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.
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 Influences of microbial pathogens are crucial for the maturation of the immune system. Caspase‐recruitment domain containing protein 15 (CARD15) is a cytosolic receptor involved in ...bacterial recognition by antigen‐presenting cells. CARD15 polymorphisms have been associated with Crohn's disease. Recently, associations with atopic phenotypes have been reported in children.
Objective Within a large population of German adults (n=1875), we evaluated eight CARD15 polymorphisms for associations with atopic phenotypes.
Methods Subjects were phenotyped by standardized questionnaires and interviews as well as total and allergen‐specific IgE measurements. Genotyping was performed using matrix‐assisted laser desorption ionization – time of flight mass spectrometry. Haplotypes were estimated using the SAS/Genetics module.
Results Subjects with a T allele at rs1077861 had a decreased risk of developing asthma (odds ratio OR=0.648, P=0.013), whereas the presence of an A allele at rs3135500 was significantly associated with an increased risk (OR=1.374, P=0.023). In addition, a CARD15 haplotype revealed to be protective against the development of asthma (OR=0.326, P=0.003). Subjects with an A allele at position rs5743266 or a T allele at rs2066842 had a significantly decreased risk of developing allergic rhinoconjunctivitis with ORs of 0.820 (P=0.049) and 0.801 (P=0.025). Polymorphism rs2066845 showed a significant association with increased total serum IgE (OR=2.155, P=0.006).
Conclusion Genetic variants of CARD15 that might result in inappropriate immunomodulation are not only associated with autoimmune diseases but also with atopic disorders.
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.
Interactions with microbial pathogens are crucial for the maturation of the immune system. The nucleotide-binding oligomerization domain protein 1 (NOD1) is a cytosolic receptor sensing a muropeptide ...found mostly in gram-negative bacterial peptidoglycans.
NOD1 is located on chromosome 7p14-p15, a region that has been linked with atopy. Recently, polymorphisms of the closely related
NOD2 have been associated with atopy-related traits.
Within a large population-based cohort of German adults (n
=
1417), a case-control population for atopic eczema (n
=
454), and a large cohort of parent-offspring trios for atopic eczema (189 trios), we evaluated 11
NOD1 polymorphisms for associations with atopic phenotypes.
Subjects were phenotyped by standardized questionnaires and interviews, skin examination, and serum IgE measurements. Genotyping was performed by using matrix-assisted laser desorption ionization–time of flight mass spectrometry.
Analyses revealed significant association of one
NOD1 haplotype with atopic eczema in the population-based cohort (
P
=
.004) and the case-control population (
P
=
.003). Another
NOD1 haplotype was associated with decreased total IgE (
P
=
.008). In addition, significant associations with total serum IgE levels were observed for polymorphisms rs2907748 (
P
=
.006), rs2907749 (
P
=
.012), and rs2075822 (
P
=
.018). These polymorphisms were significantly associated with atopic eczema and asthma in the family-based association analyses (
P
=
.001-.043). Seven polymorphisms showed significant transmission distortion for total IgE levels (
P values < .0001-.029).
These data indicate that genetic variants within
NOD1 are important determinants of atopy susceptibility.
Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we ...performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10
), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory ...skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.
A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common ...allergic diseases remain to be discovered, which could point to new therapeutic opportunities.
We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects.
We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study.
Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10−6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses.
Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.
To define further genetic risk loci for ...sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.
Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms.
Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3.
Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.
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.
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