Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

Abstract

A genome-wide screen for asthma and atopy susceptibility alleles conducted in the Hutterites, a founder population of European descent, reported evidence of linkage with a short tandem repeat polymorphism (STRP) within the type I interferon (IFN) gene cluster on chromosome 9p21. The goal of this study was to identify variation within the IFN gene cluster that influences susceptibility to asthma and atopic phenotypes. We screened approximately 25 kb of sequence, including the flanking sequence of all 15 functional genes and the single coding exon in 12, in Hutterites representing different IFNA-STRP genotypes. We identified 78 polymorphisms, and genotyped 40 of these (in 14 genes) in a large Hutterite pedigree. Modest associations (0.003oPo0.05) with asthma, bronchial hyper-responsiveness (BHR), and atopy were observed with individual variants or genes, spanning the entire 400 kb region. However, pairwise combinations of haplotypes between genes showed highly significant associations with different phenotypes (Po10 À5 ) that were localized to specific pairs of genes or regions of this cluster. These results suggest that variation in multiple genes in the type I IFN cluster on 9p22 contribute to asthma and atopy susceptibility, and that not all genes contribute equally to all phenotypes.

Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma

“…Moreover, clinical symptoms of asthma can be controlled using low doses of recombinant IFN-α (Gratzl et al, 2000). Genetic association studies have also identified several risk factors for asthma in the type I IFN system, such as variants of IFNA, IFNB and TLR gene super-families (Chan et al, 2006;Yang et al, 2006). Together with the observations in this study, we can postulate that nonatopic asthma and autoimmune disorders are closely related, and they may well be two opposite outcomes downstream of a common pathway, in which IRF5 as well as the type I IFN system are involved.…”

Ethnicity-specific Gene–Gene Interaction between IL-13 and IL-4Rα among African Americans with Asthma

“…Gene-gene interaction between IL-4 and IL-4R␣ and asthma has been demonstrated in several populations (25,26). Because no significant or moderately significant associations were found for IL-4 SNPs in our population, we did not test for interaction between this gene and IL-4R␣.…”

Differential Regulation of Human Interferon A Gene Expression by Interferon Regulatory Factors 3 and 7

“…This regulatory mechanism might be crucial for differential IFN-A gene expression and therefore might determine the amplitude of immune responses dependent on IFN-␣ subtypes that differ by their relative potencies (16,22,84). By restraining the expression of various IFN-␣ subtypes, this control level might also be an absolute requirement for the organism to maintain regulated IFN-␣ production and to prevent immunemediated and autoimmune diseases (6,81).…”