Toll-like receptors (TLR) play a pivotal role in the induction of first-line defense mechanisms of the innate immune system and trigger adaptive immune responses to microbial pathogens. Genetic ...variations in innate immunity genes have been reported to be associated with a range of inflammatory disorders. Deficiencies on the level of immunity receptors such as pathogen-recognition receptors are suspected to affect the maturation of our immune system and to avail thereby the high prevalence of atopic diseases and susceptibility of atopic patients to microbial infections. We evaluated TLR9 as susceptibility gene for atopic eczema (AE). Analyses of four tag single-nucleotide polymorphisms in two panels of families containing a total of 483 parent-affected offspring trios as well as a cohort of 274 unrelated adult AE cases and 252 hypernormal population-based controls have been performed. In both family cohorts, polymorphism C-1237T, which is located within the promoter region of the TLR9 gene, was significantly associated with AE, in particular the intrinsic subtype of AE. No associations were seen in the case-control cohort. Luciferase reporter gene assays revealed significantly higher promoter activity of the TT allelic variant at this single nucleotide polymorphism site. These observations suggest that the TLR9 promoter polymorphism C-1237T might affect AE susceptibility in particular in patients with the intrinsic variant of AE.
Summary
Background
Growing evidence suggests that atopic dermatitis (AD) is associated with an increased risk of depressive disorders and anxiety. However, existing studies were observational and may ...have uncovered correlations but could not easily disentangle noncausal or reverse‐causal associations because these associations could be confounded and may not reflect true causal relationships.
Objectives
To examine, in a two‐sample Mendelian randomization study, the potential effect of AD on the risk of depressive disorders and anxiety.
Methods
Genetic instruments from the largest available genome‐wide association study (GWAS) for AD (10 788 cases and 30 047 controls) were used to investigate the relationship to broad depression (170 756 cases and 329 443 controls), major depressive disorder (MDD; 30 603 cases and 143 916 controls) and anxiety (5580 cases and 11 730 controls). A set of complementary approaches were carried out to assess horizontal pleiotropy and related potential caveats occurring in MR studies.
Results
We observed no causal impact of AD on the risk of depressive disorders and anxiety, with close‐to‐zero effect estimates. The inverse weighted method revealed no associations of AD on broad depression odds ratio (OR) 1·014; P = 0·431, probable MDD (OR 1·002; P = 0·568), International Classification of Diseases, Ninth/Tenth Revision‐based MDD (OR 1·001; P = 0·466) or anxiety (OR 1·097; P = 0·180).
Conclusions
This MR study does not support a causal effect of AD on depression and anxiety.
What is already known about this topic?
There is growing evidence that atopic dermatitis (AD) is related to depressive disorders and anxiety.
Observational studies are prone to reverse causation and confounding, distorting true relationships.
Observational study results are inconclusive regarding the effect of AD on depression and anxiety.
What does this study add?
Using Mendelian randomization as an alternative approach to investigate causality, we did not find a causal relationship between AD and depressive disorders or anxiety.
Linked Comment: M. Standl. Br J Dermatol 2021; 185:694–695.
Summary
Aim
The PETITE study (Sigurgeirsson et al.) aimed to compare safety and efficacy of pimecrolimus 1% cream (PIM) and low‐to‐medium‐potency topical corticosteroids (TCS) in children with ...mild‐to‐moderate atopic dermatitis (AD).
Setting and design
Participants of this 5‐year drug‐company sponsored multicentre, open‐label, parallel‐group trial were recruited between April 2004 and October 2005. No details are reported regarding the study sites.
Study exposure
Infants aged ≥ 3 to < 12 months with mild‐to‐moderate AD were randomly assigned in a 1 : 1 ratio to receive either PIM or a low‐ or medium‐potency TCS cream/ointment for 5 years. No information on specific TCS products used was provided. The topical treatment was applied twice daily ‘until complete AD clearance or for as long as allowed by the label of the specific TCS’, and was reinitiated at the occurrence of first signs and symptoms of AD flares. In the PIM group, exacerbations not controlled by PIM were treated with short‐term TCSs.
Outcomes
Adverse events (AEs) and serious AEs (SAEs) were recorded ‘during clinic visits’. In a proportion of the patients, various immunological assessments including antibody titres to common vaccine antigens, immunoglobulin levels, B and T lymphocyte cell counts, and T‐cell proliferation tests were performed. The children's growth was assessed by measuring height and weight. AD severity was measured using the Investigator Global Assessment (IGA) score and the percentage of the total body surface area affected. No specific information was provided on the number and scheduling of study visits. Primary outcomes were the incidence of AEs ‘of primary clinical interest’ and those with a crude incidence of ≥ 5% in either treatment group. Secondary outcome was ‘long‐term efficacy’ defined as IGA ≤ 1 at week 3 and year 5.
Results
Patients in the PIM group experienced significantly more AEs bronchitis (P = 0·02), infected eczema (P ≤ 0·001), impetigo (P = 0·045), nasopharyngitis (P = 0·04). No significant differences were seen for the other AEs. The overall incidence of SAEs was slightly higher for PIM (20·5% vs. 17·3%; P = 0·046). The proportion of participants with IGA ≤ 1 at year 5 was 88·7% for PIM and 92·3% for TCS, a success rate difference of 3·6% (95% confidence interval 0·8–6·4) favouring TCS.
Conclusions
Sigurgeirsson et al. conclude that the long‐term management of mild‐to‐moderate AD in children with both TCS and PIM is safe, and that PIM has similar efficacy to TCS. Further, they conclude that their data support the use of PIM as a first‐line treatment of mild‐to‐moderate AD in children.
Itch is the major symptom of many allergic diseases; yet it is still difficult to measure objectively. The aim of this study was to use an evaluated itch stimulus model in lesional (LS) and ...nonlesional (NLS) atopic eczema (AE) skin and to characterize cerebral responses using functional magnetic resonance imaging (fMRI). Thermal modulation was performed on a histamine stimulus in randomized order on LS or NLS in rapid alternating order from 32°C (warm) to 25°C (cold). Subjective itch ratings were recorded. Additionally, fMRI measurements were used to analyze the cerebral processing (n = 13). Healthy skin (HS) of age-matched volunteers served as control (n = 9). Mean VAS itch intensity was significantly (P < 0.0001) higher during the relative cold 55.2 ± 8.3% (LS); 48.6 ± 8.2% (NLS) compared to the relative warm blocks 36.0 ± 7.3% (LS); 33.7 ± 7.6% (NLS). Compared to HS, the itch response was delayed in LS and NLS. Itch intensity was perceived highest in LS, followed by NLS and HS. For NLS, fMRI revealed at the beginning of the itch provocation a cerebral deactivation pattern in itch processing structures (thalamus, prefrontal, cingulate, insular, somatosensory and motor cortex). During the course of stimulation, the cerebral deactivation was reduced with time and instead an activation of the basal ganglia occurred. In contrast LS showed an activation instead of deactivation pattern already at the beginning of the stimulation in the above mentioned structures. Moderate short-term temperature modulation led to a reproducible, significant enhancement of histamine-induced itch with the strongest effect in LS. The differences in itch perception and itch kinetics between healthy volunteers and NLS in patients point towards an ongoing central inhibitory activity patients with AE, especially at the beginning of the itch provocation.
Summary
Background
The human skin offers diverse ecosystems for microbial symbionts. However, the factors shaping skin–microbiome interactions are still insufficiently characterized. This contrasts ...with the broader knowledge about factors influencing gut microbiota.
Objectives
We aimed to investigate major patterns of association of host traits, lifestyle and environmental factors with skin bacteria in two German populations.
Methods
This is a cross‐sectional study with 647 participants from two population‐based German cohorts, PopGen (n = 294) and KORA FF4 (n = 353), totalling 1794 skin samples. The V1–V2 regions of the 16S ribosomal RNA (rRNA) gene were sequenced. Associations were tested with two bacterial levels, community (beta diversity) and 16S rRNA gene amplicon sequence variants (ASVs).
Results
We validated known associations of the skin microbiota with skin microenvironment, age, body mass index and sex. These factors were associated with beta diversity and abundance of ASVs in PopGen, which was largely replicated in KORA FF4. Most intriguingly, dietary macronutrients and total dietary energy were associated with several ASVs. ASVs were also associated with smoking, alcohol consumption, skin pH, skin type, transepidermal water loss, education and several environmental exposures, including hours spent outdoors. Associated ASVs included members of the genera Propionibacterium, Corynebacterium and Staphylococcus.
Conclusions
We expand the current understanding of factors associated with the skin bacterial community. We show the association of diet with skin bacteria. Finally, we hypothesize that the skin microenvironment and host physiology would shape the skin bacterial community to a greater extent compared with a single skin physiological feature, lifestyle and environmental exposure.
What is already known about this topic?
The skin microbiome is essential for maintaining skin health.
Skin bacteria abundances are associated with skin physiology patterns (microenvironments), host traits, such as age and sex, and domestic environmental factors, such as pets.
Evaluation and translation of these associations are difficult because most studies have a limited number of candidate factors.
What does this study add?
We expand the current knowledge of factors associated with skin microbiota by revealing new factors associated with skin bacteria, including diet.
We provide a comprehensive view of the factors associated with skin microbiota, which suggests that skin microenvironment and host physiology would shape the skin bacterial community to a greater extent compared with a single skin physiological feature, lifestyle and environmental exposure.
What is the translational message?
Future clinical research involving skin microbiota should acknowledge the associations found as potential confounders.
Host factors (age, body mass index and sex) and skin microenvironments should be particularly considered because they were associated with skin bacteria at the community level.
Linked Comment: A.M. Schneider and A.M. Nelson. Br J Dermatol 2021; 185:481–483.
To cite this article: Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Høgh JK, Hellgren LI, Jemec GBE, Agner T, Weidinger S. Stratum corneum lipids, skin barrier function and filaggrin ...mutations in patients with atopic eczema. Allergy 2010; 65: 911-918. Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer chromatography. In addition, TEWL, erythema, skin hydration and pH were measured. In 27 of the 49 individuals, a 24-h irritation patch test with sodium lauryl sulphate was performed. For the analysis, both the AD group and the control group were stratified by FLG mutation status (FLGmut/FLGwt). In the FLGmut AD group, significantly lower levels of ceramide 4 and significantly higher levels of ceramide 7 were observed when compared to both healthy control groups. However, ceramide 7 levels also significantly differed between FLGwt AD and FLGwt controls, as did ceramide 1 levels. No significant differences were observed for ceramide 2, 3, 5 and 6. FLGmut individuals had significantly higher skin pH values than individuals not carrying FLG mutations. Patients with AD with FLG mutations had significantly higher erythema compared to patients with AD without FLG mutations. Our results confirm previous observations of altered ceramide levels in AD, which however appear to show no clear relationship with FLG mutations.
Omalizumab, a monoclonal antibody targeting IgE, is an established therapy for severe allergic asthma and has shown efficacy in chronic spontaneous urticaria. Small‐scale studies indicated some ...beneficial effect also in atopic dermatitis (AD). To evaluate the efficacy of omalizumab in AD and to identify markers associated with treatment response, we conducted a prospective 28‐week open‐label trial on 20 adults with moderate‐to‐severe AD. Our results confirm previous observations of a positive response in a subgroup of patients and suggest that responders are characterized by the absence of filaggrin mutations and altered lipid metabolite profiles with high levels of various glycerophospholipids.
Background
Genome‐wide association studies (GWAS) have identified many risk loci for asthma, but effect sizes are small, and in most cases, the biological mechanisms are unclear. Targeted metabolite ...quantification that provides information about a whole range of pathways of intermediary metabolism can help to identify biomarkers and investigate disease mechanisms. Combining genetic and metabolic information can aid in characterizing genetic association signals with high resolution. This work aimed to investigate the interrelation of current asthma, candidate asthma risk alleles and a panel of metabolites.
Methods
We investigated 151 metabolites, quantified by targeted mass spectrometry, in fasting serum of asthmatic and nonasthmatic individuals from the population‐based KORA F4 study (N = 2925). In addition, we analysed effects of single‐nucleotide polymorphisms (SNPs) at 24 asthma risk loci on these metabolites.
Results
Increased levels of various phosphatidylcholines and decreased levels of various lyso‐phosphatidylcholines were associated with asthma. Likewise, asthma risk alleles from the PDED3 and MED24 genes at the asthma susceptibility locus 17q21 were associated with increased concentrations of various phosphatidylcholines with consistent effect directions.
Conclusions
Our study demonstrated the potential of metabolomics to infer asthma‐related biomarkers by the identification of potentially deregulated phospholipids that associate with asthma and asthma risk alleles.
To cite this article: Maintz L, Yu C‐F, Rodríguez E, Baurecht H, Bieber T, Illig T, Weidinger S, Novak N. Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine ...oxidase serum activities. Allergy 2011; 66: 893–902.
Background: Histamine intolerance (HIT) is associated with an excess of histamine because of an impaired function of the histamine‐degrading enzyme diamine oxidase (DAO). The genetic background of HIT is unknown yet.
Methods: Case–control association study of all haplotype tagging and four previously reported DAO SNPs and one HNMT Single nucleotide polymorphism with symptoms of HIT and DAO serum activity in 484 German individuals including 285 patients with clinical symptoms of HIT and 199 controls.
Results: Diamine oxidase serum activity was significantly associated with seven SNPs within the DAO gene. The minor allele at rs2052129, rs2268999, rs10156191 and rs1049742 increased the risk for a reduced DAO activity whereas showing a moderate protective effect at rs2071514, rs1049748 and rs2071517 in the genotypic (P = 2.1 × 10−8, 7.6 × 10−10, 8.3 × 10−10, 0.009, 0.005, 0.00001, 0.006, respectively) and allelic genetic model (P = 2.5 × 10−11, 5.4 × 10−13, 8.9 × 10−13, 0.00002, 0.006, 0.0003, 0.005, respectively). Reporter gene assays at rs2052129 revealed a lower promoter activity (P = 0.016) of the minor allele. DAO mRNA expression in peripheral blood mononuclear cells of homozygous carriers of the minor allele at rs2052129, rs2268999, rs10156191 was lower (P = 0.002) than homozygous carriers of the major allele. Diamine oxidase variants were not associated with the HIT phenotype per se, only with DAO activity alone and the subgroup of HIT patients displaying a reduced DAO activity.
Conclusions: DAO gene variants strongly influence DAO expression and activity but alone are not sufficient to fully effectuate the potentially associated disease state of HIT, suggesting an interplay of genetic and environmental factors.
Background: Atopic disorders are the result of complex interactions between genetic and environmental factors. Associations analyses between the promoter polymorphism rs1800875 in the mast cell ...chymase gene (CMA1) and atopy‐related phenotypes have yielded inconsistent results.
Methods: We sequenced the CMA1 locus in 24 unrelated healthy individuals with serum IgE levels <50% percentile and 24 individuals with atopic eczema and serum IgE levels >90% percentile. Seven CMA1 single nucleotide polymorphisms (SNPs) were evaluated for evidence of associations with atopic phenotypes within a large population of German adults (n = 1875). Subjects were phenotyped by standardized questionnaires and interviews, skin prick testing and serum IgE measurements. Genotyping was performed using MALDI‐TOF MS (Matrix‐Assisted Laser Desorption Ionization–Time of Flight mass spectrometry).
Results: Promoter polymorphism rs1800875 was significantly associated with atopic eczema. No associations between any other single SNP and atopic phenotypes could be detected. Haplotype reconstruction revealed four of 128 possible haplotypes reaching estimated frequencies of 3% or more. Two of these haplotypes showed a borderline‐significant association with atopic eczema, which did not remain significant after correction for multiple testing.
Conclusions: Results confirm previous observations of a significant association between the CMA1 promoter polymorphism rs1800875 and atopic eczema, but not with serum IgE levels, and support the hypothesis that CMA1 serves as candidate gene for atopic eczema.
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