Nonpathogenic common variants of IFNGR1 and IFNGR2 in association with total serum IgE levels.
ABSTRACT Atopy is an immune disorder in which a Th2 dominant mechanism leads to high IgE levels and the clinical disorder asthma. It has been postulated that the Th1 cytokine IFNgamma, acting through its heterodimeric receptors, IFNgammaR1 and IFNgammaR2, in the induction/proliferation of Th1 cells, might suppress the Th2 responses that may underlie atopic asthma. However, neither murine nor human variants of IFNgamma associate with atopy. Several dysfunctional mutations have been identified in IFNgamma receptor genes (IFNGR1 and IFNGR2) in relation to severe and selective infections with poorly pathogenic organisms. However, little is known about common polymorphisms and their functional role in atopy. To test whether such variants of IFNGR1 and IFNGR2 relate to atopic asthma, we conducted a genetic association study in both British (n = 300) and Japanese (n = 200) populations. An intronic variant of IFNGR1 showed marginal association with total serum IgE levels in the British population compared with those with total IgE levels <30 IU/ml and those with >120-500 IU/ml [odds ratio = 2.00 (95% CI 1. 00-4.07), P = 0.048]. A coding variant, Gln64Arg of the IFNGR2, also associated with total serum IgE levels in the British population [chi(2) = 5.08, P = 0.024]. Further genetic and functional analyses are needed to clarify the role of variants of IFNgamma receptor genes in atopic immune disorder among different ethnic groups.
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ABSTRACT: In every study involving human immune parameters, large inter-subject variability occurs which can make interpretation of results difficult. The aim of this study was to evaluate whether genetic variants in cytokine receptors could associate with variability in laboratory immune measures. A total of 207 normal volunteers were recruited in this study. Immunoregulatory profiles were measured by flow cytometry and genotyping assays were performed by allelic discrimination real-time PCR. Immunoregulatory profiles were categorized according to various single nucleotide polymorphisms (SNPs) of cytokine receptorsincluding T-56C and G-611A of IFN-γ receptor I (IFNGR1); Q64R of IFNGR2; and Ile50Val, Q576R and S503P of IL4R. Results reveal that Th1 levels were significantly higher in the heterozygous of the IFNGR1 T-56C polymorphism (minor allele) compared to wild-type (WT, major allele) (p=0.006). For the Q576R of IL4R, Th1/Th2 ratio was significantly lower for the homozygous SNP (Arg/Arg) compared to the WT (Gln/Gln) (p=0.035). In addition, the significant interaction effects of demographic characteristics on SNP-immune parameter associations were reported as well. We conclude that cytokine receptor polymorphisms might associate with variability in laboratory immune measures. Approach of SNP analysis of cytokine receptors can be useful in categorizing baseline immune responses to more accurately evaluate clinical immune data.Human immunology 09/2013; · 2.55 Impact Factor
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ABSTRACT: Asthma is a heterogeneous disease for which a strong genetic basis is firmly established. Although the generally accepted definition includes three domains of symptoms (variable airway obstruction, airway hyper-responsiveness, and airway inflammation), there is general agreement that, rather than being a single disease entity, asthma consists of related, overlapping syndromes. A considerable proportion of asthma is IgE-mediated, but the observation that not all individuals with asthma are atopic adds to the heterogeneity. Although a genetic basis for asthma is undeniable, elucidation of polymorphisms that are "causal" is greatly hampered by variability in the clinical phenotype, which is likely due to the multiple molecular mechanisms underlying the complex pathological processes involved in disease development and progression. One objective of this review is to consider progress that has been made to date in gene discovery in the field of asthma, with a focus on the evolution of molecular genetic methods that have led to the discoveries thus far, and with a particular focus on the major advances owed to the published genome-wide association studies (GWAS) on asthma to date. A second objective is to consider a Darwinian approach toward understanding the genetic underpinnings of asthma, including evidence supporting a modified Hygiene Hypothesis, which suggests that there are co-associations between asthma risk polymorphisms and polymorphisms associated with another IgE-mediated disease, schistosomiasis. The overall conclusion is that the huge research efforts and expense committed to asthma genetics have changed the perception about disease etiology in general and the functional relevance of the asthma genes identified thus far in particular.Proceedings of the American Thoracic Society 05/2011; 8(2):143-8.