Peisong Gao

Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma.

Atopy is an immune disorder characterized by heightened immunoglobulin E (IgE) production and leads to the clinical disorders of asthma, eczema and rhinitis1. Interleukin 4 (IL4) is a pleiotropic cytokine which plays a crucial role in IgEdependent atopic disorders2; it is central to B cells switching to IgE antibody production and to the maturation of T-helper cells to the Th2 phenotype (type-2 Thelper lymphocyte). Human IL4 operates through the IL4 receptor (IL4R) and thereby Stat6 (signal transducer and activator of transcription 6) activation3. Mice deficient in Stat6 (refs 4,5) or the IL4Rα chain6 lack IgE production and Th2 inflammatory reactions. IL4Rα is therefore a crucial component required for IL4 binding and signal transduction. A cytoplasmic variant of IL4Rα, an Arg576Gln substitution (numbering from the first ATG), has been recently identified and is found in excess in a study of a group of individuals with hyper-IgE syndrome and severe eczema7; functional assays showed impaired binding of the negative regulatory molecule, protein tyrosine phosphatase, SHP-1, and increased expression of CD23 was found on peripheral blood mononuclear cells after being challenged with IL4. Stat6 activation, however, was not upregulated and no information was provided on cellular IgE synthesis. An extracellular variant, Thr49Ile, in IL4Rα of BALB/c mice alters the ligandbinding affinity of IL4Rα (ref. 8). An Ile50Val (numbering for mature peptide) variant of human IL4Rα has also been identified9,10 and it is, to date, the only known extracellular variant of human IL4Rα (ref. 11). To test whether the Ile50Val variant promotes dysregulation of IgE synthesis, we first conducted a genetic association study for serum IgE levels in a Japanese population. There was a significant difference in Ile/Val 50 genotype frequencies between control and atopic subjects (Table 1); Ile50 associated with atopic asthma but not with non-atopic asthma; Ile50 specifically and significantly associated with raised total serum IgE levels and mite-specific IgE. The association with atopy was especially strong in children. The high frequency of Ile50 homozygotes (approximately 60%) in the childhood atopic asthma group described here, and the significant skewing from Hardy-Weinberg equilibrium (P<0.0001), suggest a largely recessive genetic effect for Ile50 on atopy; the previously reported

A Genome-Wide Association Study on African-Ancestry Populations For Asthma

BACKGROUNDnAsthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed.nnnOBJECTIVESnWe sought to test the hypothesis that some genes might contribute to the profound disparities in asthma.nnnMETHODSnWe performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma.nnnRESULTSnA meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated.nnnCONCLUSIONSnThis study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.

Variation in dinucleotide (GT) repeat sequence in the first exon of the STAT6 gene is associated with atopic asthma and differentially regulates the promoter activity in vitro

Upregulation of the IL-4/IL-13 mediated Th2 response is a characteristic of allergic diseases such as asthma, a common and often debilitating disease.1 STAT6 is a critical signalling molecule in the Th2 signalling pathway, and mice lacking STAT6 are protected from allergic pulmonary manifestations.2 The importance of STAT6 in asthma is also evident from studies showing that STAT6 gene expression is markedly upregulated in airway epithelial cells in asthma.3 STAT6 is important in the expression of VCAM-1 in endothelial cells and of chemokines, such as eotaxin, in epithelial cells following stimulation with IL-4 and IL-13.4 As a consequence, STAT6 has been considered a strong candidate for predisposition to atopic asthma. Indeed, the human STAT6 gene is mapped to chromosome 12q13.3−q14.1, a region linked to total serum IgE concentration and atopy in several populations.5 A number of common polymorphisms have been identified, including a GT repeat in exon 1 and three common SNPs (G4219A, A4491G, and A4671G; GenBank AF067575) in the 3′ untranslated region of the human STAT6 gene.6–9 Although all four of these polymorphisms have been shown to be associated with allergic phenotypes in various populations, their functional relevance remains unclear.nnDinucleotide repeats are the most frequent of the simple repeats distributed throughout the human genome, and many of these exhibit length polymorphisms. Investigations into the effect of dinucleotide repeats on gene expression have shown enhanced10 or decreased transcriptional activity11,12 in the context of different genes and cell types. These regulatory effects have been proposed to be due, in part, to the fact that dinucleotide repeats have potential to form alternative DNA structures, such as Z-, H- and cruciform DNA.13 The Z-DNA sequences in human genes tend to be located near transcription sites, which makes it possible that they play …

Negative association between asthma and variants of CC16(CC10) on chromosome 11q13 in British and Japanese populations

The gene encoding Clara cell-derived inflammatory molecule CC16 has been cited as a candidate gene for atopic asthma on chromosome 11q13. A genetic association study was performed with variants of the CC16 gene on chromosome 11q13 in relation to asthma in British (n=275) and Japanese (n=300) populations. No significant association was found between asthma and CC16 genotypes, irrespective of atopic status in these two populations. These data suggest that CC16 might not be the major locus for asthma on 11q13.

A review of the genetic epidemiology of resistance to parasitic disease and atopic asthma: common variants for common phenotypes?

Purpose of reviewAn inverse relationship between resistance to certain parasitic diseases and measures of atopy and asthma has long been observed. A possible explanation is that genetic determinants which confer protection against detrimental worm burdens are the same determinants involved in atopic asthma. The focus of this review is to consider the potential candidate genes that have been elucidated as part of molecular, genomic and genetic studies of parasite biology, host–parasite interactions and classic genetic epidemiology studies on parasitic disease and allergic asthma. Recent findingsComparative studies of the Plasmodium and Schistosoma spp. genomes have revealed a number of proteins that are homologous to humans. A number of linkage and association studies on susceptibility/resistance to parasitic diseases, including malaria and schistosomiasis, overlap with associations that have been identified for susceptibility to atopy and asthma. SummaryIn response to parasitic approaches in maintaining survival, the human host has evolved genetic adaptations that minimize severe manifestations of disease, which conversely appear to contribute to allergic disease. A clearer understanding of this process will elucidate the complex pathways and mechanisms involved in these traits.

Critical Role for Mast Cell Stat5 Activity in Skin Inflammation

SUMMARY Atopic dermatitis (AD) is a chronic inflammatory skin disease. Here, we show that phospholipase C-β3 (PLC-β3)-deficient mice spontaneously develop AD-like skin lesions and more severe allergen-induced dermatitis than wild-type mice. Mast cells were required for both AD models and remarkably increased in the skin of Plcb3−/− mice because of the increased Stat5 and reduced SHP-1 activities. Mast cell-specific deletion of Stat5 gene ameliorated allergen-induced dermatitis, whereas that of Shp1 gene encoding Stat5-inactivating SHP-1 exacerbated it. PLC-β3 regulates the expression of periostin in fibroblasts and TSLP in keratinocytes, two proteins critically involved in AD pathogenesis. Furthermore, polymorphisms in PLCB3, SHP1, STAT5A, and STAT5B genes were associated with human AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels of phospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis.

Genetic Variants in Interferon Regulatory Factor 2 (IRF2) are Associated with Atopic Dermatitis and Eczema Herpeticum

Interferon regulatory factor 2 (IRF2) is a member of a family of transcriptional factors involved in the modulation of interferon induced immune responses to viral infection. To test whether genetic variants in IRF2 predict risk of AD and ADEH, we genotyped 78 IRF2 tagging single nucleotide polymorphisms (SNPs) in both European American (n=435) and African American (n = 339) populations. Significant associations were observed between AD and two SNPs (rs793814, P = 0.007, odds ratio (OR) = 0.52; rs3756094, P = 0.037, OR = 0.66) among European Americans and one SNP (rs3775572, P = 0.016, OR = 0.46) among African Americans. Significant associations were also observed between ADEH and five SNPs (P = 0.049-0.022) among European Americans. The association with ADEH was further strengthened by haplotype analyses, wherein a 5-SNP (CAGGA) haplotype showed the strongest association with ADEH (P = 0.0008). Eight IRF2 SNPs were significantly associated with IFNγ production post-herpes simplex virus (HSV) stimulation (P = 0.048-0.0008), including an AD-associated SNP (rs13139310, P = 0.008). Our findings suggest distinct markers in IRF2 may be associated with AD and ADEH, which may depend upon ethnic ancestry, and genetic variants in IRF2 may contribute to an abnormal immune response to HSV.

Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma

Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FcɛRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 × 10−5) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6′-sulfo-sLex, a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.

Genetic variants in the mannose receptor gene ( MRC1 ) are associated with asthma in two independent populations

Mannose receptor is a member of the C-type lectin receptor family involved in pathogen molecular pattern recognition and thought to be critical in shaping host immune responses and maintaining homeostasis. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with asthma in two independent populations. Seven single-nucleotide polymorphisms (SNPs; rs2477637, rs2253120, rs2477631, rs2477664, rs692527, rs1926736, and rs691005) in the MRC1 gene locus were genotyped and evaluated regarding association with asthma in 870 unrelated Japanese subjects (446 asthmatics, 424 controls). The same markers were validated in 176 unrelated African–American subjects (86 asthmatics, 90 controls). Suggestive evidence of association between five SNPs (rs2477637, rs2253120, rs2477664, rs692527, and rs1926736) and asthma was observed in the analysis of the Japanese population independent of sex, age, smoking status, and atopic status. SNPs rs692527 and rs691005 showed significant association with asthma in the African–American population. Haplotypes containing two linked SNPs (rs692527 and rs1926736) were significantly associated with asthma in both Japanese and African–American populations. Our results suggest that sequence variations in the MRC1 gene are associated with the development of asthma in two independent and ethnically diverse populations.