Background A subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the ...IFN-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype. Objective We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+. Methods We performed targeted sequencing of interferon pathway genes ( IFNG , IFNGR1 , IFNAR1 , and IL12RB1 ) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis. Results We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency <5%), and 86 (17.4%) novel variants, of which 2.8% were coding synonymous, 93.3% were noncoding (64.6% intronic), and 3.8% were missense. We identified 6 rare IFNGR1 missense variants, including 3 damaging variants (Val14Met V14M, Val61Ile, and Tyr397Cys Y397C) conferring a higher risk for ADEH+ ( P = .031). Variants V14M and Y397C were confirmed to be deleterious, leading to partial IFNGR1 deficiency. Seven common IFNGR1 SNPs, along with common protective haplotypes (2-7 SNPs), conferred a reduced risk of ADEH+ ( P = .015-.002 and P = .0015-.0004, respectively), and both SNP and haplotype associations were replicated in an independent African American sample ( P = .004-.0001 and P = .001-.0001, respectively). Conclusion Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.
Abstract Background Chronic schistosomiasis and its severe complication, periportal fibrosis, are characterized by a predominant Th2 response. To date, specific SNPs in ST2 have been some of the most ...consistently associated genetic variants for asthma. Objectives We investigated the role of ST2 (a receptor for the Th2 cytokine IL-33) in chronic and late-stage schistosomiasis caused by S. japonicum , and the potential effect of ST2 genetic variants on stage of disease and ST2 expression. Methods 947 adult participants (339 with end-stage schistosomiasis and liver cirrhosis, 307 with chronic infections without liver fibrosis, and 301 health controls) were recruited from a S. japonicum -endemic area (Hubei, China). Six ST2 SNPs were genotyped. Serum sST2 was measured by ELISA, and ST2 expression in normal liver tissues, HBV-induced fibrotic liver tissues and S. japonicum -induced fibrotic liver tissues was measured by immunohistochemistry. Results: sST2 levels were significantly higher in the end-stage group (36.04 95 %CI 33.85;38.37) compared to chronic cases and controls (22.7 95% CI 22.0;23.4, p-value < 1E-10). In addition, S. japonicum -induced fibrotic liver tissues showed increased ST2 staining compared to normal liver tissues (p-value=0.0001). Markers rs12712135, rs1420101 and rs6543119 were strongly associated with sST2 levels (p-values 2E-10, 5E-05 and 6E-05 respectively), and these results were replicated in an independent cohort from Brazil living in a S. mansoni endemic region. Conclusion We demonstrate for the first time that end-stage schistosomiasis is associated with elevated sST2 levels, and show that ST2 genetic variants are associated with sST2 levels in patients with schistosomiasis.
Allergic asthma is a complex disorder that results from a combination of genetic and environmental factors. Studies suggest that helminth infections can activate a regulatory network characterized by ...the production of regulatory cytokines, such as interleukin 10 and transforming growth factor β1 (TGF-β1) and subsequently protect against immune-mediated diseases, such as asthma. On the other hand, TGF-β1 is increased in the lungs of individuals with asthma and may modulate airway inflammation. The role of TGF- β 1 single-nucleotide polymorphisms (SNPs) in allergic disease remains inconclusive.
To evaluate the effects of genetic variations in the TGF-β1 on allergy and helminths infections in children.
We tested for association among 4 TGF-β1 SNPs and allergic asthma, specific IgE, skin prick test result, and IL-10 production in 1,335 Brazilians. In addition, we analyzed the association with markers of helminth infection (parasite burden, anti-Ascaris IgE, and worm specific IgG4). The polymorphisms were genotyped using Taq Man probes.
We found an association between rs1800470 (C allele) and atopic wheezing (odds ratio OR, 0.60; 95% confidence interval CI, 0.37-0.95) and markers of allergy (OR, 0.41; 95% CI, 0.22-0.79). In contrast, a positive association was observed between the haplotype ACCA and Trichuris trichiura infection (OR, 1.85; P = .003) and Ascaris lumbricoides infection (OR, 2.01; P < .001). This haplotype was also associated with increased IL-10 production (β = 50.7; P < .001).
Individuals with TGF-β1 polymorphisms have an increased susceptibility to helminth infections and a lower risk of developing allergy. These studies suggest that immune modulation of allergic disease results not only from environmental factors but also from genetic susceptibility and IL-10 production.
Background Helminth infections are associated with protection against allergies. It is postulated that IL-10 production after helminth infection suppresses skin hypersensitivity and increases IgG4 ...production, protecting against allergies. Objective We aimed to determine whether IL10 polymorphisms are associated with helminth infection and the risk of wheeze and allergy. Methods Twelve IL10 single nucleotide polymorphisms were genotyped in 1353 children aged 4 to 11 years living in a poor urban area in Salvador, Brazil. Wheezing status, Ascaris lumbricoides and Trichuris trichiura infection, IL-10 production by peripheral blood leukocytes stimulated with A lumbricoides extract, serum total IgE levels, specific IgE levels, skin prick test responses to common aeroallergens, and IgG4 and IgE anti– A lumbricoides antibody levels were measured in all children. Association tests were performed by using logistic or linear regression when appropriate, including sex, age, helminth infection, and principal components for ancestry informative markers as covariates by using PLINK. Results Allele G of marker rs3024496 was associated with the decreased production of IL-10 by peripheral blood leukocytes in response to A lumbricoides stimulation. Allele C of marker rs3024498 was negatively associated with helminth infection or its markers. Marker rs3024492 was positively associated with the risk of atopic wheeze, total IgE levels, and skin prick test responses to cockroach. Conclusions Our findings suggest that IL10 polymorphisms might play a role in the production of IL-10, helminth infection, and allergy. We hypothesize that polymorphisms related to protection against helminths, which would offer an evolutionary advantage to subjects in the past, might be associated with increased risk of allergic diseases.
Background Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of ...the genetic risk. Objectives We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. Methods We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case–parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. Results Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. Conclusions This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.
Single-variant tests for common variants (minor allele frequency (MAF) >=5%) were performed using logistic regression adjusting for first two principal components, and low frequency variants (those ...with MAF<5%) were tested using Fisher's exact test.
Rationale Null mutations in Filaggrin (FLG) located within the Epidermal Differentiation Complex (EDC; chr1:151972910-153642037) are known to increase risk for atopic dermatitis (AD); but the role of ...variants within additional genes in the EDC is not well understood.
Contribution of FLG mutations to S. aureus colonization in mild, moderate and severe AD was assessed by including interaction between EASI and FLG mutations in logistic regression models adjusting ...for total IgE, age, and sex.
While our evidence for risk of bacterial colonization is less striking in the EDC, extensive analysis is underway to include SNVs across the genome, insertion/deletions and gene-level tests.
Rationale The gene encoding dipeptidyl-peptidase 10 (DPP10) was originally identified as an asthma candidate gene through positional cloning and subsequently a genome-wide association study (GWAS) ...meta-analysis However, the precise DPP10 locus conferring risk to asthma is unclear.
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