although genome-wide association studies (GWAS) have linked common variants at the TRAF3 locus with several immune traits and autoimmune and atopic conditions ( 4 – 8 ), and the TRAF3 variant p.R118W (rs143813189-T) has been reported in association with herpes simplex encephalitis (HSE) in a single case ( 9 ), TRAF3’s role in humans is yet to be fully determined. Here, we describe the breadth of impact on human immunity, and mechanism of action, of rare and common genetic variants in TRAF3 .…”

Section: Introductionmentioning

confidence: 99%

Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

et al. 2022

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Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients’ B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4 + T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

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“…Inspecting many GWAS studies that identified this gene with a strong association are signified with skin-related pathologies. Recently, it was shown that gene variants are causal for Atopic dermatitis in the Japanese [35] and Finnish populations (FINNGEN, freeze 5). Other cohorts identified the gene to be associated with psoriasis, asthma, hay fever or eczema.…”

Section: Resultsmentioning

confidence: 99%

Recessive and sex-dependent genetic effects in primary hypertension

Zucker

Linial

2022

Preprint

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BackgroundEssential hypertension is a polygenic disease that affects almost half of the adult population in the USA. It is a major risk factor for renal, cerebrovascular, and cardiovascular diseases. Previous studies used UK-Biobank (UKB) GWAS results for hypertension to create a polygenic risk score (PRS), with the top and bottom 5% of the PRS translating to a 4-fold difference in the estimated risk. The heritability of hypertension is estimated to be high (30–60%), yet the underlying mechanisms and the associated genes are largely unknown.MethodsIn this study, we used a gene-based method, the proteome-wide association study (PWAS), to detect associations mediated by the effects of variants on protein function. PWAS was applied to individuals of European ancestry from the UKB, with 74,090 cases of clinical diagnosis of essential (primary) hypertension (ICD-10, I10) and 200,734 controls. PWAS aggregates the signal from all variants affecting each coding gene and provides scores for dominant, recessive, and hybrid genetic heritability.ResultsPWAS identified 70 statistically significant associated genes (FDR-q-value <0.05) and 127 genes with a weaker threshold (FDR-q-value <0.1). The overlap with GWAS summary statistics (total 1,362 genes) is only partial, with 23 and 62 genes identified exclusively by PWAS from a total of 70 and 127 genes, respectively), among them 18% were assigned recessive inheritance. Furthermore, PWAS analysis, separately performed on females and males from UKB genotyping imputed data, revealed sex-dependent genetics. There are 22 genes unique in females, with only 2 in males. We identified 6 female-specific genes that were not identified by PWAS for the entire group (70 genes). Only one associated gene (SH2B3) is shared between the sexes. Many of the female-significant genes from PWAS are enriched in cellular immunity functions.ConclusionsWe conclude that hypertension displays sex-dependent genetics with an overlooked recessive inheritance, postulating that the underlying mechanism is substantially different for males and females. Studying hypertension by a gene-based association method improves interpretability and clinical utility.

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Eight novel susceptibility loci and putative causal variants in atopic dermatitis

Cited by 50 publications

References 57 publications

Atopic Dermatitis: The Fate of the Fat

Atopic Dermatitis: The Fate of the Fat

Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

Recessive and sex-dependent genetic effects in primary hypertension

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